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    Clinical Trial Results:
    A Phase 3, Multi-centre, Randomised, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of SD-101 Cream in Patients with Epidermolysis Bullosa

    Summary
    EudraCT number
    		 2014-002288-14
    Trial protocol
    		 AT   NL   GB   IT   DE   PL   ES   LT   BE  
    Global end of trial date
    05 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SD-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02384460
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Scioderm, Inc., An Amicus Therapeutics Company
    Sponsor organisation address
    1 Cedar Brook Drive, Cranbury, United States, NJ 08512
    Public contact
    Patient Advocacy, Amicus Therapeutics, Inc, clinicaltrials@amicusrx.com
    Scientific contact
    Patient Advocacy, Amicus Therapeutics, Inc, clinicaltrials@amicusrx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001590-PIP01-13
    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
    05 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the efficacy and safety of SD-101-6.0 versus SD-101-0.0 (placebo) in subjects with simplex, recessive dystrophic, or junctional non-Herlitz epidermolysis bullosa (EB).
    Protection of trial subjects
    This study was designed and monitored in accordance with sponsor procedures, which comply with the ethical principles of Good Clinical Practice, as required by the major regulatory authorities and in accordance with the Declaration of Helsinki and its updates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 2015
    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: 3
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    United States: 60
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    Israel: 6
    Worldwide total number of subjects
    169
    EEA total number of subjects
    76
    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)
    11
    Children (2-11 years)
    84
    Adolescents (12-17 years)
    31
    Adults (18-64 years)
    42
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of 210 subjects screened for this study, 169 subjects were randomly assigned, on a 1:1 basis, to treatment with SD-101-6.0 or placebo at 31 study centres in 13 countries. The first subject was enrolled on 11 March 2015 and the last subject completed the study on 05 July 2017.

    Pre-assignment
    Screening details
    		 Subjects had to be 1 month of age or older with a diagnosis of simplex, recessive dystrophic, or junctional non-Herlitz EB and a target wound with a surface area of 10 to 50 cm^2 in size and at least 21 days old to be considered for participation in the study. Subjects who did not meet all inclusion/exclusion criteria were eligible for rescreening.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    All study centre personnel, subjects, and the sponsor were blinded to study drug assignment. Tubes of study drug were identical and SD-101-6.0 and SD-101-0.0 (placebo) were indistinguishable with regard to appearance, smell, and sensation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SD-101-6.0
    Arm description
    		 Subjects applied SD-101-6.0 cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SD-101-6.0
    Investigational medicinal product code
    Other name
    Allantoin 6% concentration, Zorblisa
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    SD-101 is a white, crystalline powder that is formulated within an odourless, soft, white cream base. SD-101-6.0 cream contains allantoin, a diureide glyoxlylic acid, at a concentration of 6% and other excipients. Subjects applied the cream topically, once a day to the entire body.

    Arm title
    		 Placebo
    Arm description
    		 Subjects applied SD-101-0.0 (placebo) cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.
    Arm type
    		 Placebo

    Investigational medicinal product name
    SD-101-0.0
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    SD-101 is a white, crystalline powder that is formulated within an odourless, soft, white cream base. SD-101-0.0 (placebo) cream contains no allantoin, but otherwise contains the same excipients as SD-101-6.0. Subjects applied the cream topically, once a day to the entire body.

    Number of subjects in period 1
    		SD-101-6.0 Placebo
    Started
    82
    87
    Completed
    75
    80
    Not completed
    7
    7
         Other: elective medical treatment
    1
    -
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    5
    2
         Other: non compliance
    1
    -
         Other: returned to previous therapeutic regimen
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SD-101-6.0
    Reporting group description
    		 Subjects applied SD-101-6.0 cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects applied SD-101-0.0 (placebo) cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.

