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    Clinical Trial Results:
    Randomised, double blind, placebo controlled, multicentre study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy.

    Summary
    EudraCT number
    2016-000401-36
    Trial protocol
    GB   BE   DE   NL   IT   ES   FR  
    Global end of trial date
    22 Feb 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Jan 2023
    First version publication date
    07 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DSC/14/2357/48 (EDYPIS)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03373968
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND: 126598
    Sponsors
    Sponsor organisation name
    ITALFARMACO S.p.A.
    Sponsor organisation address
    Via dei Lavoratori 54, Cinisello Balsamo , Italy, 20092
    Public contact
    Clinical Trial Transparency Manager, Italfarmaco S.p.A., +39 02 66041503, info@italfarmaco.com
    Scientific contact
    Clinical Trial Transparency Manager, Italfarmaco S.p.A., +39 02 66041503, 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
    10 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the effects of givinostat versus placebo administered chronically over 18 months to slow disease progression in ambulant DMD subjects
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    United States: 43
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Italy: 37
    Worldwide total number of subjects
    179
    EEA total number of subjects
    106
    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)
    155
    Adolescents (12-17 years)
    24
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were randomised in 2:1 ratio of givinostat versus placebo. 118 subjects were enrolled in the givinostat group, and 61 subjects were enrolled in the placebo group.

    Pre-assignment
    Screening details
    A total of 359 subjects were screened. 36 subjects passed screening but were not randomised. 144 failed screening. 179 subjects were randomized with a 2:1 ratio: 118 subjects in the givinostat group, and 61 in 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, Monitor, Data analyst, Assessor
    Blinding implementation details
    Subjects receiving givinostat or placebo received medication indistinguishable in appearance. Personnel involved in the study (Investigators, nurses, all other site personnel, clinical research associates (CRAs), Medical Monitors, project managers, and personnel involved in data management) remained blinded at all times, unless under exceptional circumstances when knowledge of the study drug was essential for treating the subject, such as in case of an AE.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Givinostat
    Arm description
    Givinostat oral suspension (10 mg/mL) twice daily (bid).
    Arm type
    Active comparator

    Investigational medicinal product name
    Givinostat
    Investigational medicinal product code
    Other name
    TF2357
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid

    Arm title
    Placebo
    Arm description
    Placebo oral suspension (10 mg/mL) twice daily (bid).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.

    Number of subjects in period 1
    Givinostat Placebo
    Started
    118
    61
    Completed
    111
    59
    Not completed
    7
    2
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Givinostat
    Reporting group description
    Givinostat oral suspension (10 mg/mL) twice daily (bid).

    Reporting group title
    Placebo
    Reporting group description
    Placebo oral suspension (10 mg/mL) twice daily (bid).

    Reporting group values
    Givinostat Placebo Total
    Number of subjects
    118 61 179
    Age categorical
    Units: Subjects
        Children (2-11 years)
    100 49 149
        Adolescents (12-17 years)
    18 12 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.78 ( 2.022 ) 9.97 ( 2.082 ) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    118 61 179
    Subject analysis sets

    Subject analysis set title
    Givinostat ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose • > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid • > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid • > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid • > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid • > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid • > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid • > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid • > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid • > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid

    Subject analysis set title
    Placebo ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.

    Subject analysis sets values
    Givinostat ITT Placebo ITT
    Number of subjects
    118
    61
    Age categorical
    Units: Subjects
        Children (2-11 years)
    100
    49
        Adolescents (12-17 years)
    18
    12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.78 ( 2.022 )
    9.97 ( 2.082 )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    118
    61

    End points

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    End points reporting groups
    Reporting group title
    Givinostat
    Reporting group description
    Givinostat oral suspension (10 mg/mL) twice daily (bid).

    Reporting group title
    Placebo
    Reporting group description
    Placebo oral suspension (10 mg/mL) twice daily (bid).

    Subject analysis set title
    Givinostat ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose • > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid • > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid • > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid • > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid • > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid • > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid • > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid • > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid • > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid

    Subject analysis set title
    Placebo ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.

