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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled study to evaluate the micro-macroscopic effects on muscles, the safety and tolerability, and the efficacy of givinostat in patients with Becker Muscular Dystrophy.

    Summary
    EudraCT number
    2017-001629-41
    Trial protocol
    NL   IT  
    Global end of trial date
    19 Mar 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    27 May 2022
    First version publication date
    27 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DSC/15/2357/53
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03238235
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    ITALFARMACO S.p.A.
    Sponsor organisation address
    Viale dei Lavoratori, 54, Cinisello Balsamo, MIlano, Italy, 20092
    Public contact
    Clinical Trial Transparency Manager, Italfarmaco SpA, ITALFARMACO S.p.A., +39 0264431, info@italfarmaco.com
    Scientific contact
    Clinical Trial Transparency Manager, Italfarmaco SpA, ITALFARMACO S.p.A., +39 0264431, info@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
    19 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the histological effects of givinostat versus placebo administered over 12 months.
    Protection of trial subjects
    This study was conducted in compliance with the study protocol, the recommendations on biomedical research on human subjects of the Declaration of Helsinki, International Conference of Harmonization – Good Clinical Practice Guidelines (ICH GCP E6 (R2)) and all applicable national laws and regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Jan 2018
    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
    Netherlands: 6
    Country: Number of subjects enrolled
    Italy: 45
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    51
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible patients were randomized in a 2:1 ratio to receive givinostat or placebo for 12 months. Randomization was stratified by concomitant steroid use at baseline (yes or no).

    Pre-assignment
    Screening details
    70 ambulant patients had provided written informed consent to participate in this study. They underwent a 4-week screening period to determine their study eligibility. 51 patients (72.86%) completed screening successfully and were randomized as follow: 34 patients (66.67%) were assigned to the givinostat group and 17 (33.33%) to the placebo group.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor
    Blinding implementation details
    This was a double-blind, placebo-controlled study. Placebo was indistinguishable from the active product in color, appearance, smell and taste. Personnel involved in the study (Investigators, nurses, all other site personnel, clinical research associates [CRA], medical monitors, project managers, data managers and statisticians) were blinded at all times unless knowledge of the study treatment was necessary for the patient’s safety.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Givinostat - ITT
    Arm description
    Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose). With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients. The investigational study drug was administered for 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    ITF2357
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose) and more precisely in the morning after breakfast and in the evening after dinner using a graduated dosing syringe. With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients and corresponded to the reduced dose of the original protocol (i.e., 26.7-46.7 mg b.i.d according to body weight, i.e., low dose).

    Arm title
    Placebo - ITT
    Arm description
    Matching placebo was administered in the same formulation, same times and same way of givinostat. This means that placebo was administered as oral suspension bid after meals.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was administered in the same formulation, same times and same way of givinostat. This means that placebo was administered as oral suspension bid after a meal (i.e., in the morning after breakfast and in the evening after dinner) using a graduated dosing syringe.

    Number of subjects in period 1
    Givinostat - ITT Placebo - ITT
    Started
    34
    17
    Completed
    30
    17
    Not completed
    4
    0
         Adverse event, non-fatal
    2
    -
         unable to travel to the site due to pandemic
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Givinostat - ITT
    Reporting group description
    Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose). With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients. The investigational study drug was administered for 12 months.

    Reporting group title
    Placebo - ITT
    Reporting group description
    Matching placebo was administered in the same formulation, same times and same way of givinostat. This means that placebo was administered as oral suspension bid after meals.

    Reporting group values
    Givinostat - ITT Placebo - ITT Total
    Number of subjects
    34 17 51
    Age categorical
    Units: Subjects
        18-65
    34 17 51
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.5 ( 11.56 ) 39.2 ( 9.84 ) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    34 17 51

    End points

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    End points reporting groups
    Reporting group title
    Givinostat - ITT
    Reporting group description
    Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose). With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients. The investigational study drug was administered for 12 months.

    Reporting group title
    Placebo - ITT
    Reporting group description
    Matching placebo was administered in the same formulation, same times and same way of givinostat. This means that placebo was administered as oral suspension bid after meals.

    Primary: Mean change from baseline in total fibrosis comparing the histology of muscle biopsies after 12 months of treatment

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    End point title
    Mean change from baseline in total fibrosis comparing the histology of muscle biopsies after 12 months of treatment
    End point description
    Mean change from baseline in total fibrosis was calculated both on log scale in the ITT and back-transformed on the original scale in ITT. Here only log scale values are reported for the primary endpoint.
    End point type
    Primary
    End point timeframe
    At baseline and at visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    29
    15
    Units: percentage
        geometric mean (standard deviation)
    0.14 ( 0.437 )
    -0.06 ( 0.625 )
    Statistical analysis title
    Givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.8282
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.38
    Notes
    [1] - ANCOVA model was performed considering the difference between log of total fibrosis at Visit 11 and log baseline values as the dependent variable; log baseline value was included as covariate, treatment and concomitant steroid use at baseline as independent class variables.