    Reporting group values
    		 SD-101-6.0 Placebo Total
    Number of subjects
    		 82 87 169
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 5 6 11
        Children (2-11 years)
    		 37 47 84
        Adolescents (12-17 years)
    		 19 12 31
        Adults (18-64 years)
    		 21 21 42
        From 65-84 years
    		 0 1 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.8 ( 13.15 ) 13.9 ( 13.12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 33 48 81
        Male
    		 49 39 88
    Race
    Units: Subjects
        White/Caucasian
    		 69 72 141
        Black/African American
    		 5 3 8
        Asian
    		 4 8 12
        Other
    		 1 1 2
        Not Reported
    		 3 3 6
    EB type
    Units: Subjects
        Simplex
    		 10 8 18
        Recessive dystrophic
    		 57 62 119
        Junctional non-Herlitz
    		 15 17 32

    End points

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    End points reporting groups
    Reporting group title
    SD-101-6.0
    Reporting group description
    		 Subjects applied SD-101-6.0 cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects applied SD-101-0.0 (placebo) cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.

    Primary: Time to Complete Target Wound Closure Within 3 Months.

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    End point title
    		 Time to Complete Target Wound Closure Within 3 Months.
    End point description
    Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialisation without drainage. Time to target wound closure was measured from the date of the first administration of the study drug to the date of target wound closure. Subjects were censored if they did not have a response within 3 months, or withdrew earlier before the confirmation of their target wound closing. This primary end point displays the mean time to complete target wound closure, analysed using a Kaplan-Meier approach. Analysis was performed on subjects from the intent-to-treat (ITT) population with post-baseline wound closure data and whose target wound had closed within 3 months.
    End point type
    Primary
    End point timeframe
    From baseline to Month 3 visit
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    39 [1]
    45 [2]
    Units: Days
        arithmetic mean (standard deviation)
    41.6 ( 25.50 )
    53.6 ( 28.59 )
    Notes
    [1] - Number of subjects analysed were those whose target wound had closed within 3 months.
    [2] - Number of subjects analysed were those whose target wound had closed within 3 months.
    Statistical analysis title
    		 Cox Model Analysis
    Statistical analysis description
    Cox proportional hazards model compares treatment groups with baseline target wound size, target wound age and EB type as covariates.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.985 [3]
    Method
    		 Cox Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.651
         upper limit
    		 1.549
    Notes
    [3] - p-value is from Type 3 tests to present as overall p-value for each term in the model.

    Primary: Percentage of Subjects Experiencing Complete Closure of The Target Wound Within 3 Months

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    End point title
    		 Percentage of Subjects Experiencing Complete Closure of The Target Wound Within 3 Months
    End point description
    Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialisation without drainage. Subjects were considered responders if they experienced complete wound closure at the Week 2 or Months 1, 2, or 3 visits. If a target wound was documented to have closed at a given visit, it was considered closed at all subsequent visits. This primary end point displays the percentage of subjects from the ITT population who had complete target wound closure by the end of the study period (i.e. 3 months). Analysis was performed on subjects with post-baseline wound closure data.
    End point type
    Primary
    End point timeframe
    From baseline to Month 3 visit
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    79
    84
    Units: Percentage of Subjects
        number (not applicable)
    49.4
    53.6
    Statistical analysis title
    		 Logistic Regression Analysis
    Statistical analysis description
    Comparison between treatment groups of complete closure of target wound within 3 months was performed using logisitic regression modelling with multiple imputation.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.39 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.733
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.365
         upper limit
    		 1.474
    Notes
    [4] - Multiple imputation is implemented by two steps. First step using Markov Chain Monte Carlo (MCMC) to get monotonic missing data pattern. In second step, a logistic regression model is used, with the following covariates included in the imputation model: treatment, EB type, baseline target wound size, target wound age, and non-missing data from earlier time points. The seed number is 010005 and the number of imputations is 5.
    [5] - p-value is from Type 3 tests to present as overall p-value for each term in the model

    Secondary: Percentage of Subjects Experiencing Complete Closure of The Target Wound at Month 1 and Month 2 Visits

