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    Clinical Trial Results:
    A phase I/II study evaluating allogeneic mesenchymal stromal cells in adults with recessive dystrophic epidermolysis bullosa

    Summary
    EudraCT number
    2014-004500-30
    Trial protocol
    GB  
    Global end of trial date
    10 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Feb 2019
    First version publication date
    28 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADSTEM001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02323789
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Professor John A. McGrath, King's College London, 44 207188 6409, john.mcgrath@kcl.ac.uk
    Scientific contact
    Professor John A. McGrath, King's College London, 44 207188 6409, john.mcgrath@kcl.ac.uk
    Sponsor organisation name
    Guy's and St Thomas' NHS Foundation Trust
    Sponsor organisation address
    Great Maze Pond, London, United Kingdom, SE19RT
    Public contact
    Professor John A. McGrath, Guy's and St Thomas NHS Foundation Trust, 44 207188 6409, john.mcgrath@kcl.ac.uk
    Scientific contact
    Professor John A. McGrath, Guy's and St Thomas NHS Foundation Trust, 44 207188 6409, john.mcgrath@kcl.ac.uk
    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
    12 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of allogeneic intravenously administered MSCs in adults with RDEB over a 12-month period
    Protection of trial subjects
    Study participants will be instructed that further information can be obtained at any time from the Investigator, and that they are free to withdraw their consent and to discontinue participation in the study at any time without prejudice
    Background therapy
    The study subjects can continue to receive their regular medication(s).
    Evidence for comparator
    n/a
    Actual start date of recruitment
    12 Jun 2015
    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: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Guy‟s and St Thomas‟ NHS Trust is a local, regional and national referral centre for adults with EB with an extensive database. Trial participants were recruited from this one site during 2017-2017.

    Pre-assignment
    Screening details
    The screening assessments (V1) will be conducted up to 200 days prior to Day 0. Inclusion Criteria 1) Individuals with a diagnosis of RDEB confirmed by DNA analysis. 2) Individuals 18 years of age or above, and under the age of 65, both male and female 3) Individuals that have voluntarily signed and dated an informed consent form (ICF) prior to

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Phase I/II, non-randomised, open-label trial.

    Arms
    Arm title
    Full study
    Arm description
    8 visits over 12 months are planned for the first eight eligible patients, and over 8 months for the last two eligible patients. Each study subject will receive two intravenous infusions (day 0 and day 14).
    Arm type
    Experimental

    Investigational medicinal product name
    TC-MSC (mesenchymal stem cells)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    TC-MSC (mesenchymal stem cells received two intravenous infusions (day 0 and day 14).

    Number of subjects in period 1
    Full study
    Started
    10
    Completed
    9
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    10 10
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    10 10
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    5 5
        Male
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Full study
    Reporting group description
    8 visits over 12 months are planned for the first eight eligible patients, and over 8 months for the last two eligible patients. Each study subject will receive two intravenous infusions (day 0 and day 14).

    Primary: Safety

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    End point title
    Safety [1]
    End point description
    Lack of serious and severe adverse events (SAEs) related to the administration of the investigational medicinal product over a 8 or a 12 month period. SAEs are defined as any occurrence related to the administration of the IMP that results in death, or is life threatening or requires hospitalization or prolongation of existing hospitalization.
    End point type
    Primary
    End point timeframe
    Up to 12 months post first infusion
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See attached document for all results and charts for both primary and secondary endpoints.
    End point values
    Full study
    Number of subjects analysed
    9
    Units: whole
    9
    Attachments
    RESULTS
    No statistical analyses for this end point