    Secondary: Mean change from baseline in fat fraction of the vastus lateralis after 12 months of treatment (MRS)

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    End point title
    Mean change from baseline in fat fraction of the vastus lateralis after 12 months of treatment (MRS)
    End point description
    Evaluations were performed comparing Magnetic Resonance Spectroscopy (MRS) at baseline and after 12 months of treatment with givinostat versus placebo. Mean absolute change from baseline in fat fraction was reported both for vastus lateralis and soleus.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    33
    17
    Units: percentage
    arithmetic mean (standard deviation)
        Fat fraction in vastus lateralis
    1.06 ( 6.17 )
    3.82 ( 5.69 )
    Statistical analysis title
    Givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.1991
    Method
    ANCOVA
    Parameter type
    log difference of the least square means
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.03
    Notes
    [2] - ANCOVA model was performed considering baseline fat fraction of vastus lateralis or fat fraction in the soleus value as covariate and treatment and concomitant steroid use at baseline as independent class variables.

    Secondary: Mean change from baseline of fat fraction of lower limb muscles, thigh and pelvic girdle after 12 months of treatment (Dixon MRI)

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    End point title
    Mean change from baseline of fat fraction of lower limb muscles, thigh and pelvic girdle after 12 months of treatment (Dixon MRI)
    End point description
    Mean change of fat fraction of lower limb muscles (quadriceps,hamistrings,triceps sure), tigh (whole and medial) and pelvic girdle was measured using Dixon Magnetic Resonance Imaging (MRI) technique. Previous studies have shown that MRI can visualize structural alterations of muscle in muscular dystrophies and that fat fraction measured by MRI or magnetic resonance spectroscopy (MRS) highly correlates with lower limb function. Although longitudinal data on MRI/MRS particularly from randomised clinical trials are still limited, fatty degeneration of the muscle, in particular Muscle Fat Fraction (MFF) evaluated by MRI Dixon technique of the thigh muscles showed excellent correlation with clinical function in BMD patients, and might be a promising surrogate outcome marker in clinical trials. For the reason described above, MFF evaluated by MRI with Dixon technique as well as MRS are secondary endpoints of the study.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    33 [3]
    17 [4]
    Units: percentage
    arithmetic mean (standard deviation)
        whole tigh
    0.70 ( 1.684 )
    1.98 ( 1.761 )
        quadriceps
    0.38 ( 1.991 )
    2.25 ( 1.945 )
        medial tigh
    0.24 ( 2.139 )
    1.71 ( 2.913 )
        hamstrings
    1.50 ( 2.839 )
    1.97 ( 2.460 )
        triceps surae
    1.37 ( 2.672 )
    3.13 ( 1.999 )
        pelvis girdle
    0.32 ( 2.193 )
    1.69 ( 1.776 )
    Notes
    [3] - n=22 and not 33 only for fat fraction in triceps surae
    [4] - n=11 and not 17 only in fat fraction of triceps surae
    Statistical analysis title
    Givinostat vs placebo for whole thigh
    Statistical analysis description
    Estimated between-group difference for the whole thigh
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0149
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.43
         upper limit
    -0.28
    Notes
    [5] - ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    Givinostat vs placebo for quadriceps
    Statistical analysis description
    Estimated between-group difference for quadriceps
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.0022
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -1.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.18
         upper limit
    -0.75
    Notes
    [6] - ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    Givinostat vs placebo for medial thigh
    Statistical analysis description
    Estimated between-group difference for medial thigh
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.1165
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.06
         upper limit
    0.01
    Notes
    [7] - ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    Givinostat vs placebo for hamstrings
    Statistical analysis description
    Estimated between-group difference for hamstrings
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.4869
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.24
         upper limit
    1.08
    Notes
    [8] - ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    Givinostat vs placebo for triceps surae
    Statistical analysis description
    Estimated between-group difference for triceps surae. Please note that since for triceps sure analysis n=22 for givinostat and n= 11 for placebo, the number of subjects involved in this particular analysis is 33 and not 50 as indicated below.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0939
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.47
         upper limit
    0.29
    Notes
    [9] - ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    Givinostat vs placebo for pelvis girdle
    Statistical analysis description
    Estimated between-group difference for pelvis girdle
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.1579
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.13
         upper limit
    0.36
    Notes
    [10] - ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.