    Primary: Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment

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    End point title
    Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment
    End point description
    The time (in seconds) to climb 4 standard-sized stairs is a TFT that represents stair-climbing ability. The test was evaluated by qualified functional evaluators (ie, physiotherapists) who were different from the site personnel who reviewed subjects’ safety results. The test was performed in a standardized manner described in a specific site manual. Baseline 4SC was the measurement taken at the randomization assessment, unless this was missing, in which case baseline was taken as the last non missing value recorded prior to or on the date of first study treatment. The shorter the time, the better the outcome.
    End point type
    Primary
    End point timeframe
    18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    81
    39
    Units: seconds
        least squares mean (standard error)
    1.27 ( 0.040 )
    1.48 ( 0.058 )
    Statistical analysis title
    Givinostat vs Placebo
    Statistical analysis description
    Log transformation applied
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0345 [2]
    Method
    ANCOVA
    Parameter type
    generalised least square mean ratio
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.745
         upper limit
    0.989
    Notes
    [1] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in 4SC at Month 18 with baseline values for: 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.
    [2] - LS Means, CIs, and p-values are obtained from ANCOVA model on change from baseline in 4SC at Month 18 with baseline values for the above-mentioned parameters as covariates, with steroid use and treatment group as independent classification factors.

    Secondary: Mean Change From Baseline in Time to Rise From Floor After 18 Months of Treatment

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    End point title
    Mean Change From Baseline in Time to Rise From Floor After 18 Months of Treatment
    End point description
    An analysis of time (in seconds) to rise from the floor by change from baseline at 18 months is presented for the Target Population in the ITT analysis set. The shorter the time, the better the outcome
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    81
    39
    Units: second
        least squares mean (confidence interval 95%)
    9.33 (5.821 to 12.838)
    12.61 (7.491 to 17.724)
    Statistical analysis title
    Givinostat vs Placebo
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.3044
    Method
    ANCOVA
    Parameter type
    difference in least square means
    Point estimate
    -3.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.573
         upper limit
    3.018
    Notes
    [3] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in time to rise from the Floor at Month 18 with baseline values for: 4SC, time to rise from floor, time to run/walk 10 m, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

    Secondary: Mean Change From Baseline in the Six-minute Walking Test (6MWT) After 18 Months of Treatment

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    End point title
    Mean Change From Baseline in the Six-minute Walking Test (6MWT) After 18 Months of Treatment
    End point description
    This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. A modified version of the 6MWT recommended by American Thoracic Society (2002) for use in adults was performed. The longer the walked distance the better the outcome.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    81
    39
    Units: Meters
        least squares mean (confidence interval 95%)
    -38.43 (-50.704 to -26.153)
    -48.38 (-66.288 to -30.482)
    Statistical analysis title
    Givinostat vs Placebo
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.3723 [5]
    Method
    ANCOVA
    Parameter type
    difference in least square means
    Point estimate
    9.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.071
         upper limit
    31.983
    Notes
    [4] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in distance walked at the end of the 6-minute walking test (6MWT) at Month 18 with baseline values for: 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification actors.
    [5] - LS means, CIs, p-values were obtained from analysis of covariance model on change from baseline in distance walked at the end of the 6MWT at Month18.

    Secondary: Mean Change From Baseline in Total North Star Ambulatory Assessment (NSAA) Score After 18 Months of Treatment

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    End point title
    Mean Change From Baseline in Total North Star Ambulatory Assessment (NSAA) Score After 18 Months of Treatment
    End point description
    The total North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne Muscular Dystrophy (DMD). It is usually used to monitor the progression of the disease and treatment effects. The 17 items of the NSAA, ranging from standing to running 10 meters, were graded using the standard score card with each assessment rated as 0 – unable to achieve independently, 1 – modified method but achieves goal independent of physical assistance from another, or 2 – normal with no obvious modification of activity. This scale is ordinal with 0 as the minimum score (indicating full dysfunctionality, i.e. the worst outcome) and with 34 as the maximum score indicating fully-independent function (the best outcome).
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    81
    39
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -2.66 (-3.563 to -1.759)
    -4.58 (-5.891 to -3.260)
    Statistical analysis title
    Givinostat vs Placebo
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.0209
    Method
    ANCOVA
    Parameter type
    difference in least square means
    Point estimate
    1.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.295
         upper limit
    3.533
    Notes
    [6] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in total NSAA score at Month 18 with baseline values for: total NSAA score, 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