    Secondary: Secondary Endpoints

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    End point title
    Secondary Endpoints
    End point description
    1. Presence of new type VII collagen at the dermal-epidermal junction post treatment on Day 28, Day 60, and Month 6. 2. Changes in general markers of inflammation at Day 14, Day 28, Day 60, Day 100, Month 6 (for all patients) and Month 12 (for the first eight eligible patients) or Month 8 (for the last two eligible patients) compared to baseline. 3. Changes in specific markers of inflammation on Day 14, Day 28, Day 60 and Month 6 compared to baseline using ELISA and LUMINEX platforms. Specific inflammatory markers include: HMGB-1, TNF α, IFN γ, IL-17A, IL1 β, IL-10, MMP-2, MMP-9, MMP-11 and TIMP-1. 4. Changes in the clinical appearance of the skin assessed with clinical photographs 5. Differences in quality of life data at Day 28, Day 60, Day 100, Month 6 (for all patients) and Month 12 (for the first eight eligible patients) or Month 8 (for the last two eligible patients) compared to baseline. 6 Changes in BEBSS & EBDASI scores at Day 28 60 100 & month 6 & 12 (8 for final 2 pts)
    End point type
    Secondary
    End point timeframe
    Up to 12 months post first infusion
    End point values
    Full study
    Number of subjects analysed
    9
    Units: whole
    9
    No statistical analyses for this end point

    Secondary: Secondary Endpoints continued

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    End point title
    Secondary Endpoints continued
    End point description
    Change in pruritus score using the Leuven Itch Scale (LIS) at Day 28, Day 60, Day 100, Month 6 (for all patients) and Month 12 (for the first eight eligible patients) or Month 8 (for the last two eligible patients) compared to baseline. 8. Quantification of total blister numbers over the entire body surface area at Day 28, Day 60, Day 100, Month 6 (for all patients) and Month 12 (for the first eight eligible patients) or Month 8 (for the last two eligible patients) compared to baseline. 9. Increase in the skin strength measured by time to blister formation after negative pressure skin suction test at Day 28, Day 60, Day 100, Month 6 (for all patients) and Month 12 (for the first eight eligible patients) or Month 8 (for the last two eligible patients) compared to baseline
    End point type
    Secondary
    End point timeframe
    Up to 12 months post infustion
    End point values
    Full study
    Number of subjects analysed
    9
    Units: whole
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months post first infustion for the first 8 participants and 8 months post first infusion for the final 2 participants.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Whole Trial
    Reporting group description
    -

    Serious adverse events
    Whole Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Renal and urinary disorders
    Deranged renal funcion
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Squamous cell carcinoma (SCC) lower leg
    Additional description: Squamous cell carcinoma identified on lower leg of two patients - both admitted to hospital for excision of SCC. Classed as important medical event (disease progression) bet met SAE criteria due to hospitalization of more than 24 hours
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Whole Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
    General disorders and administration site conditions
    Nightmares
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Loose & frequent stools
    Additional description: Known history of IBS
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin infection affecting back
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Infections and infestations
    Sore Throat
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Ear Infection
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Chest Infection
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2015
    • A change to the exclusion criteria, to exclude subjects with both a) positive C7 ELISA and b) a positive indirect immunofluorescence (IIF) with binding to the base of salt split skin. • The removal of a secondary end point relating to quality of life data, which will now be captured as part of a nested study with an independent application to an Ethics Committee. • A new secondary end point to perform flow cytometry to evaluate the cytotoxic T-cell signature at 24 to 48 hours post first infusion. This will involve an optional blood test and for all patients who partake in this an additional visit will be required, which has also been added to the protocol (visit 2a). • The number of skin biopsies have also been reduced from 6 to 4, so the visit schedule has been updated accordingly to reflect these changes and a new table has been included in v3.0 to make the procedures per visit easier to see. • The removal of the data monitoring committee section as this study only has a trial steering committee. • The statistics section has been updated to explain that attempts will be made to replace patients that do not completed at least 6 months of the trial and No interim analysis will now be performed.
    27 Jan 2016
    It includes a change to one of the inclusion criteria, as highlighted below: Protocol v3.0 wording: ‘Individuals with a diagnosis of RDEB confirmed by DNA analysis and skin immunofluorescence for partial or complete absence of type VII collagen.’ Protocol v4.0 New wording: ‘Individuals with a diagnosis of RDEB confirmed by DNA analysis.’
    03 Apr 2017
    The protocol has been amended to change the conduct and management of the trial by removing visit 2a and reducing the follow up for the final two patients in the trial from 12 to 8 months.

    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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