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    Clinical Trial Results:
    A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, and Effects on Histology and Different Clinical Parameters of Givinostat in Ambulant Children with Duchenne Muscular Dystrophy

    Summary
    EudraCT number
    		 2012-002566-12
    Trial protocol
    		 IT  
    Global end of trial date
    17 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2020
    First version publication date
    08 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DSC/11/2357/43
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01761292
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ITALFARMACO S.p.A.
    Sponsor organisation address
    Via dei Lavoratori, 54, Cinisello Balsamo (MI), Italy, 20092
    Public contact
    Clinical R&D Department, Italfarmaco, +39 02 64431, s.cazzaniga@italfarmaco.com
    Scientific contact
    Clinical R&D Department, Italfarmaco, +39 02 64431, s.cazzaniga@italfarmaco.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
    17 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the histologic effects of Givinostat administered chronically at the selected daily dose
    Protection of trial subjects
    The study was performed in accordance with local national laws (as applicable), the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and the guidelines of the Declaration of Helsinki adopted by the 18th World Medical Assembly in Helsinki, Finland in 1964 and amended by subsequent assemblies in Tokyo, Japan in 1975; Venice, Italy in 1983; Hong Kong in 1989; Somerset West, South Africa in 1996, and in Edinburgh, Scotland in October 2000.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 1 pt discontinued due to an AE during Part 1; all other pts completed the study. Another pt was enrolled in Part 1 but started the treatment in Part 2. Hence, 19 pts completed Part 2. These 19 pts continued to Extension 1. 1 pt withdrew consent & discontinued at the beginning of Extension 2. The remaining 18 completed Extensions 2 and 3.

    Pre-assignment
    Screening details
    		 Twenty-one patients were screened in this study: 1 patient failed the screening, 20 were enrolled in Part 1 but only 19 were treated in Part 1; 1 was discontinued in Part 1; 19 were treated in Part 2 (18 who have completed Part 1 + 1 enrolled in Part 1 but not treated in Part 1).

    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
    		 25 mg BID
    Arm description
    		 Out of the 20 enrolled children, the first 4 were treated at a low dose of givinostat (25 mg BID). None of the stopping criteria were met after 2 weeks at the low dose, an intermediate dose was used for the treatment of an additional 8 children. The 4 children previously treated at the low dose were also switched to the intermediate dose (50 mg BID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    ITF2357
    Other name
    Pharmaceutical forms
    Capsule, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Givinostat oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 and 25 mg BID and 37.5 mg BID during Part 2. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient’s weight during Extensions 2 and 3. Study drug safety and tolerability continued to be measured in patients during Extension 3.

    Arm title
    		 50 mg BID
    Arm description
    		 The second tested dose was 50 mg BID. 8 children were treated at this dose for at least 2 weeks. A stopping criteria was met, the dose was considered not tolerated and all subjects discontinued the treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    ITF2357
    Other name
    Pharmaceutical forms
    Capsule, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Givinostat oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 and 25 mg BID and 37.5 mg BID during Part 2. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient’s weight during Extensions 2 and 3. Study drug safety and tolerability continued to be measured in patients during Extension 3.

    Arm title
    		 37.5 mg BID
    Arm description
    		 Out of the 20 enrolled children, the first 4 were treated at a low dose of givinostat (25 mg BID). The second dose i.e. 50 mg BID was not considered tolerated, a stopping criteria was met, therefore an intermediate dose was tested. 7 out of 8 children were treated at 37.5 mg BID for at least 2 weeks and none of the stopping criteria were met. Once all 20 children enrolled during Part 1 had been treated for at least 2 weeks, the recommended dose (RD) i.e. 37.5 mg BID to be used in Part 2 was determined. All the children enrolled were switched to the RD level (37.5 mg BID), which was administered for the subsequent 12 months (Part 2). During the Part 2 the dose was reduced for safety in 12 children (i.e. treated at 25 mg BID). At the end of Part 2, patients continued to receive givinostat at the dose ongoing at 12 months and were treated for additional 40 months (Extensions 1, 2, and 3 up to month 52). Due to patients growth the dose was adjusted by patient’s weight.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    ITF2357
    Other name
    Pharmaceutical forms
    Capsule, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Givinostat oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 and 25 mg BID and 37.5 mg BID during Part 2. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient’s weight during Extensions 2 and 3. Study drug safety and tolerability continued to be measured in patients during Extension 3.