    Secondary: Mean change from baseline in cross-sectional area (CSA) of lower limb muscles and pelvic girdle after 12 months of treatment (Dixon MRI)

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    End point title
    Mean change from baseline in cross-sectional area (CSA) of lower limb muscles and pelvic girdle after 12 months of treatment (Dixon MRI)
    End point description
    Mean change of CSA of lower limb muscles and pelvic girdle was measured using Dixon Magnetic Resonance Imaging (MRI) technique. Previous studies have shown that MRI can visualize structural alterations of muscle in muscular dystrophies and that fat fraction measured by MRI or magnetic resonance spectroscopy (MRS) highly correlates with lower limb function. Although longitudinal data on MRI/MRS particularly from randomised clinical trials are still limited, fatty degeneration of the muscle, in particular Muscle Fat Fraction (MFF) evaluated by MRI Dixon technique of the thigh muscles showed excellent correlation with clinical function in BMD patients, and might be a promising surrogate outcome marker in clinical trials. For the reason described above, MFF evaluated by MRI with Dixon technique as well as MRS are secondary endpoints of the study.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    33 [11]
    17 [12]
    Units: area in cm2
    arithmetic mean (standard deviation)
        Whole thigh
    2.55 ( 4.514 )
    2.14 ( 4.906 )
        Quadriceps
    0.94 ( 1.950 )
    1.04 ( 2.244 )
        Medial Thigh
    0.76 ( 2.081 )
    0.42 ( 1.871 )
        Hamstrings
    0.85 ( 1.780 )
    0.68 ( 1.767 )
        Triceps surae
    0.65 ( 3.037 )
    0.63 ( 3.114 )
        Pelvis girdle
    1.21 ( 2.962 )
    0.88 ( 3.421 )
    Notes
    [11] - n=22 and not 33 only for triceps surae
    [12] - n=11 and not 17 only for triceps surae
    Statistical analysis title
    Givinostat vs placebo for the whole thigh
    Statistical analysis description
    This analysis regards the whole thigh
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    superiority [13]
    P-value
    = 0.777
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.45
         upper limit
    3.26
    Notes
    [13] - ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo in quadriceps
    Statistical analysis description
    This analysis regards quadriceps
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    = 0.8926
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.35
         upper limit
    1.18
    Notes
    [14] - ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo in medial thigh
    Statistical analysis description
    This analysis regards medial thigh
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.572
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    1.58
    Notes
    [15] - ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo in hamstrings
    Statistical analysis description
    This analysis regards in hamstrings
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    = 0.8386
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.97
         upper limit
    1.18
    Notes
    [16] - ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo in triceps surae
    Statistical analysis description
    This analysis regards in triceps surae. Please note that in this particular analysis the number of subjects is 33 and not 50 as reported hereunder, since n=22 in givinostat group and n=11 in the placebo group, for a total of 33.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.8591
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.68
         upper limit
    2.25
    Notes
    [17] - ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo in pelvis girdle
    Statistical analysis description
    This analysis regards pelvis girdle.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.7392
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    2.24
    Notes
    [18] - ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables

    Secondary: Mean change from baseline in biopsy histological parameters (muscle fiber area [MFA], mean adipose tissue, other histological structures etc.) after 12 months of treatment - slide 1

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    End point title
    Mean change from baseline in biopsy histological parameters (muscle fiber area [MFA], mean adipose tissue, other histological structures etc.) after 12 months of treatment - slide 1
    End point description
    Biopsy histological parameters (slide 1) analysed were: muscle fiber area fraction (MFA), adipose tissue, other histological structures, Mean value of fibers with nuclear centralization and Mean value of total number of fibers. This latter is calculated as the sum of the number of fibers of available fields analyzed on Slide I for each patient.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. 12 months after the treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    29
    15
    Units: percentage
    arithmetic mean (standard deviation)
        MFA
    -4.53 ( 12.892 )
    0.01 ( 21.768 )
        Adipose tissue
    -0.07 ( 1.896 )
    -0.29 ( 3.639 )
        Other histological structures
    0.39 ( 1.464 )
    0.83 ( 2.359 )
        Fiber with nuclear centralizations
    0.80 ( 9.525 )
    1.20 ( 14.950 )
        Total number of fibers Slide 1
    -7.10 ( 32.145 )
    -2.67 ( 51.854 )
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    this analysis regards the MFA (%) at visit 11
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.634
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    2.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.87
         upper limit
    12.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.256
    Notes
    [19] - ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the adipose tissue (%) at visit 11. For this comparison, log difference of the least square means and Log SE are reported.
    Comparison groups
    Placebo - ITT v Givinostat - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    P-value
    = 0.4893
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.54
         upper limit
    0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.224
    Notes
    [20] - ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the other histological structures (%) at visit 11. For this comparison, log difference of the least square means and Log SE are reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.1498
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    0.13
    Notes
    [21] - ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards fiber with nuclear centralizations (%) at visit 11. For this comparison, log difference of the least square means and Log SE are reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    = 0.1055
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    -0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.59
         upper limit
    0.06
    Notes
    [22] - ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards total number of fibers (%) at visit 11. For this comparison, log difference of the least square means and Log SE are reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.6265
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.26
    Notes
    [23] - ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.