    Secondary: Cumulative Loss of Function on the NSAA

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    End point title
    Cumulative Loss of Function on the NSAA
    End point description
    Analysis of cumulative loss of function on the NSAA over 18 months of treatment is presented for the Target Population in the ITT analysis set. It has been expressed as estimated cumulative failures.
    End point type
    Secondary
    End point timeframe
    over 18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    81
    39
    Units: estimated cumulative failures
        number (confidence interval 95%)
    3.42 (2.692 to 4.334)
    5.56 (4.002 to 7.715)
    Statistical analysis title
    Givinostat vs Placebo
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0202 [8]
    Method
    negative binomial regression model
    Parameter type
    Ratio of cumulative failures]
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.408
         upper limit
    0.927
    Notes
    [7] - Estimated cumulative failures, ratio of cumulative failures, CIs, and p-values are obtained from a negative binomial regression on the subject cumulative number of failures across all post-baseline visits. Total failed items at baseline, baseline values for: 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose were included as independent covariates, with treatment group and steroid use included as indep classification factors.
    [8] - Estimated cumulative failures, their ratio were obtained from a negative binomial regression on the cumulative N of failures across all visits.

    Secondary: Mean Change From Baseline of Muscle Strength Normalized Overtime

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    End point title
    Mean Change From Baseline of Muscle Strength Normalized Overtime
    End point description
    The mean change of muscle strength normalized was evaluated by knee extension and elbow flexion normalized by subject weight, both measured by hand-held myometry (HHM).
    End point type
    Secondary
    End point timeframe
    over 18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    81
    39
    Units: N/kg normalized
    least squares mean (confidence interval 95%)
        Overall knee extension
    -0.32 (-0.441 to -0.197)
    -0.50 (-0.681 to -0.328)
        Overall elbow flexion
    -0.10 (-0.174 to -0.031)
    -0.19 (-0.292 to -0.085)
    Statistical analysis title
    Givinostat vs Placebo
    Statistical analysis description
    Overall knee extension
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0902
    Method
    ANCOVA
    Parameter type
    Difference in least square means]
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.401
    Notes
    [9] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in normalized muscle strength at Month 18 with baseline normalised muscle strength and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.
    Statistical analysis title
    Givinostat vs Placebo
    Statistical analysis description
    Overall elbow flexion
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.1818
    Method
    ANCOVA
    Parameter type
    difference in least square means
    Point estimate
    0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.041
         upper limit
    0.213
    Notes
    [10] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in normalised muscle strength at Month 18 with baseline normalized muscle strength and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

    Secondary: Mean Change From Baseline in Vastus Lateralis Muscle Fat Fraction (VL MFF) at 18 Months

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    End point title
    Mean Change From Baseline in Vastus Lateralis Muscle Fat Fraction (VL MFF) at 18 Months
    End point description
    Vastus lateralis muscle fat fraction (VL MFF) was expressed as fat infiltration in this muscle. Fat infiltration was assessed by Magnetic Resonance (MRS).
    End point type
    Secondary
    End point timeframe
    at 18 months
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    77
    37
    Units: percentage of fat
        least squares mean (confidence interval 95%)
    7.63 (6.098 to 9.172)
    10.56 (8.331 to 12.783)
    Statistical analysis title
    Givinostat vs Placebo
    Comparison groups
    Givinostat ITT v Placebo ITT
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.0354
    Method
    ANCOVA
    Parameter type
    difference in least square means
    Point estimate
    -2.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.641
         upper limit
    -0.204
    Notes
    [11] - LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in VL MFF at Month 18 with baseline VL MFF and rederived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