    Number of subjects in period 1
    		25 mg BID 50 mg BID 37.5 mg BID
    Started
    4
    8
    8
    Completed
    4
    7
    7
    Not completed
    0
    1
    1
         Adverse event, non-fatal
    -
    1
    -
         Was not treated in Part 1
    -
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    25 mg BID
    Reporting group description
    		 Out of the 20 enrolled children, the first 4 were treated at a low dose of givinostat (25 mg BID). None of the stopping criteria were met after 2 weeks at the low dose, an intermediate dose was used for the treatment of an additional 8 children. The 4 children previously treated at the low dose were also switched to the intermediate dose (50 mg BID).

    Reporting group title
    50 mg BID
    Reporting group description
    		 The second tested dose was 50 mg BID. 8 children were treated at this dose for at least 2 weeks. A stopping criteria was met, the dose was considered not tolerated and all subjects discontinued the treatment.

    Reporting group title
    37.5 mg BID
    Reporting group description
    		 Out of the 20 enrolled children, the first 4 were treated at a low dose of givinostat (25 mg BID). The second dose i.e. 50 mg BID was not considered tolerated, a stopping criteria was met, therefore an intermediate dose was tested. 7 out of 8 children were treated at 37.5 mg BID for at least 2 weeks and none of the stopping criteria were met. Once all 20 children enrolled during Part 1 had been treated for at least 2 weeks, the recommended dose (RD) i.e. 37.5 mg BID to be used in Part 2 was determined. All the children enrolled were switched to the RD level (37.5 mg BID), which was administered for the subsequent 12 months (Part 2). During the Part 2 the dose was reduced for safety in 12 children (i.e. treated at 25 mg BID). At the end of Part 2, patients continued to receive givinostat at the dose ongoing at 12 months and were treated for additional 40 months (Extensions 1, 2, and 3 up to month 52). Due to patients growth the dose was adjusted by patient’s weight.

    Reporting group values
    		 25 mg BID 50 mg BID 37.5 mg BID Total
    Number of subjects
    		 4 8 8 20
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 4 8 8 20
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.8 ( 0.96 ) 8.8 ( 1.16 ) 7.9 ( 1.13 ) -
    Gender categorical
    Units: Subjects
        Male
    		 4 8 8 20
    Subject analysis sets

    Subject analysis set title
    Overall - ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. ITT analysis population was set up to 19 patients during Extension 1.

    Subject analysis set title
    Overall - Evaluable population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The evaluable population included all patients who were in Part 2 of the study, received givinostat of at least 80% dose in Part 2, had at least 1 baseline and 1 postbaseline assessment of biopsies, and had no major protocol violations.

    Subject analysis set title
    Overall - Baseline - Evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The evaluable population included all patients who were in Part 2 of the study, received givinostat of at least 80% dose in Part 2, had at least 1 baseline and 1 postbaseline assessment of biopsies, and had no major protocol violations.

    Subject analysis set title
    Overall - Baseline - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. Twenty patients were included in the ITT population.

    Subject analysis set title
    Overall - Part 2/EoT - Evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The evaluable population included all patients who were in Part 2 of the study, received givinostat of at least 80% dose in Part 2, had at least 1 baseline and 1 postbaseline assessment of biopsies, and had no major protocol violations.

    Subject analysis set title
    Overall - Part 2/EoT - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. Twenty patients were included in the ITT population.

    Subject analysis set title
    Overall - Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all children who received any investigational product. The dose level under which the patient was analyzed was the dose of investigational product that was actually received; 19 patients were included in the safety population of Part 1 and 19 patients were included in the safety population of Part 2. In all Extensions, the Safety Analysis Population was set up to 20 patients (100%), including all patients who received any investigational product.