    Secondary: Mean change from baseline in Motor function Measurement (MFM) score after 12 months of treatment

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    End point title
    Mean change from baseline in Motor function Measurement (MFM) score after 12 months of treatment
    End point description
    Motor function measurement (MFM) scores assessed were: Standing and transfers (D1) score, Axial and proximal motor function (D2) score, Mean distal motor function (D3) score and mean total score, using the Motor Function Measurement scale with givinostat versus placebo.
    End point type
    Secondary
    End point timeframe
    At baseline, and at visit 11 (ie. after 12 months of tretament)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: score
    arithmetic mean (standard deviation)
        Standing and transfers (D1)
    -1.28 ( 4.900 )
    -3.92 ( 4.166 )
        Axial and proximal motor function (D2)
    -0.16 ( 1.667 )
    -0.16 ( 2.077 )
        Mean distal motor function (D3)
    0.00 ( 2.345 )
    0.28 ( 2.042 )
        Mean total score
    -0.58 ( 2.435 )
    -1.59 ( 1.652 )
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards standing and transfers (D1) at visit 11. For this comparison, log difference of the least square means is reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.0602
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.13
    Notes
    [24] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards axial and proximal motor function (D2) at visit 11. For this comparison, log difference of the least square means is reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    = 0.5906
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.01
    Notes
    [25] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards in Distal motor function (D3) at visit 11. For this comparison, log difference of the least square means is reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.7799
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.01
    Notes
    [26] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the total score at visit 11. For this comparison, log difference of the least square means is reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    = 0.1116
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.03
    Notes
    [27] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.

    Secondary: Mean change from baseline in the Time Function Test (TFT) "Time to climb 4 standard steps" after 12 months of treatment

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    End point title
    Mean change from baseline in the Time Function Test (TFT) "Time to climb 4 standard steps" after 12 months of treatment
    End point description
    Overall, the time function tests (TFT) accomplished in this study are the following: Time to climb 4 standard steps, Time to walk/run 10 meters, Time to rise from the floor. Herunder the Time to climb 4 standard steps is reported.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    32
    15
    Units: seconds
        arithmetic mean (standard deviation)
    3.09 ( 31.929 )
    -2.21 ( 10.439 )
    Statistical analysis title
    givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.8914
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    0.28
    Notes
    [28] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate

    Secondary: Mean change from baseline in 6 Minute Walking Test (6MWT) after 12 months of treatment

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    End point title
    Mean change from baseline in 6 Minute Walking Test (6MWT) after 12 months of treatment
    End point description
    The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. The 6MWT was performed indoors on a flat, smooth path, at least 30 m long and 3 m wide, with a cone at each end around which the patient had to walk. Six progressively numbered markers were used to mark the distance travelled at each minute. Five progressively lettered markers were used to indicate any falls. Here, the maximum distance walked after 6 minutes is reported.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. 12 month of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: metre
        arithmetic mean (standard deviation)
    -9.07 ( 45.850 )
    -13.21 ( 24.236 )
    Statistical analysis title
    Givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.8106
    Method
    ANCOVA
    Parameter type
    Log difference of least square means
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.11
         upper limit
    0.08
    Notes
    [29] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.

    Secondary: Proportion of patients with < 10% worsening in 6MWT after 12 months of treatment

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    End point title
    Proportion of patients with < 10% worsening in 6MWT after 12 months of treatment
    End point description
    Percentage of patients who lost less than 10% in the 6MWT
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. 12 month of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: percent
        number (not applicable)
    20.59
    5.88
    Statistical analysis title
    Givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    = 0.1626
    Method
    Mantel-Haenszel
    Parameter type
    difference of proportion
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.7
    Notes
    [30] - The proportion of patients with < 10% worsening after 12 months of therapy was compared between arms using a stratified Cochran Mantel-Haenszel (CMH) chi square test with a two-sided α=0.05 level. The proportion, along with its exact two-sided 95% CI, was computed within each treatment group. A two-sided 95% CI for difference of proportion between the treatment groups was also computed.

    Secondary: Proportion of patients who lose the ability to rise from floor till the end of the study

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    End point title
    Proportion of patients who lose the ability to rise from floor till the end of the study
    End point description
    Proportion of patients who lost the ability to rise from floor during the rise from the floor test
    End point type
    Secondary
    End point timeframe
    From baseline to the end of study (EOS)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: percent
        number (not applicable)
    0
    5.88
    No statistical analyses for this end point

    Secondary: Proportion of patients who lose ambulation till the end of the study

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    End point title
    Proportion of patients who lose ambulation till the end of the study
    End point description
    percentage of patients who lose ambulation during the study (6MWT not done) was assessed. Here the data at visit 11 are reported.
    End point type
    Secondary
    End point timeframe
    Throughout the study till EOS (i.e. 12 month of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: percent
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Mean change from baseline in muscle strength evaluated by knee extension, elbow flexion, as measured by Hand Held Myometry (HHM)

