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    Clinical Trial Results:
    An International, Multicenter, Randomized, Double-Blind, Parallel-Group Phase 2 Study Evaluating the Safety and Efficacy of Diacerein 1% Ointment Topical Formulation in Subjects with Epidermolysis Bullosa Simplex (EBS) [DELIVERS Study]

    Summary
    EudraCT number
    2016-004427-24
    Trial protocol
    DE   AT   NL   GB   FR  
    Global end of trial date
    31 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Oct 2019
    First version publication date
    30 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCP-020-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03154333
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND: 131 384
    Sponsors
    Sponsor organisation name
    Castle Creek Pharmaceuticals, LLC
    Sponsor organisation address
    6 Century Drive , Parsippany, NJ , United States, NJ 07054
    Public contact
    Dr. Mary Spellman, Castle Creek Pharmaceuticals, LLC , 001 8622860400, mspellman@castlecreekpharma.com
    Scientific contact
    Dr. Mary Spellman, Castle Creek Pharmaceuticals, LLC , 001 8622860400, mspellman@castlecreekpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to compare the efficacy of diacerein 1% ointment to control ointment when applied once daily for 8 weeks in subjects with epidermolysis bullosa simplex (EBS).
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonization (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 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
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Netherlands: 4
    Worldwide total number of subjects
    54
    EEA total number of subjects
    24
    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)
    37
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    12
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were screened for inclusion and exclusion criteria at Visit 1 (Week -6). Subjects must have had a genotypic confirmation of an EBS protocol-defined mutation through prior genetic testing or via a blood or saliva genetic assessment as part of the study.

    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
    Blinding implementation details
    This study used a double-blind design. The study drugs were indistinguishable in appearance, packaging, and labeling.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Diacerein 1%
    Arm description
    At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive diacerein 1% ointment to all EBS lesions in the Assessment Area.
    Arm type
    Experimental

    Investigational medicinal product name
    Diacerein
    Investigational medicinal product code
    CCP-020
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    During the 8-week Treatment Period, Diacerein was administered from Visit 2 (Week 0) to Visit 6 (Week 8) once daily in the evening to EBS lesions in the Assessment Area (regardless of lesion resolution) and Treatment Area (until lesion(s) resolution). The subject/caregiver applied sufficient quantity of Diacerein to cover all EBS lesions and to approximately ¾ inch (2 cm) of uninvolved skin surrounding each lesion with a thin layer and gently rubbed it in.

    Arm title
    Control
    Arm description
    At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive control ointment to all EBS lesions in the Assessment Area.
    Arm type
    Placebo

    Investigational medicinal product name
    Control
    Investigational medicinal product code
    Other name
    Vehicle
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    During the 8-week Treatment Period, the control ointment was administered from Visit 2 (Week 0) to Visit 6 (Week 8) once daily in the evening to EBS lesions in the Assessment Area (regardless of lesion resolution) and Treatment Area (until lesion(s) resolution). The subject/caregiver applied sufficient quantity of the control ointment to cover all EBS lesions and to approximately ¾ inch (2 cm) of uninvolved skin surrounding each lesion with a thin layer and gently rubbed it in.

    Number of subjects in period 1
    Diacerein 1% Control
    Started
    28
    26
    Completed
    21
    21
    Not completed
    7
    5
         Study terminated by Sponsor
    6
    5
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Diacerein 1%
    Reporting group description
    At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive diacerein 1% ointment to all EBS lesions in the Assessment Area.

    Reporting group title
    Control
    Reporting group description
    At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive control ointment to all EBS lesions in the Assessment Area.

    Reporting group values
    Diacerein 1% Control Total
    Number of subjects
    28 26 54
    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)
    0 0 0
        Children (2-11 years)
    19 18 37
        Adolescents (12-17 years)
    1 4 5
        Adults (18-64 years)
    8 4 12
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    14 16 30
        Male
    14 10 24

    End points

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    End points reporting groups
    Reporting group title
    Diacerein 1%
    Reporting group description
    At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive diacerein 1% ointment to all EBS lesions in the Assessment Area.

    Reporting group title
    Control
    Reporting group description
    At Visit 2 (Week 0), eligible subjects randomized in a 1:1 ratio to receive control ointment to all EBS lesions in the Assessment Area.