    Subject analysis sets values
    		 Overall - ITT population Overall - Evaluable population Overall - Baseline - Evaluable Overall - Baseline - ITT Overall - Part 2/EoT - Evaluable Overall - Part 2/EoT - ITT Overall - Safety population
    Number of subjects
    19
    18
    18
    19
    18
    19
    20
    Age categorical
    Units: Subjects
        Children (2-11 years)
    20
    18
    18
    19
    18
    19
    20
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Male
    20
    18
    18
    19
    18
    19
    20

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    25 mg BID
    Reporting group description
    		 Out of the 20 enrolled children, the first 4 were treated at a low dose of givinostat (25 mg BID). None of the stopping criteria were met after 2 weeks at the low dose, an intermediate dose was used for the treatment of an additional 8 children. The 4 children previously treated at the low dose were also switched to the intermediate dose (50 mg BID).

    Reporting group title
    50 mg BID
    Reporting group description
    		 The second tested dose was 50 mg BID. 8 children were treated at this dose for at least 2 weeks. A stopping criteria was met, the dose was considered not tolerated and all subjects discontinued the treatment.

    Reporting group title
    37.5 mg BID
    Reporting group description
    		 Out of the 20 enrolled children, the first 4 were treated at a low dose of givinostat (25 mg BID). The second dose i.e. 50 mg BID was not considered tolerated, a stopping criteria was met, therefore an intermediate dose was tested. 7 out of 8 children were treated at 37.5 mg BID for at least 2 weeks and none of the stopping criteria were met. Once all 20 children enrolled during Part 1 had been treated for at least 2 weeks, the recommended dose (RD) i.e. 37.5 mg BID to be used in Part 2 was determined. All the children enrolled were switched to the RD level (37.5 mg BID), which was administered for the subsequent 12 months (Part 2). During the Part 2 the dose was reduced for safety in 12 children (i.e. treated at 25 mg BID). At the end of Part 2, patients continued to receive givinostat at the dose ongoing at 12 months and were treated for additional 40 months (Extensions 1, 2, and 3 up to month 52). Due to patients growth the dose was adjusted by patient’s weight.

    Subject analysis set title
    Overall - ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. ITT analysis population was set up to 19 patients during Extension 1.

    Subject analysis set title
    Overall - Evaluable population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The evaluable population included all patients who were in Part 2 of the study, received givinostat of at least 80% dose in Part 2, had at least 1 baseline and 1 postbaseline assessment of biopsies, and had no major protocol violations.

    Subject analysis set title
    Overall - Baseline - Evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The evaluable population included all patients who were in Part 2 of the study, received givinostat of at least 80% dose in Part 2, had at least 1 baseline and 1 postbaseline assessment of biopsies, and had no major protocol violations.

    Subject analysis set title
    Overall - Baseline - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. Twenty patients were included in the ITT population.

    Subject analysis set title
    Overall - Part 2/EoT - Evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The evaluable population included all patients who were in Part 2 of the study, received givinostat of at least 80% dose in Part 2, had at least 1 baseline and 1 postbaseline assessment of biopsies, and had no major protocol violations.

    Subject analysis set title
    Overall - Part 2/EoT - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. Twenty patients were included in the ITT population.

    Subject analysis set title
    Overall - Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all children who received any investigational product. The dose level under which the patient was analyzed was the dose of investigational product that was actually received; 19 patients were included in the safety population of Part 1 and 19 patients were included in the safety population of Part 2. In all Extensions, the Safety Analysis Population was set up to 20 patients (100%), including all patients who received any investigational product.

    Primary: Change From Baseline to Part 2 in the Value of Muscle Fiber Area % (MFA%) Comparing the Histology Biopsies Before and After 12 Months of Treatment With Givinostat