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    End point title
    Mean change from baseline in muscle strength evaluated by knee extension, elbow flexion, as measured by Hand Held Myometry (HHM)
    End point description
    Muscle strength (knee extension and elbow flexion) was tested on all four limbs using a MICROFET myometer held perpendicularly to the direction of the force of the muscle groups being tested and at a set distance from the joint. A “make test” was adopted with the patient holding an isometric contraction for 3-5 seconds. Three measurements were taken and recorded for each limb. The highest values of muscle strength at the knee and elbow (three attempts) were considered for the analysis. A summary of muscle strength was assessed by hand-held myometry considering the following parameters: mean left knee extension, mean right knee extension, mean left elbow flexion, mean right elbow flexion.
    End point type
    Secondary
    End point timeframe
    at visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    33 [31]
    16 [32]
    Units: newton
    arithmetic mean (standard deviation)
        mean left knee extension
    -2.51 ( 19.011 )
    -4.79 ( 10.519 )
        mean right knee extension
    -1.32 ( 12.397 )
    -1.82 ( 6.501 )
        mean left elbow flexion
    4.19 ( 27.317 )
    -0.07 ( 7.353 )
        mean right elbow flexion
    4.55 ( 31.556 )
    -1.07 ( 12.098 )
    Notes
    [31] - LKE n=32 , LEF,REF n=31
    [32] - n=14 (LKE,LEF); n=15 (REF)
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This Analisys regards LKE, this group involved 46 patients and not 49
    Comparison groups
    Placebo - ITT v Givinostat - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.5099
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    3.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.27
         upper limit
    14.41
    Notes
    [33] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This Analisys regards RKE
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    = 0.7355
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.73
         upper limit
    8.06
    Notes
    [34] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This Analisys regards LEF this group involved 45 patients and not 49
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.6037
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    3.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.22
         upper limit
    19.06
    Notes
    [35] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This Analisys regards REF this group involved 46 patients and not 49
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    = 0.6178
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    4.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.35
         upper limit
    20.55
    Notes
    [36] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.

    Secondary: Mean changes from baseline in quality of life (QoL) after 12 months of treatment

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    End point title
    Mean changes from baseline in quality of life (QoL) after 12 months of treatment
    End point description
    QoL is assessed by the 36-item Short Form survey [SF36]). The SF-36 is a set of generic, coherent, and easily administered patient reported outcomes that is widely utilized by managed care organizations for routine monitoring and assessment of care outcomes in adult patients. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score, the greater the disability.
    End point type
    Secondary
    End point timeframe
    At visit 11 ( i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: score on a scale
    arithmetic mean (standard deviation)
        Physical Functioning
    -1.03 ( 16.274 )
    -5.00 ( 11.989 )
        Role-Physical
    -2.21 ( 19.697 )
    0.37 ( 16.006 )
        Bodily Pain
    5.12 ( 19.384 )
    2.12 ( 15.227 )
        General Health
    0.82 ( 14.532 )
    1.47 ( 13.267 )
        Vitality
    0.55 ( 11.654 )
    3.68 ( 12.705 )
        Social Functioning
    2.94 ( 22.415 )
    8.82 ( 20.139 )
        Role-Emotional
    0.00 ( 20.205 )
    4.90 ( 15.607 )
        Mental Health
    4.12 ( 15.977 )
    4.41 ( 13.793 )
        Physical Component Summary
    -0.17 ( 5.633 )
    -1.20 ( 5.535 )
        Mental Component Summary
    1.41 ( 7.345 )
    3.70 ( 7.177 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in fat fraction of the soleus after 12 months of treatment (MRS)

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    End point title
    Mean change from baseline in fat fraction of the soleus after 12 months of treatment (MRS)
    End point description
    Evaluations were performed comparing Magnetic Resonance Spectroscopy (MRS) at baseline and after 12 months of treatment with givinostat versus placebo. Mean absolute change from baseline in fat fraction was reported both for vastus lateralis and soleus
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    27
    14
    Units: percentage
        arithmetic mean (standard deviation)
    -1.07 ( 4.187 )
    0.43 ( 3.322 )
    Statistical analysis title
    Givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    = 0.7849
    Method
    ANCOVA
    Parameter type
    difference of the least share means
    Point estimate
    -0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.22
         upper limit
    1.69
    Notes
    [37] - ANCOVA model was performed considering baseline fat fraction of vastus lateralis or fat fraction in the soleus value as covariate and treatment and concomitant steroid use at baseline as independent class variables.

    Secondary: Mean change from baseline in contractile area of lower limb muscles (MRI) after 12 months of treatment