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    End point title
    		 Percentage of Subjects Experiencing Complete Closure of The Target Wound at Month 1 and Month 2 Visits
    End point description
    Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialisation without drainage. The percentage of subjects who completed target wound closure at the Month 1 and Month 2 study visits is displayed. If a target wound was documented to have closed at a given visit, it was considered closed at all subsequent visits. Analysis was performed on subjects from the ITT population with post-baseline wound closure data.
    End point type
    Secondary
    End point timeframe
    From baseline to Month 1 and Month 2 visits
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    79
    84
    Units: Percentage of Subjects
    number (not applicable)
        Month 1
    31.6
    22.6
        Month 2
    43.0
    42.9
    Statistical analysis title
    		 Logistic Regression Analysis at Month 1
    Statistical analysis description
    Comparison between treatment groups of complete closure of target wound within 1 month was performed using logisitic regression modelling with multiple imputation.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.212 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.633
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.758
         upper limit
    		 3.517
    Notes
    [6] - Multiple imputation is implemented by two steps. First step using MCMC to get monotonic missing data pattern. In second step, a logistic regression model is used, with the following covariates included in the imputation model: treatment, EB type, baseline target wound size, target wound age, and non-missing data from earlier time points. The seed number is 010005 and the number of imputations is 5.
    [7] - p-value is from Type 3 tests to present as overall p-value for each term in the model
    Statistical analysis title
    		 Logistic Regression Analysis at Month 2
    Statistical analysis description
    Comparison between treatment groups of complete closure of target wound within 2 months was performed using logisitic regression modelling with multiple imputation.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.802 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.891
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.436
         upper limit
    		 1.821
    Notes
    [8] - Multiple imputation is implemented by two steps. First step using MCMC to get monotonic missing data pattern. In second step, a logistic regression model is used, with the following covariates included in the imputation model: treatment, EB type, baseline target wound size, target wound age, and non-missing data from earlier time points. The seed number is 010005 and the number of imputations is 5.
    [9] - p-value is from Type 3 tests to present as overall p-value for each term in the model

    Secondary: Change from Baseline in Body Surface Area Index (BSAI) of Lesional Skin at Month 3 Visit

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    End point title
    		 Change from Baseline in Body Surface Area Index (BSAI) of Lesional Skin at Month 3 Visit
    End point description
    Lesional skin was defined as areas that contained any of the following: blisters, erosions, ulcerations, scabbing, bullae, or eschars, as well as areas that were weeping, sloughing, oozing, crusted, or denuded. BSAI was calculated as a percentage, ranging from 0% to 100%, of affected body surface area, recorded for each defined body region (ie, head/neck, upper limbs, trunk [includes groin], and lower limbs), multiplied by the weighting factor, then summed for all body regions. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to Month 3 visit
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    75
    78
    Units: Percentage of BSAI
        least squares mean (standard error)
    -4.637 ( 1.404 )
    -5.319 ( 1.354 )
    Statistical analysis title
    		 Mixed Model Repeated Measures (MMRM) Analysis
    Statistical analysis description
    The MMRM approach (using restricted maximum likelihood [REML] estimation) is used on each multiply-imputed data set. The model includes treatment, baseline BSAI of lesional skin, EB type, visit, and visit-treatment interaction as the fixed effects.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.706 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    0.682
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.873
         upper limit
    		 4.238
    Notes
    [10] - Multiple imputation is used by two steps. First step using MCMC to get monotonic missing data pattern. In second step, a linear regression model is used, with the following covariates included in the imputation model: treatment, EB type, baseline BSAI of lesional skin, and non-missing data from earlier time points. The seed number is 010005 and the number of imputations is 5.
    [11] - The p-value is calculated based on the hypothesis testing for the difference of LS-means between treatment and placebo.

    Secondary: Change from Baseline in BSAI of Total Body Wound Burden at Month 3 Visit

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    End point title
    		 Change from Baseline in BSAI of Total Body Wound Burden at Month 3 Visit
    End point description
    Total body wound burden was calculated using BSAI. A wound was defined as an open area on the skin (ie, epidermal covering disrupted). BSAI was calculated as a percentage, ranging from 0% to 100%, of affected body surface area, recorded for each defined body region (ie, head/neck, upper limbs, lower limbs,trunk [includes groin], and multiplied by the weighting factor, then summed for all body regions. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to Month 3 visit
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    75
    79
    Units: Percentage of BSAI
        least squares mean (standard error)
    -3.050 ( 0.816 )
    -2.922 ( 0.813 )
    Statistical analysis title
    		 MMRM Analysis
    Statistical analysis description
    The MMRM approach (using REML estimation) is used on each multiply-imputed data set. The model includes treatment, baseline BSAI of lesional skin, EB type, visit, and visit-treatment interaction as the fixed effects.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.9 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.116
         upper limit
    		 1.861
    Notes
    [12] - Multiple imputation is used by two steps. First step using MCMC to get monotonic missing data pattern. In second step, a linear regression model is used, with the following covariates included in the imputation model: treatment, EB type, baseline BSAI of lesional skin, and non-missing data from earlier time points. The seed number is 010005 and the number of imputations is 5.
    [13] - The p-value is calculated based on the hypothesis testing for the difference of LS-means between treatment and placebo.