    Secondary: Number of Subjects Experiencing Treatment-emergent AEs (TEAEs), Serious AEs (SAEs), Mild TEAE Moderate TEAE, Severe TEAE

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    End point title
    Number of Subjects Experiencing Treatment-emergent AEs (TEAEs), Serious AEs (SAEs), Mild TEAE Moderate TEAE, Severe TEAE
    End point description
    Adverse Events are unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial. Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study, that is the end of 18° month
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    118
    61
    Units: Count of Participants
        Subjects with TEAE
    112
    57
        Subjects with serious AE
    8
    2
        Subjects with mild AE
    69
    39
        Subjects with moderate AE
    38
    17
        Subjects with severe AE
    5
    1
    No statistical analyses for this end point

    Secondary: Evaluation of Acceptability/Palatability of the Oral Suspension

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    End point title
    Evaluation of Acceptability/Palatability of the Oral Suspension
    End point description
    Acceptability and palatability of the oral suspension over time are presented. More in details, child perception of the medicine at the three timepoints hereunder specified; parent perception of the medicine based on the child's reaction at the same three timepoints; and parent problems administering the medication at the same timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Week 4, EOS, early withdrawal
    End point values
    Givinostat ITT Placebo ITT
    Number of subjects analysed
    118
    61
    Units: Count of Participants
        Child perception - week 4 - dislike very much
    31
    11
        Child perception - week 4 - dislike a little
    21
    17
        Child perception - week 4 - not sure
    30
    16
        Child perception - week 4 - like a little
    19
    12
        Child perception - week 4 - like very much
    11
    3
        Child perception - EOS - dislike very much
    21
    7
        Child perception - EOS - dislike a little
    24
    13
        Child perception - EOS - not sure
    34
    16
        Child perception - EOS - like a little
    19
    10
        Child perception - EOS - like very much
    7
    9
        Child perception - early withdrawal - dislike very
    1
    0
        Child perception - early withdrawal - dislike a li
    1
    0
        Child perception - early withdrawal - not sure
    2
    0
        Child perception - early withdrawal - like a littl
    1
    0
        Child perception - early withdrawal - like very mu
    0
    0
        Parent perception - week 4 - unpleasant
    50
    31
        Parent perception - week 4 - not sure
    28
    10
        Parent perception - week 4 - pleasant
    35
    18
        Parent perception - EOS - unpleasant
    42
    14
        Parent perception - EOS - not sure
    40
    22
        Parent perception - EOS - pleasant
    26
    19
        Parent perception - early withdrawal - unpleasant
    1
    0
        Parent perception - early withdrawal - not sure
    3
    0
        Parent perception - early withdrawal - pleasant
    1
    0
        Parent admin problems - week 4 - yes
    6
    1
        Parent admin problems - week 4 - no
    107
    58
        Parent admin problems - EOS - yes
    5
    0
        Parent admin problems - EOS - no
    102
    55
        Parent admin - early withdrawal - yes
    0
    0
        Parent admin - early withdrawal - no
    5
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study, Visits 4 and 7 (month 1), at Visit 9 (month 2), at Visit 10 (month 3), at Visit 11 (month 6), at Visit 12 (month 9), at Visit 13 (month 12), at Visit 14 (month 15), at Visit 15 (EOS, month 18) and at the FUV (ie, 4 weeks ± 7 days).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Givinostat SAF
    Reporting group description
    Givinostat oral suspension (10 mg/mL) twice daily. The Safety set (SAF) consisted of all randomized subjects who received at least one dose of the IMP. The SAF population was analyzed according to the actual treatment received and was used to present results on safety data.

    Reporting group title
    Placebo SAF
    Reporting group description
    Placebo oral suspension (10 mg/mL) twice daily. The Safety set (SAF) consisted of all randomized subjects who received at least one dose of the IMP. The SAF population was analyzed according to the actual treatment received and was used to present results on safety data.