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    End point title
    Mean change from baseline in contractile area of lower limb muscles (MRI) after 12 months of treatment
    End point description
    Contractile area evaluations were performed (in the whole thigh, quadriceps, medial thigh, pelvic girdle, hamstring and triceps surae comparing Magnetic Resonance Images (MRI) at baseline and after 12 months of treatment with givinostat versus placebo.
    End point type
    Secondary
    End point timeframe
    at visit 11 (i.e after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    33 [38]
    17 [39]
    Units: area in cm2
    arithmetic mean (standard deviation)
        Whole thigh
    0.49 ( 2.164 )
    -0.94 ( 1.783 )
        Quadriceps
    0.22 ( 1.052 )
    -0.31 ( 1.059 )
        Medial thigh
    0.40 ( 1.094 )
    -0.14 ( 0.843 )
        Hamstrings
    -0.13 ( 0.971 )
    -0.49 ( 0.951 )
        Triceps surae
    -0.59 ( 2.615 )
    -1.58 ( 2.649 )
        Pelvis girdle
    0.31 ( 1.433 )
    -0.49 ( 0.957 )
    Notes
    [38] - n=22 only in the triceps surae, instead of being 33
    [39] - n=11 only in triceps surae, instead of being 17
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This comparison regards Contractile Area in Whole Thigh at Visit 11
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    P-value
    = 0.0375
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    2.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.577
    Notes
    [40] - ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This comparison regards Contractile Area in quadriceps at Visit 11
    Comparison groups
    Placebo - ITT v Givinostat - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    = 0.0528
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    1.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.296
    Notes
    [41] - ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This comparison regards Contractile Area in medial thigh at Visit 11
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    P-value
    = 0.2012
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [42] - ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This comparison regards Contractile Area in hamstrings at Visit 11. In this area values are provided as Log Difference of Least Square Means (95% CI), and Log SE
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    = 0.1939
    Method
    ANCOVA
    Parameter type
    Log difference of least square means
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033
    Notes
    [43] - ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This comparison regards Contractile Area itriceps surae at Visit 11. Please note that the number of subjects involved in this analysis is 33 (22 for givinostat and 11 for placebo) and not 50 as reported below
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [44]
    P-value
    = 0.4676
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.33
         upper limit
    2.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.494
    Notes
    [44] - ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    Givinostat vs placebo
    Statistical analysis description
    This comparison regards Contractile Area pelvis girdle at Visit 11.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.1549
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.336
    Notes
    [45] - ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables

    Secondary: Mean change from baseline in biopsy histological parameters after 12 months of treatment - slide 2

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    End point title
    Mean change from baseline in biopsy histological parameters after 12 months of treatment - slide 2
    End point description
    Biopsy histological parameters (slide 2) analysed were: regenerative fibers and Mean value of total number of fibers. This latter is calculated as the sum of the number of fibers of available fields analyzed on Slide II for each patient.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    29
    15
    Units: percentage
    arithmetic mean (standard deviation)
        regenerative fibers
    -0.40 ( 8.426 )
    0.82 ( 4.092 )
        total number of fibers slide II
    -39.24 ( 100.834 )
    -7.67 ( 82.690 )
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the regenerative fibers (%). For this comparison, log difference of the least square means and Log SE are reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    P-value
    = 0.1562
    Method
    ANCOVA
    Parameter type
    Log difference of least square means
    Point estimate
    -0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.345
    Notes
    [46] - ANCOVA model was performed considering baseline biopsy histological parameters (Slide II) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the regenerative fibers (%).
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    = 0.8846
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -2.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.05
         upper limit
    28.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.099
    Notes
    [47] - ANCOVA model was performed considering baseline biopsy histological parameters (Slide II) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.

    Secondary: Mean change from baseline in biopsy histological parameters after 12 months of treatment - slide 3

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    End point title
    Mean change from baseline in biopsy histological parameters after 12 months of treatment - slide 3
    End point description
    Biopsy histological parameters (slide 2) analysed were: CSA Type I (μm2), CSA Type II (μm2), total CSA (μm2), total number of fibers slide III. This latter is calculated as the sum of the number of fibers of available fields analyzed on Slide III for each patient.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    29
    15
    Units: area in μm2
    arithmetic mean (standard deviation)
        CSA Type I
    -62.01 ( 2316.099 )
    243.82 ( 4017.531 )
        CSA Type II
    -669.06 ( 2361.490 )
    412.22 ( 2637.085 )
        Total CSA
    -307.57 ( 1946.462 )
    558.15 ( 2027.072 )
        Total number of fibers slide III
    -4.83 ( 30.236 )
    -17.80 ( 29.121 )
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the CSA Type I at visit 11. For this comparison, log difference of the least square means and Log SE are reported.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.9493
    Method
    ANCOVA
    Parameter type
    Log difference of least square means
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [48] - ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the CSA Type II at visit 11.
    Comparison groups
    Placebo - ITT v Givinostat - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    P-value
    = 0.324
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -619.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1872.37
         upper limit
    633.98
    Notes
    [49] - ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the total CSA at visit 11.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    P-value
    = 0.307
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    -572.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1690.73
         upper limit
    545.64
    Notes
    [50] - ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables
    Statistical analysis title
    givinostat vs placebo
    Statistical analysis description
    This analysis regards the total number of fibers at visit 11.
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority [51]
    P-value
    = 0.4054
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    4.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.62
         upper limit
    16.06
    Notes
    [51] - ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables

    Secondary: Mean change from baseline in the Time Function Test (TFT) "Time to walk/run 10 meters" after 12 months of treatment