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    End point title
    		 Change From Baseline to Part 2 in the Value of Muscle Fiber Area % (MFA%) Comparing the Histology Biopsies Before and After 12 Months of Treatment With Givinostat
    End point description
    The primary endpoint was the change in histology comparing the brachial biceps biopsies before and after ≥12 months of treatment with Givinostat. Muscle biopsies: A first brachial biceps biopsy (baseline) was taken prior to the first dose of study drug. A second brachial biceps biopsy was taken at Visit 10 (12 months) from the opposite arm. The muscle biopsy samples from the biceps muscle were collected by open biopsy. The minimum amount of muscle tissue required was a piece of muscle of at least 0.5 × 0.5 × 0.5 cm.
    End point type
    Primary
    End point timeframe
    After12 months of treatment
    End point values
    		 Overall - Baseline - Evaluable Overall - Part 2/EoT - Evaluable
    Number of subjects analysed
    18
    18
    Units: percentage change
        arithmetic mean (standard deviation)
    51.003 ( 9.6138 )
    64.909 ( 8.3469 )
    Statistical analysis title
    		 Overall - Part2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - Evaluable v Overall - Part 2/EoT - Evaluable
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 t-test, 2-sided
    Parameter type
    		 absolute mean change
    Point estimate
    13.906
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.5657
         upper limit
    		 16.2466
    Notes
    [1] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.
    [2] - The paired t-test or non-parametric signed rank test for 2 means (paired observations) (as is appropriate) was applied for testing the statistical significance of the Change From Baseline to End of Study. MFA% P < 0.05 was set as significant.

    Secondary: Change from baseline to end of study in cross sectional area (CSA)

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    End point title
    		 Change from baseline to end of study in cross sectional area (CSA)
    End point description
    This histological parameter was evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat.
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    		 Overall - Baseline - ITT Overall - Part 2/EoT - ITT
    Number of subjects analysed
    18
    18
    Units: μm2
        arithmetic mean (standard deviation)
    1191.087 ( 400.9813 )
    2056.356 ( 781.3925 )
    Statistical analysis title
    		 Overall - Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.

    Secondary: Change from baseline to end of study in fibrosis, necrosis, fatty replacement

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    End point title
    		 Change from baseline to end of study in fibrosis, necrosis, fatty replacement
    End point description
    These histological parameters were evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat.
    End point type
    Secondary
    End point timeframe
    After 12 months
    End point values
    		 Overall - Baseline - ITT Overall - Part 2/EoT - ITT
    Number of subjects analysed
    18
    18
    Units: percentage of total area
    arithmetic mean (standard deviation)
        Total fibrosis
    46.128 ( 9.6129 )
    33.488 ( 8.2430 )
        Perimysial fibrosis
    23.469 ( 8.6600 )
    15.884 ( 5.5629 )
        Endomysial fibrosis
    22.660 ( 6.5066 )
    17.604 ( 3.7859 )
        Fatty replacement
    0.886 ( 0.6970 )
    0.584 ( 0.6000 )
        Necrosis
    1.983 ( 0.7311 )
    1.019 ( 0.3172 )
    Statistical analysis title
    		 Total fibrosis - Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Absolute mean change
    Point estimate
    -12.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.953
         upper limit
    		 -10.328
    Variability estimate
    Standard deviation
    Dispersion value
    4.6493
    Notes
    [4] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.
    Statistical analysis title
    		 Perimysial fibrosis - Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Absolute mean change
    Point estimate
    -7.585
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.8062
         upper limit
    		 -4.3634
    Variability estimate
    Standard deviation
    Dispersion value
    6.4779
    Notes
    [5] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.
    Statistical analysis title
    		 Endomysial fibrosis - Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0032
    Method
    		 t-test, 2-sided
    Parameter type
    		 Absolute mean change
    Point estimate
    -5.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1653
         upper limit
    		 -1.9461
    Variability estimate
    Standard deviation
    Dispersion value
    6.2531
    Notes
    [6] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.
    Statistical analysis title
    		 Fatty replacement - Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0002
    Method
    		 t-test, 2-sided
    Parameter type
    		 Absolute mean change
    Point estimate
    -0.302
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4391
         upper limit
    		 -0.165
    Variability estimate
    Standard deviation
    Dispersion value
    0.2756
    Notes
    [7] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.
    Statistical analysis title
    		 Necrosis - Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Absolute mean change
    Point estimate
    -0.964
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.275
         upper limit
    		 -0.6524
    Variability estimate
    Standard deviation
    Dispersion value
    0.626
    Notes
    [8] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.