    Primary: Achievement ≥60% reduction in BSA of EBS in the assessment area

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    End point title
    Achievement ≥60% reduction in BSA of EBS in the assessment area
    End point description
    The primary efficacy endpoint of this study was the proportion of subjects who achieved ≥60% reduction in body surface area (BSA) of Epidermolysis Bullosa Simplex (EBS) lesions within the Assessment Area from Baseline to Week 8.
    End point type
    Primary
    End point timeframe
    The primary efficacy endpoint was examined from Baseline/Visit 2 (Week 0) to Visit 6 (Week 8).
    End point values
    Diacerein 1% Control
    Number of subjects analysed
    28
    26
    Units: Subjects
    16
    14
    Statistical analysis title
    Comparison in ≥60% reduction in BSA of EBS
    Comparison groups
    Diacerein 1% v Control
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.9666
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1.62
    Notes
    [1] - Subjects who achieved ≥60% reduction in BSA of EBS lesions within the Assessment Area from Baseline to Week 8 for the diacerein 1% group compared to the control group for the ITT Population.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Week 0 Day 1 through the study until the end.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Diacerein 1%
    Reporting group description
    -

    Reporting group title
    Control
    Reporting group description
    -

    Serious adverse events
    Diacerein 1% Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 26 (7.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 26 (3.85%)
         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: 5%
    Non-serious adverse events
    Diacerein 1% Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 28 (78.57%)
    21 / 26 (80.77%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    4
    Skin abrasion
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Nasal congestion
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Nausea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 26 (3.85%)
         occurrences all number
    5
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Pruritus
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 28 (14.29%)
    2 / 26 (7.69%)
         occurrences all number
    4
    2
    Skin infection
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 26 (11.54%)
         occurrences all number
    4
    4
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 26 (7.69%)
         occurrences all number
    1
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Mar 2017
    Global Protocol Amendment 1, dated 17 March 2017. The key changes to the primary endpoint were as follows: - Removal of the LSA and addition of the IGA at Visit 8 (Week 16). - Inclusion Criterion 1 was updated to reflect an increase in the subject’s minimum age from 6 months to 4 years. - Inclusion Criterion 5 was revised to the minimum IGA score of 3. - PK sampling was removed from the protocol. - Genotyping criteria were expanded. - Sample size was recalculated.
    08 Jun 2017
    Global Protocol Amendment 2. The key changes were as follows: - Clarification of BSA of an EBS lesion and LSA Area. - Inclusion Criterion 2, clarification of eligibility criteria. - Inclusion Criterion 3, clarification of eligibility criteria. - Treatment Area clarified (not to exceed 30% BSA). - Inclusion Criterion 5 and 6,clarification of eligibility criteria. - An IDMC added to conduct interim analysis. - Exclusion Criterion 11 clarification of eligibility criteria. - Exclusion Criterion 12 clarification of eligibility criteria. - PK was added to protocol . - Subject withdrawals clarified. - Clarified study procedures and safety reporting, where necessary.
    02 Jan 2018
    Global Protocol Amendment 3a. - Clarification dose and treatment rationale. - Clarification risk and/or benefits to subjects. - Primary objective updated to include reduction in BSA of EBS lesions. - Secondary objective updated to include changes in IGA scores. - Primary endpoint updated. - Key secondary endpoint was added and other secondary endpoints were updated. - PK endpoints clarified. - eDiary instructions clarified and updated. - Number of sites were updated. - The list of permitted topical products and therapies was further updated. - Siblings of those enrolled were not allowed in the study, was removed. - Clarification on exclusion of subjects with controlled diabetes and HbA1c<6.5% . - Describing prohibited therapies was removed. - Instructions for treatment of EBS were clarified. - Laboratory tests updated. - Use of body charts to record the location of EBS lesion revised. - Definitions of occluded lesions clarified. - Pruritus and pain scales updated. - SAEs and AESI clarified. - Contraception methods clarified. - Safety methods updated to include ECG.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Oct 2018
    Following the interim analysis on 40 randomized subjects, the IDMC made the recommendation to the Sponsor to terminate the study on the basis that the primary BSA endpoint was unlikely to achieve statistical significance. Per this recommendation, Castle Creek terminated the study but allowed patients to roll over into a separate open-label extension study.
    -

    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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