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    End point title
    Mean change from baseline in the Time Function Test (TFT) "Time to walk/run 10 meters" after 12 months of treatment
    End point description
    Overall, the time function tests (TFT) accomplished in this study are the following: Time to climb 4 standard steps, Time to walk/run 10 meters, Time to rise from the floor. Herunder the Time to walk/run 10 meters is reported
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: seconds
        arithmetic mean (standard deviation)
    0.25 ( 7.114 )
    0.26 ( 1.089 )
    Statistical analysis title
    givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority [52]
    P-value
    = 0.4346
    Method
    ANCOVA
    Parameter type
    log difference of least square means
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.23
         upper limit
    0.1
    Notes
    [52] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate

    Secondary: Mean change from baseline in the Time Function Test (TFT) "Time to rise from floor" after 12 months of treatment

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    End point title
    Mean change from baseline in the Time Function Test (TFT) "Time to rise from floor" after 12 months of treatment
    End point description
    Overall, the time function tests (TFT) accomplished in this study are the following: Time to climb 4 standard steps, Time to walk/run 10 meters, Time to rise from the floor. Herunder the Time to rise from the floor is reported.
    End point type
    Secondary
    End point timeframe
    At visit 11 (i.e. after 12 months of treatment)
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    29
    10
    Units: seconds
        arithmetic mean (standard deviation)
    2.08 ( 6.204 )
    1.69 ( 4.417 )
    Statistical analysis title
    Givinostat vs placebo
    Comparison groups
    Givinostat - ITT v Placebo - ITT
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    P-value
    = 0.7629
    Method
    ANCOVA
    Parameter type
    difference of least square means
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.51
         upper limit
    4.75
    Notes
    [53] - Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.

    Secondary: Number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) throughout the study (EOS)

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    End point title
    Number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) throughout the study (EOS)
    End point description
    All treatment emergent adverse events (TEAEs) and the serious adverse events (SAEs) were collected with their relationship to the study drug
    End point type
    Secondary
    End point timeframe
    From baseline through the end of the study
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: number
    number (not applicable)
        TEAE
    30
    9
        SAE
    0
    0
    No statistical analyses for this end point

    Secondary: Type, incidence, and severity of TEAEs and SAEs throughout the study

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    End point title
    Type, incidence, and severity of TEAEs and SAEs throughout the study
    End point description
    Treatment-emergent AEs (TEAEs): events with an onset date after study treatment initiation. Deaths, SAEs and AEs leading to withdrawal of study treatment are also listed.
    End point type
    Secondary
    End point timeframe
    From baseline to EOS
    End point values
    Givinostat - ITT Placebo - ITT
    Number of subjects analysed
    34
    17
    Units: number
    number (not applicable)
        fatal TEAE
    0
    0
        mild TEAE
    30
    9
        moderate TEAE
    12
    1
        severe TEAE
    5
    0
        SAE
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were assessed throughout the study: from visit 1 and V2 (screening) up to visit 11 (week 48, month 12 which corresponds to EOS) and visit 12 (FUV=follow up visit 4 weeks after the last dose of study treatment).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Givinostat - safety
    Reporting group description
    -