    Secondary: Change From Baseline to End of Study in Number of Hypercontracted Fibers

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    End point title
    		 Change From Baseline to End of Study in Number of Hypercontracted Fibers
    End point description
    This histological parameter was evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. The number of fibers is calculated per microscopic field (20x).
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    		 Overall - Baseline - ITT Overall - Part 2/EoT - ITT
    Number of subjects analysed
    18
    18
    Units: number of fibers
        arithmetic mean (standard deviation)
    1.977 ( 0.7139 )
    0.773 ( 0.5429 )
    Statistical analysis title
    		 Part 2/EoT vs Baseline
    Comparison groups
    Overall - Part 2/EoT - ITT v Overall - Baseline - ITT
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Absolute mean change
    Point estimate
    -1.204
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5334
         upper limit
    		 -0.8749
    Variability estimate
    Standard deviation
    Dispersion value
    0.6621
    Notes
    [9] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.

    Secondary: Change from Baseline in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the 6-Minute Walk Test

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    End point title
    		 Change from Baseline in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the 6-Minute Walk Test
    End point description
    This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. The longer the walked distance the better the outcome.
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    		 Overall - Baseline - ITT Overall - Part 2/EoT - ITT
    Number of subjects analysed
    19
    18
    Units: meters
        arithmetic mean (standard deviation)
    453.0 ( 62.23 )
    432.2 ( 63.60 )
    Statistical analysis title
    		 Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.53
         upper limit
    		 -6.61
    Variability estimate
    Standard deviation
    Dispersion value
    36.11
    Notes
    [10] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.

    Secondary: Change from Baseline in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the North Star Ambulatory Assessment (NSAA)

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    End point title
    		 Change from Baseline in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the North Star Ambulatory Assessment (NSAA)
    End point description
    The NSAA was graded using the standard scorecard with each assessment rated as 0 – unable to achieve independently, 1 – modified method but achieves goal independent of physical assistance from another, or 2 – normal with no obvious modification of activity. The higher the score, the better the outcome.
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    		 Overall - Baseline - ITT Overall - Part 2/EoT - ITT
    Number of subjects analysed
    19
    19
    Units: score on a scale
        arithmetic mean (standard deviation)
    28.1 ( 5.13 )
    25.2 ( 7.39 )
    Statistical analysis title
    		 Part 2/EoT vs Baseline
    Comparison groups
    Overall - Baseline - ITT v Overall - Part 2/EoT - ITT
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.36
         upper limit
    		 -1.32
    Variability estimate
    Standard deviation
    Dispersion value
    3.15
    Notes
    [11] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.

    Secondary: Change from baseline in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the performance of upper limb (PUL)

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    End point title
    		 Change from baseline in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the performance of upper limb (PUL)
    End point description
    The PUL was devised to assess motor performance in the upper limb for patients with Becker and Duchenne muscular dystrophy. The purpose is to assess change that occurs in motor performance of the upper limb over time from when a child is still ambulant until he loses all arm function when non-ambulant. The PUL will be administered according to the guidelines developed by the Physiotherapy Working Group. The revised version (1.2) of the PUL included 22 items taking into account the rescoring and additional items to reduce the floor effect. These include one entry item to define the starting functional level, and 21 items subdivided into shoulder level (score range: 0-16), elbow level (score range 0-34) and distal level (score range: 0-24) dimension. The total score being the sum of all scores of the subscales (score range: 0-74). For all items, the higher the score, the better the outcome.
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    		 Overall - Baseline - ITT Overall - Part 2/EoT - ITT
    Number of subjects analysed
    19
    19
    Units: score on a scale
        arithmetic mean (standard deviation)
    71.7 ( 2.40 )
    71.6 ( 2.81 )
    Statistical analysis title
    		 Part 2/EoT vs Baseline
    Comparison groups
    Overall - Part 2/EoT - ITT v Overall - Baseline - ITT
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 1.14
    Variability estimate
    Standard deviation
    Dispersion value
    2.69
    Notes
    [12] - The system inappropriately adds up the number of patients in each arm. Since it is a crossover study, the subjects in the two groups are the same and therefore the comparison is intra-group.