    Secondary: Change from Baseline in Itching Score at Day 7

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    End point title
    		 Change from Baseline in Itching Score at Day 7
    End point description
    Itching was assessed using the 5 point Itch Man Pruritus Assessment Tool. For subjects up to 5 years of age itching was assessed using caretaker’s response and subjects 6 years of age and older self-reported their itching assessments based on the following scores: 0=Comfortable, no itch, 1=itches a little, does not interfere with activity, 2=itches more, sometimes interferes with activity, 3=itches a lot, difficult to be still, concentrate, 4=itches most terribly, impossible to sit still or concentrate. Itching scores were categorised into three groups based on improvement: Improved or No Itching, Not Improved, and Missing. An itching score reduction from baseline greater than or equal to 1 point on the scale was classed as improved. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to Day 7
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    77
    79
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.5 ( 1.31 )
    -0.3 ( 1.24 )
    Statistical analysis title
    		 Logistic Regression Analysis
    Statistical analysis description
    The proportion of subjects experiencing improvement in itching versus non-improvement (including missing) was compared between the two treatment groups for Day 7 using the logistic regression model with baseline itching score, and EB type as covariates.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.262 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.445
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.759
         upper limit
    		 2.752
    Notes
    [14] - p-value is from Type 3 Tests to present as overall p-value for each term in the model.

    Secondary: Change from Baseline in Pain Score at Day 7

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    End point title
    		 Change from Baseline in Pain Score at Day 7
    End point description
    Change in pain assessed at Day 7, compared to baseline was measured using the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioural Scale for subjects 1 month to 3 years of age. Each of the five FLACC categories is scored from 0-2, which results in a total score between 0 and 10 with 0=Relaxed and comfortable, 1-3=Mild discomfort, 4-6=Moderate pain and 7-10=Severe discomfort/pain. For Subjects 4 years of age and older the “Wong Faces Pain Scale” was used. This scale shows a series of faces ranging from a happy face at 0 which represents "no hurt" to a crying face at 10 which represents "hurts worst". Pain scores were categorised into three groups based on improvement: Improved or No Pain, Not Improved, and Missing. A pain score reduction from baseline greater than or equal to 2 points on the scale was classed as improved. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to Day 7
    End point values
    		 SD-101-6.0 Placebo
    Number of subjects analysed
    77
    80
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.3 ( 2.57 )
    -0.6 ( 3.07 )
    Statistical analysis title
    		 Logistic Regression Analysis
    Statistical analysis description
    The proportion of subjects experiencing improvement in pain versus non-improvement (including missing) was compared between the two treatment groups for Day 7 using the logistic regression model with baseline pain score, and EB type as covariates.
    Comparison groups
    SD-101-6.0 v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.098 [15]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.596
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.323
         upper limit
    		 1.1
    Notes
    [15] - p-value is from Type 3 Tests to present as overall p-value for each term in the model.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to 3 months.
    Adverse event reporting additional description
    Adverse events (AE) were defined as treatment emergent (TEAEs) if the AE occurred on or after the first date of application of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SD-101-6.0
    Reporting group description
    		 Subjects applied SD-101-6.0 cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects applied SD-101-0.0 (placebo) cream once a day for a period of 90 days. The first study drug treatment was applied at the study centre after randomisation and completion of baseline assessments. Efficacy measurements and safety assessments were carried out at study visits at Week 2 and Months 1, 2 and 3.