    Reporting group title
    Placebo - safety
    Reporting group description
    -

    Serious adverse events
    Givinostat - safety Placebo - safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Givinostat - safety Placebo - safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 34 (88.24%)
    12 / 17 (70.59%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Surgical and medical procedures
    Tooth repair
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Umbilical hernia repair
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Hyperpyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Edema peripheral
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    Nasal congestion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Sleep apnea syndrome
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Blood phosphorus increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Blood potassium increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Blood sodium increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 17 (5.88%)
         occurrences all number
    8
    2
    C-reactive protein increased
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Heart rate increased
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Platelet count decreased
         subjects affected / exposed
    20 / 34 (58.82%)
    0 / 17 (0.00%)
         occurrences all number
    40
    0
    Weight increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count increased
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Face injury
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 17 (17.65%)
         occurrences all number
    2
    5
    Head injury
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 17 (5.88%)
         occurrences all number
    5
    1
    Rib fracture
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Tooth injury
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Post procedural haematoma
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    Procedural pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    Dizziness
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Hand-arm vibration syndrome
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Paresthesia
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 17 (11.76%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Lymphocytosis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 17 (5.88%)
         occurrences all number
    7
    2
    Diarrhoea
         subjects affected / exposed
    16 / 34 (47.06%)
    0 / 17 (0.00%)
         occurrences all number
    95
    0
    Dyspepsia
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 17 (5.88%)
         occurrences all number
    6
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Dyshidrotic eczema
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Muscle hypertrophy
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Muscular weakness
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    Myalgia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Periarthritis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Influenza
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 17 (5.88%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 17 (5.88%)
         occurrences all number
    1
    4
    Rhinitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    10 / 34 (29.41%)
    1 / 17 (5.88%)
         occurrences all number
    25
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2018
    The main purposes of protocol amendment 1 are: 1. To specify that the fat fraction and cross section evaluations by means of Dixon MRI will involve muscles of the lower leg, as well as those of the thigh and pelvic girdle as originally planned. 2. To modify the age limit stated in Inclusion Criterion 1. Age has been raised from 60 to 65 years after Investigators advised of the presence of potential patients over the age of 60 who otherwise meet all eligibility criteria. 3. To delete the repetition of the functional tests (i.e. time to climb 4 standard steps, time to rise from floor, time to walk 10 meters, motor function measure and muscle strength) at the randomization visit, since noteworthy changes are not expected in these patients within 1 month of screening. Only 6MWT will be performed and the average of the scores at screening and randomization will be used as baseline value. 4. To correct the information related to the evaluation of serum circulating proteins as potential biomarkers for BMD. These analyses will not be carried out through SomaScan® technique because the central laboratory originally chosen for this study no longer provides this service. Biomarker evaluation will be performed by a different provider using an ELISA-based system. 5. To increase the frequency of thyroid function monitoring to ensure patient safety. Monitoring will now be carried out monthly until the third month and then every 3 months until the end of the study. 6. To include information on the backup system for randomization and treatment assignment. The Interactive Voice Response System (IVRS) will be used in the unlikely case of Web Response System (IWRS) unavailability. 7. To correct the information on the urine analysis, which will be done by dipstick on site and not by the central lab. 8. To include minor changes to increase clarity and correct typographic errors.
    31 Jul 2018
    The main purpose of Amendment 2 is to address safety issue, namely thrombocytopenia arising following the treatment of the first 21 patients enrolled in the present study. More precisely, preliminary blinded results therefore suggests that the starting dose of the current protocol would be difficult to manage outside of a clinical trial environment, and since the current dose reduction rule is adequate in keeping an acceptable level of platelets, a new starting dose corresponding to the reduced dose of the original protocol (i.e. 26.7-46.7 mg b.i.d according to body weight) is now proposed by the Sponsor and Investigator. In addition, new safety rules are applied, allowing the study drug to be reduced by 20% from the new starting dose if the patient meets stopping criteria. Furthermore, to provide the highest degree of safety, the study protocol has been amended to intensify patient monitoring (i.e. Additional unscheduled visits with a cardiologist at the discretion of study clinicians; Additional safety assessments (blood tests) at the discretion of study clinicians). Other minor changes have been made to the protocol.
    13 Dec 2019
    The main purposes of amendment 3 are as follows: 1. The protocol has been integrated with pertinent information added to the latest version of the Investigator’s Brochure (Version 20.0). Section 4.2.2 – Clinical Experience with Givinostat Including Risks and Benefits – has been updated with new information concerning hemorrhagic drug-related AEs. Section 8.7.2 – Prior and concomitant medications – now includes P-glycoproteins (P-gp) as medications whose use requires caution. The study drug is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate and therefore co-administration of P-gp inhibitors may result in increased plasma concentrations of givinostat. Increased oral absorption is usually of limited clinical concern except for drugs that have a narrow therapeutic index, which is not the case of givinostat. Nevertheless, Pgp inhibitors should be properly managed in clinical studies and a new appendix listing P-gp inhibitors has been added to the protocol. 2. Section 9.1.10 – End of Study Visit – and Table 5 – Schedule of Assessments – now indicate that MRI/MRS and biopsy evaluations scheduled for the end of study visit may be performed on different days and that treatment is to continue up to the last assessment. 3. Section 13.10 - Interim Analyses – besides the interim analysis foreseen to check the sample size assumption, it was decided to plan an additional interim analysis to obtain a preliminary overview of the baseline patient characteristics after study enrollment is completed. 4. The Interim analysis section of the synopsis has been updated according to the protocol changes described in item 3.
    17 Jun 2020
    1.The main purposes of amendment 4 is to amend the primary endpoint. More precisely, the change of total fibrosis is considered a more indicative outcome measure of the possible effect of givinostat relative to the assessment of CSA and, hence, it is to be evaluated as the primary endpoint for the trial. 2. Sections “Sample size determination” (13.1) and “Statistical Analysis” (13) were revised according to the change of the primary endpoint described above. With a reasonable allowance of 5% of patients with unevaluable biopsies at the end of study, the total number ofpatients to be randomized is 51. Moreover, in the context of the new primary endpoint (it is expected that total fibrosis (%) will increase less in the givinostat group than in the placebo group) a LOCF analysis is considered not appropriate because any missing follow-up value will be replaced by that subject’s previously observed value (i.e. the baseline value) and this approach can be questionable and not conservative, for this reason a multiple imputation method will be used to handle missing data. 3. Sections “Study Design” (6.1 and 6.2) and “Interim Analysis” (13) were updated including a description of conclusions on the first blinded interim analysis performed on the first 20 baseline biopsies which led the protocol amendment n. 4. as described above. The details about methodology and the results are reported in the specific SAP and Statistical Report available as stand-alone documents. 4. Section “Biomarker” (11.3) was modified to indicate that patients who have already concluded the study may be asked to return to the center for a blood sample collection necessary for LTBP4 and Osteopontin genotyping if the sample was not already collected.

    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.
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