    Serious adverse events
    Givinostat SAF Placebo SAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 118 (6.78%)
    2 / 61 (3.28%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 118 (0.85%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Givinostat SAF Placebo SAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 118 (88.14%)
    55 / 61 (90.16%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    6 / 118 (5.08%)
    0 / 61 (0.00%)
         occurrences all number
    6
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 118 (7.63%)
    0 / 61 (0.00%)
         occurrences all number
    10
    0
    Pyrexia
         subjects affected / exposed
    15 / 118 (12.71%)
    5 / 61 (8.20%)
         occurrences all number
    18
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 118 (11.02%)
    9 / 61 (14.75%)
         occurrences all number
    13
    9
    Epistaxis
         subjects affected / exposed
    8 / 118 (6.78%)
    5 / 61 (8.20%)
         occurrences all number
    21
    9
    Oropharyngeal pain
         subjects affected / exposed
    7 / 118 (5.93%)
    1 / 61 (1.64%)
         occurrences all number
    8
    1
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    11 / 118 (9.32%)
    4 / 61 (6.56%)
         occurrences all number
    14
    4
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    14 / 118 (11.86%)
    3 / 61 (4.92%)
         occurrences all number
    19
    6
    Platelet count decreased
         subjects affected / exposed
    21 / 118 (17.80%)
    0 / 61 (0.00%)
         occurrences all number
    26
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    11 / 118 (9.32%)
    3 / 61 (4.92%)
         occurrences all number
    32
    6
    Fall
         subjects affected / exposed
    15 / 118 (12.71%)
    13 / 61 (21.31%)
         occurrences all number
    24
    18
    Ligament sprain
         subjects affected / exposed
    8 / 118 (6.78%)
    3 / 61 (4.92%)
         occurrences all number
    9
    4
    Limb Injury
         subjects affected / exposed
    6 / 118 (5.08%)
    2 / 61 (3.28%)
         occurrences all number
    8
    2
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    8 / 118 (6.78%)
    1 / 61 (1.64%)
         occurrences all number
    12
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 118 (23.73%)
    14 / 61 (22.95%)
         occurrences all number
    41
    30
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    19 / 118 (16.10%)
    0 / 61 (0.00%)
         occurrences all number
    27
    0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    6 / 118 (5.08%)
    3 / 61 (4.92%)
         occurrences all number
    11
    4
    Eye disorders
    Eye disorders
         subjects affected / exposed
    5 / 118 (4.24%)
    4 / 61 (6.56%)
         occurrences all number
    8
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    25 / 118 (21.19%)
    9 / 61 (14.75%)
         occurrences all number
    52
    16
    Abdominal pain upper
         subjects affected / exposed
    17 / 118 (14.41%)
    7 / 61 (11.48%)
         occurrences all number
    21
    9
    Constipation
         subjects affected / exposed
    8 / 118 (6.78%)
    1 / 61 (1.64%)
         occurrences all number
    9
    1
    Diarrhoea
         subjects affected / exposed
    43 / 118 (36.44%)
    11 / 61 (18.03%)
         occurrences all number
    117
    16
    Dyspepsia
         subjects affected / exposed
    2 / 118 (1.69%)
    4 / 61 (6.56%)
         occurrences all number
    3
    4
    Nausea
         subjects affected / exposed
    8 / 118 (6.78%)
    4 / 61 (6.56%)
         occurrences all number
    9
    6
    Vomiting
         subjects affected / exposed
    34 / 118 (28.81%)
    8 / 61 (13.11%)
         occurrences all number
    64
    12
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 118 (9.32%)
    1 / 61 (1.64%)
         occurrences all number
    18
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 118 (5.08%)
    8 / 61 (13.11%)
         occurrences all number
    9
    8
    Myalgia
         subjects affected / exposed
    11 / 118 (9.32%)
    2 / 61 (3.28%)
         occurrences all number
    18
    2
    Pain in extremity
         subjects affected / exposed
    8 / 118 (6.78%)
    7 / 61 (11.48%)
         occurrences all number
    14
    10
    Infections and infestations
    Ear infection
         subjects affected / exposed
    3 / 118 (2.54%)
    4 / 61 (6.56%)
         occurrences all number
    5
    4
    Gastroenteritis
         subjects affected / exposed
    9 / 118 (7.63%)