    Secondary: Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test

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    End point title
    		 Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test
    End point description
    This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. The longer the walked distance the better the outcome.
    End point type
    Secondary
    End point timeframe
    At 24, 36, and 52 months
    End point values
    		 Overall - ITT population
    Number of subjects analysed
    19 [13]
    Units: meters
    arithmetic mean (standard deviation)
        Extension 1
    -80.0 ( 110.69 )
        Extension 2
    -127.0 ( 110.40 )
        Extension 3
    -287.8 ( 159.47 )
    Notes
    [13] - n=18 at month 36 (Extension 2) and month 52 (Extension 3).
    No statistical analyses for this end point

    Secondary: Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA)

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    End point title
    		 Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA)
    End point description
    The NSAA was graded using the standard scorecard with each assessment rated as 0 – unable to achieve independently, 1 – modified method but achieves goal independent of physical assistance from another, or 2 – normal with no obvious modification of activity.
    End point type
    Secondary
    End point timeframe
    At 24, 36, and 52 months
    End point values
    		 Overall - ITT population
    Number of subjects analysed
    18
    Units: score on a scale
    arithmetic mean (standard deviation)
        Extension 1
    -5.2 ( 5.06 )
        Extension 2
    -7.4 ( 5.90 )
        Extension 3
    -15.2 ( 7.83 )
    No statistical analyses for this end point

    Secondary: Change from baseline in muscular function after 24 (Extension 1), 36 (Extension 2), and 52 months (Extension 3) of treatment with Givinostat at the selected daily dose based on the performance of upper limb (PUL)

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    End point title
    		 Change from baseline in muscular function after 24 (Extension 1), 36 (Extension 2), and 52 months (Extension 3) of treatment with Givinostat at the selected daily dose based on the performance of upper limb (PUL)
    End point description
    The PUL was devised to assess motor performance in the upper limb for patients with Becker and Duchenne muscular dystrophy. The purpose is to assess the change that occurs in motor performance of the upper limb over time from when a child is still ambulant until he loses all arm function when non-ambulant. The PUL will be administered according to the guidelines developed by the Physiotherapy Working Group. The revised version of the PUL included 22 items taking into account the rescoring and additional items to reduce the floor effect. These include one entry item to define the starting functional level, and 21 items subdivided into shoulder level, elbow level, and distal level dimension. For weaker patients, a low score on the entry item (modified Brooke) means high-level items do not need to be performed. Scoring options varied across the scale between 0–1 and 0–6, according to performance. The higher the score the better the outcome.
    End point type
    Secondary
    End point timeframe
    At 24, 36, and 52 months
    End point values
    		 Overall - ITT population
    Number of subjects analysed
    18
    Units: score on a scale
    arithmetic mean (standard deviation)
        Extension 1
    -0.2 ( 2.71 )
        Extension 2
    -0.2 ( 2.75 )
        Extension 3
    -4.4 ( 6.09 )
    No statistical analyses for this end point

    Secondary: Number of children experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and type and severity of TEAEs