    Serious adverse events
    		 SD-101-6.0 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 82 (4.88%)
    8 / 87 (9.20%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 SD-101-6.0 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 82 (59.76%)
    46 / 87 (52.87%)
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 87 (3.45%)
         occurrences all number
    2
    3
    Fall
         subjects affected / exposed
    3 / 82 (3.66%)
    1 / 87 (1.15%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 82 (3.66%)
    2 / 87 (2.30%)
         occurrences all number
    3
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 82 (6.10%)
    9 / 87 (10.34%)
         occurrences all number
    6
    12
    Pain
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 87 (4.60%)
         occurrences all number
    1
    4
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 87 (2.30%)
         occurrences all number
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 82 (4.88%)
    4 / 87 (4.60%)
         occurrences all number
    4
    6
    Rhinorrhoea
         subjects affected / exposed
    2 / 82 (2.44%)
    4 / 87 (4.60%)
         occurrences all number
    2
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 82 (10.98%)
    8 / 87 (9.20%)
         occurrences all number
    11
    8
    Blister
         subjects affected / exposed
    3 / 82 (3.66%)
    2 / 87 (2.30%)
         occurrences all number
    3
    3
    Rash
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 87 (3.45%)
         occurrences all number
    2
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 87 (2.30%)
         occurrences all number
    2
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 82 (13.41%)
    3 / 87 (3.45%)
         occurrences all number
    12
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 82 (4.88%)
    9 / 87 (10.34%)
         occurrences all number
    5
    11
    Skin infection
         subjects affected / exposed
    3 / 82 (3.66%)
    9 / 87 (10.34%)
         occurrences all number
    5
    11
    Wound infection
         subjects affected / exposed
    6 / 82 (7.32%)
    5 / 87 (5.75%)
         occurrences all number
    8
    5
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 82 (1.22%)
    6 / 87 (6.90%)
         occurrences all number
    1
    7
    Ear infection
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 87 (4.60%)
         occurrences all number
    1
    4
    Pharyngitis
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 87 (4.60%)
         occurrences all number
    1
    4
    Skin bacterial infection
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 87 (4.60%)
         occurrences all number
    1
    5
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 87 (4.60%)
         occurrences all number
    1
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2014
    • The primary efficacy endpoint was clarified to be complete closure of the target wound within 2 months. • Median time to complete target wound closure was added as a secondary efficacy endpoint. • Some secondary efficacy endpoints were re-categorised. • Sample size was increased from 90 subjects to 130 subjects and the number of study centres was increased from 10 to 15. • The option to enter Study SD-006, extension study, was added. • The minimum target lesion size specified was increased from 5 cm^2 to 10 cm^2 based on results from Study SD-003. • Investigator responsibilities for reporting Serious AEs was added at the request of a European regulatory agency. •A statement indicating that a draft statistical analysis plan (SAP) would be completed before randomisation of the first subject was added, as requested by Food and Drugs Administration (FDA). • Regulatory requirements were broadened to include those that are applicable outside the United States, at the request of European regulatory agencies.
    19 Sep 2016
    • The single primary endpoint (i.e, complete target wound closure within 2 months) was revised to be 2 co-primary efficacy endpoints: the time to complete target wound closure within 3 months and the proportion of subjects experiencing complete target wound closure within 3 months. • Estimation of total body wound burden was re-categorised from an exploratory efficacy endpoint to be a secondary efficacy endpoint. • Secondary efficacy endpoints were added to capture the proportion of subjects experiencing complete target wound closure within 2 months and 1 month. • Exploratory efficacy endpoints were added to capture percentage change from baseline in total body wound burden and lesional skin based on BSAI at additional time points. • Enrollment was changed from approximately 130 subjects to up to 150 subjects to allow for 2 potential interim analyses after ~90 and ~125 subjects were enrolled. • Statistical methods were modified to support the evaluation of co-primary and secondary endpoints in a step-down procedure while controlling the type I error rate and addressing multiplicity.
    10 Mar 2017
    • Co-primary efficacy endpoints were renamed as 2 primary efficacy endpoints for consistency with the SAP in response to comments from FDA. Secondary efficacy endpoints were renamed as key secondary efficacy endpoints, and exploratory endpoints were renamed as other secondary efficacy endpoints. • Other secondary efficacy endpoints were re-ordered to reflect the SAP and change in target wound characteristics was added as another secondary efficacy endpoint. • The interim analyses were omitted because enrollment increased and it was no longer considered necessary.

    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.
    None reported
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