    3 / 61 (4.92%)
         occurrences all number
    12
    3
    Influenza
         subjects affected / exposed
    3 / 118 (2.54%)
    4 / 61 (6.56%)
         occurrences all number
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    31 / 118 (26.27%)
    19 / 61 (31.15%)
         occurrences all number
    50
    27
    Rhinitis
         subjects affected / exposed
    6 / 118 (5.08%)
    7 / 61 (11.48%)
         occurrences all number
    11
    8
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 118 (5.93%)
    8 / 61 (13.11%)
         occurrences all number
    9
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 118 (6.78%)
    0 / 61 (0.00%)
         occurrences all number
    10
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    14 / 118 (11.86%)
    1 / 61 (1.64%)
         occurrences all number
    22
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2016
    Final Protocol Version 1.0 dated 07 MAY 2016 was amended for the following reasons: • To amend the wording of an inclusion criterium to limit the exclusion of patient due to operator error of stopwatch. • To amend the stratification process at randomization, including 2 additional strata based on type of steroids because new data suggest that Deflazacort use is associated with more prolonged time to loss of ambulation and increased frequency of side effects. • To change the MRI cohort in MR cohort because the magnetic resonance spectroscopy (MRS) exam was added at the same time points of MRI test. The reason of the inclusion of MRS is explained in the next bullet point. • To change the Key secondary endpoints in the MR cohort related to imaging data using the data from MRS instead of MRI data by 3 point-Dixon technique. Both teniques are responsive to disease progression, but MRS is considered the gold standard for quantification of drug effects in vivo, and Fat Fraction measures from single-voxel spectroscopy have been shown to be associated with function in DMD. Moreover, MRS is the most direct and sensitive approach to discriminate water and fat proton component signals in MR. • To amend the wording of an exclusion criterium related to MR cohort in order to include also MRS exam. • To specify the type of Raven progressive matrices to be used for assessing the cognitive function. • To better clarify the pharmacokinetics procedures, by limiting the decision of site personnel to collect the PK samples • To allow personnel authorized by the Investigator to perform blood collection during visits 5, 6 and 8 in order to facilitate the management of these visits. • to correct some typographic mistakes existing in the final protocol version 1.0 (dated 07 MAY 2016).
    05 Sep 2016
    Final Protocol Version 2.0 dated 13 JUL 2016 was amended for the following reasons: · To address relevant GNAs regarding to the VHP procedure VHP934 (VHP2016102); · To add the acceptability/palatability test as suggested by PDCO during the PIP discussion; · To better clarify the pharmacokinetics sampling and procedures; · To better clarify the time window of the Visits; · To update the functional algorithm after an additional discussion was performed with the statistician to include also 6MWT in the algorithm; · To specify the videos procedures which will be followed to ensure and maintain during the study, quality standard of functional evaluators; · To add “age” as covariate in the statistical analysis as discussed with the PDCO during the PIP discussion. . to correct some misleading or unclear sentences existing in the final protocol version 2.0 (dated 13 JUL 2016).
    12 Jul 2017
    Final Protocol Version 3.0 dated 05 SEP 2016 (For European sites) and Final Protocol Version 3.1 dated 04 OCT 2016 were amended for the main following reasons: · To address relevant FDA comments regarding to the ‘May Proceed Letter’ (dated 18Oct2016); · To modify the exclusion criterion n.1 related to the exposure to another investigational drug (only for the European sites because for the US and Canada sites the criterion was already amended); · To modify the exclusion criterion n. 6 related to the ankle joint contractures to render it more applicable to the target population and to permit the recruitment of a wider number of children affected by Duchenne Muscular Dystrophy; · To better clarify the pharmacokinetics sampling and procedures; · To better clarify the time window of some assessments; · To add a blood sample for the evaluation of serum biomarkers related to DMD and to insert them as exploratory assessments and endpoints; · To add in the schedule of Assessment the possibility to perform the genetic test to confirm the diagnosis of DMD, as requested in the relevant inclusion criterion. . to correct some misleading or unclear sentences existing in the final protocol versions 3.0 and 3.1 (dated 05 SEP 2016 and 04 OCT 2016).