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    End point title
    		 Number of children experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and type and severity of TEAEs
    End point description
    Summary of Treatment-emergent Adverse Events (TEAE) Reporting from Baseline to the End of Extension 3 (Month 52). In the analysis were included: Any TEAE, Any treatment-related TEAE, Any mild or moderate or severe TEAE, Any life-threatening or disabling TEAE, Any TEAE resulting in death, any serious adverse event, and Any TEAE resulting in study discontinuation.
    End point type
    Secondary
    End point timeframe
    Part 1, Part 2, and Extensions 1, 2, and 3
    End point values
    		 Overall - Safety population
    Number of subjects analysed
    20
    Units: participants
        TEAEs
    20
        Any treatment-related TEAE
    20
        Any mild TEAE
    20
        Any moderate TEAE
    16
        Any severe TEAE
    9
        Any life-threatening or disabling TEAE
    1
        Any TEAE resulting in death
    0
        Any SAE
    8
        Any TEAE resulting in study discontinuation
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed throughout the study: in Part 1, Part 2, Extension 1, Extension 2, Extension 3. Extensions 1, 2 and 3 together represent Part 3 of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety population included all children who received any investigational product. The dose level under which the patient was analyzed was the dose of investigational product that was actually received.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 20 (40.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 20 (5.00%)
         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
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Gait disturbance
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Peripheral swelling
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    9 / 20 (45.00%)
         occurrences all number
    20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 20 (50.00%)
         occurrences all number
    12
    Dyspnoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Laryngeal inflammation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Intraocular pressure increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Platelet count decreased
         subjects affected / exposed
    13 / 20 (65.00%)
         occurrences all number
    39
    White blood cell count decreased
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    7
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    9
    Femur fracture
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Foot fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Head injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Laceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ligament injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    7
    Limb injury
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Lower limb fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Muscle strain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Spinal cord injury sacral
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tendon injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tibia fracture
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Congenital, familial and genetic disorders
    Gilbert's syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Extrasystoles
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Left ventricular dilatation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Palpitations
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Sinus tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Lens discoloration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lenticular opacities
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 20 (55.00%)
         occurrences all number
    19
    Cholitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    15 / 20 (75.00%)
         occurrences all number
    66
    Faeces soft
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Frequent bowel movements
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Haemorrhoids
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Stomatitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Dermatosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ecchymosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Erythema annulare
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Intertrigo
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nail dystrophy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Solar dermatitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Delayed puberty
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Hypothyroidism
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Back pain
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Fracture pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Muscular weakness
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Neck pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    5
    Osteopenia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Tendinous contracture
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Tendon pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tendonitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Gastroenteritis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    9 / 20 (45.00%)
         occurrences all number
    14
    Molluscum contagiosum
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Paronychia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Tooth infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Varicella
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    8
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2012
    • Added MRI of muscle on the upper limb, if possible and if the child was compliant. • Better described the muscles to be observed during the MRI, inserting “muscle of lower limb” instead of “quadriceps femoris” and “muscle of upper limb” instead of “brachial biceps.” • Clarified the timing around the collection of PK blood samples.
    25 Mar 2013
    • Added the 25-mg hard gelatin capsule. • Changed oral suspension accountability to counting the bottles of suspension (used, empty, partially used, and unused) rather than measuring the amount of residual volume of suspension in the bottles by means of a calibrated glass cylinder.
    23 Oct 2013
    • Noted that the RD was determined to be 37.5 mg BID. • Since in some children, platelet counts below the normal range (≤ 150 × 109/L) might be observed at the RD, the platelet counts were assessed at least every 2 weeks in the first 2 months of therapy at 37.5 mg BID and the dose was lowered to 25 mg BID if persistent platelet counts ≤ 150 × 109/L were observed. • Assessments were added to explore the acceptability/palatability of the oral suspension.
    17 Apr 2014
    • Updated the study to allow the patients to continue the treatment with givinostat at least until the final analysis was performed (at 12 months following start of treatment), and in case the results were positive, to continue the study drug treatment for an additional 12 months (Extension study treatment). • Asked patients to share information regarding the type of mutation they carried in DMD. • Added PK blood samples at 12 months of treatment. • Added Peak Expiratory Flow to the assessments. • Discontinued the collection of samples to study the effect of study drug on cytokines.
    16 Mar 2015
    • Updated the study to allow patients with positive results from the first extension of the study (Extension 1) to continue study treatment for an additional 12 months in a second extension of the study (Extension 2). During Extension 2, the dose of givinostat was to be adjusted based on the weight of the children. • Asked patients to share information related to 2 biomarkers: latent TGFβ binding protein 4 (LTBP4) and osteopontin genotype.
    21 Jan 2016
    • Updated the study to allow patients on treatment in the second extension of the study to continue for an additional 12 months in a third extension (Extension 3). During Extension 3, the dose of givinostat was to be adjusted based on the weight of the children.
    11 Apr 2017
    • Updated the study to allow patients on treatment in the third extension of the study to continue for additional 4 months until the activation of the Long Term Safety study (Study N. DSC/14/2357/51 - EUDRACT: 2017-000397-10) that was submitted to the Ethic Committees and already obtained the approval in October 2017. In this way the patients who accepted to be included in the Long Term Safety study would continue the treatment with givinostat, without any interruptions.

    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.
    Because of the small sample size and of the lack of a control group, no efficacy considerations can be made regarding the effects of givinostat on muscle function.
    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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