    19 Oct 2018
    Final Protocol Version 4.0 dated 12 Jul 2017 is amended for the main following reasons: 1. To address safety issue. 2. To safeguard subject safety, a new exclusion criterion is added to the protocol excluding subjects with triglycerides > 300 mg/dL (3.42 mmol/L). 4. To increase the frequency of thyroid function monitoring (TSH, fT3 and fT4 assessments) to ensure patient safety. 5. To address the IDMC recommendation a complete blood count (CBC) test assessment has to be performed weekly for 8 consecutive weeks if the dose is reduced due to platelet count ≤150 x 109/L and/or white blood cell <3.0 x 109/L and/or hemoglobin <10.0 mg/dL for safety reasons. 6. To guarantee a right safety evaluation, spirometry should be repeated if the test does not meet ATS/ERS criteria and/or the evaluator deems that a valid attempt to perform a correct maneuver has not been made by the subject. 7. To update the Inclusion criterion #6 from “Have time to rise from floor of < 10 seconds at screening” to “Have time to rise from floor ≥ 3 seconds and < 10 seconds at screening”. The “time to rise” lower boundary is selected to avoid subjects who will not have enough function decline in 18 months if on placebo. 8. To update the Inclusion criterion #7 from “Have manual muscle testing (MMT) of quadriceps at screening ≥ Grade 3” to “Have manual muscle testing (MMT) of quadriceps at screening ≥ Grade – 3”, to permit recruiting of a wider no. of subjects. 9. To remove the Inclusion criterion (Criterion #8) 10. To update the Inclusion criterion #9 (#8 in the amended protocol). 11. 11. To update the Exclusion criterion #4
    29 Aug 2019
    Final Protocol Version 6.0 dated 19 October 2018 is amended for the main following reasons: 1. In the original protocol sample size was calculated using publicly available standard deviation (SD), in particular from DMD Phase 3 study data on ataluren and drisapersen, where subjects have specific DMD genetic mutations (ie. Skippable 51 mutations or non-sense mutations). Since in the current protocol, inclusion of subjects is not depending on type of DMD genetic mutation, in case the Standard Deviation (SD) in the current study population will be lower than the estimated SD stated in the protocol, the sponsor believes appropriate to reduce the sample size of the study. Due to this, statistiscal analysis section is updated accordingly. 2. To update the background of givinostat regarding non clinical studies and clinical experience on risks and benefits section according to the new Investigator Brochure version 20 - July 2019. 3. To correct some typographic mistakes and/or clarify some paragraphs of Protocol version 6.0 (dated 19 Oct 2018) that could be unclear.
    08 Apr 2020
    1. To amend the protocol based on the results of the pre-planned futility interim analysis as described in protocol version 7.0, performed in January 2020: it was concluded that futility on VLFF was not met and the trial should continue. 2. To amend the effect size, in 4SC 18 month change from baseline, from 3 seconds to 2 seconds. The Sponsor considers more appropriate 2 seconds based on the recent analyses performed by C-Tap (Wong B, et al. Action Duchenne International Conference, November 9–11, 2018, Birmingham, UK), where the minimally clinically important difference (MCID) for timed function tests (TFTs) in DMD was estimated at ~1.0 to 1.6 seconds. 3. Update the no. of subjects to be included in the MR cohort following the blinded sample size re-estimation done during the interim analysis in January 2020. 4. To cancel the second interim analysis following the recommendation made by FDA during the Type C meeting in October 2019. Since the second interim analysis has been deleted, the imaging endpoint has been moved to Key efficacy Endpoint. 5. To include an additional analytic method for the NSAA assessment. 6. To update the “Background on DMD” paragraph following the recent NDA approval received by Sarepta for the treatment of DMD boys. 7. To correct some typographic mistakes and/or clarify some paragraphs of Protocol version 7.0 that could be unclear.

    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 and caveats are applicable to this summary of results.
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