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    Clinical Trial Results:
    Phase I study of lentiviral-mediated COL7A1 gene-modified autologous fibroblasts in adults with recessive dystrophic epidermolysis bullosa (RDEB)

    Summary
    EudraCT number
    2014-004884-19
    Trial protocol
    GB  
    Global end of trial date
    13 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Mar 2019
    First version publication date
    27 Mar 2019
    Other versions
    Summary report(s)
    FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    LENTICOL-F
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02493816
    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 and Guy's and St Thomas' NHS Foundation Trust, 44 2071886409, john.mcgrath@kcl.ac.uk
    Scientific contact
    Professor John A McGrath, King's College London and Guy's and St Thomas' NHS Foundation Trust, 44 2071886409, 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 McGrath, Guy's and St Thomas' NHS Foundation Trust and King's College London, 44 2071886409, john.mcgrath@kcl.ac.uk
    Scientific contact
    Professor John McGrath, Guy's and St Thomas' NHS Foundation Trust and King's College London, 44 2071886409, 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
    13 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of intradermal injections of SIN LV-mediated COL7A1 gene-modified autologous fibroblasts in adults with RDEB.
    Protection of trial subjects
    Each study participant will receive three intradermal injections of ex vivo transduced autologous fibroblasts expressing codon-optimised COL7A1 as the IMP on Day 0 only. Each injection of the IMP containing 0.8–1.2x106 cells suspended in 0.25ml of 0.9% saline, will be administered intradermally into 1cm2 area of intact skin (x3). Participants will be followed up with study interventions for a 12-month period at various time points. All followups, where possible, will be co-ordinated to try to coincide with the individuals’ routine clinic reviews. Each subject will undergo an initial screening including a physical examination and assessment of disease severity. Blood analyses and skin biopsies will be performed at various time points throughout the trial. The second participant will be treated only if there is no safety concern 4 weeks after the first participant’s IMP injections. All patients with RDEB are followed up on a lifelong basis, and we will therefore be able to capture any long-term possible adverse effects related to the IMP. Subjects with positive results for HIV, Hepatitis B, Hepatitis C, HTLV or Syphilis will be excluded. Subjects will not be included who are pregnant or of child-bearing potential who are neither abstinent nor practising an acceptable means of contraception when this is in line with the usual and preferred lifestyle of the subject, as determined by the Investigator, for 12 months after the cell injections.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Sep 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
    United Kingdom: 4
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The participants were recruited by St John’s Institute of Dermatology at Guy's and St Thomas NHS Foundation Trust.

    Pre-assignment
    Screening details
    Thirty-nine RDEB adults with confirmed biallelic COL7A1 mutations by Sanger sequencing were invited to participate in the study, of which 35 patients were excluded due to failing screening.

    Period 1
    Period 1 title
    Overall Trial Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Open label SIN LV-mediated ex vivo transduced autologous fibroblasts expressing codon-optimised COL7A1 will be given to patients at a does of 0.8–1.2 million cells suspended in 0.25ml of 0.9% saline per injection over 1 cm2 of intact skin (3 intradermal injections of IMP at a single timepoint). Patients were followed up for 12 months post injection.

    Arms
    Arm title
    Treatment
    Arm description
    Patients treated with SIN LV-mediated ex vivo transduced autologous fibroblasts expressing codon-optimised COL7A1.
    Arm type
    Experimental

    Investigational medicinal product name
    SIN LV Mediated ex vivo transduced autologous fibroblasts expressing codon-optimised COL7A1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled injector
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.8 - 1.2 million cells in 0.25ml of 0.9% saline per injection; 2.4 - 3.6 million cells total dose

    Number of subjects in period 1
    Treatment
    Started
    4
    Completed
    4

    Baseline characteristics

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

    Reporting group values
    Overall Trial Period Total
    Number of subjects
    4 4
    Age categorical
    All adult patients were recruited aged between 30 and 59
    Units: Subjects
        Age range 30 to 59
    4 4
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    2 2

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Patients treated with SIN LV-mediated ex vivo transduced autologous fibroblasts expressing codon-optimised COL7A1.

    Primary: Adverse Events

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    End point title
    Adverse Events [1]
    End point description
    Adverse events (AEs) at each visit after screening over a 12month follow-up period
    End point type
    Primary
    End point timeframe
    From screening to 12 months after injection
    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: Please see attached report for full results and trial outcomes, including full list of adverse events
    End point values
    Treatment
    Number of subjects analysed
    4 [2]
    Units: Number of adverse events
    4
    Notes
    [2] - There were 45 AEs (including SAEs) in total
    No statistical analyses for this end point

    Primary: Adverse reactions

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    End point title
    Adverse reactions [3]
    End point description
    The incidence of Adverse Reactions (ARs) and Serious Adverse Reactions (SARs) at each visit after screening over a 12-month follow-up period.
    End point type
    Primary
    End point timeframe
    Screening over a 12-month follow-up period.
    Notes
    [3] - 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: Please see attached report for full results and trial outcomes, including full list of adverse reactions
    End point values
    Treatment
    Number of subjects analysed
    4 [4]
    Units: Adverse reactions
    4
    Notes
    [4] - There were 7 adverse reactions and no serious adverse reactions
    No statistical analyses for this end point

    Primary: Serious Adverse Evemts

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    End point title
    Serious Adverse Evemts [5]
    End point description
    End point type
    Primary
    End point timeframe
    From screening to 12 months post dose.
    Notes
    [5] - 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: Please see attached report for full results and trial outcomes, including full list of serious adverse events
    End point values
    Treatment
    Number of subjects analysed
    1 [6]
    Units: Number of serious adverse events
    7
    Notes
    [6] - Number of serious adverse events
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening to 12 months post dose of IMP
    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
    1 / 4 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Bowel obstruction
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroparesis postoperative
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Refeeding syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 4 (25.00%)
         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
    4 / 4 (100.00%)
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Coryzal symptoms
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Dry cough
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Nervous system disorders
    Throbbing pain over injection site
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Increased itch over forearms
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Itch over skin biopsy site
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Eye disorders
    Conjuctivitis
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    Sub-conjunctival haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Tiredness
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Occasional dizzy spells
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Oesophageal dilation
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    Oesophageal blisters
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Oesophageal spasm
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Microscopic haematuia
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Difficult micurition
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Tattoo site swollen
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Injection site erythema
         subjects affected / exposed
    4 / 4 (100.00%)
         occurrences all number
    4
    Injection site bruising
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Left leg skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    Forearm skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    2
    Left ear skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Increased blistering on elbows, shins and forearms
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Left hand skin infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Pseudomonas infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Streptococcal infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Candida infection
         subjects affected / exposed
    1 / 4 (25.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasm causing feet deformities
         subjects affected / exposed
    1 / 4 (25.00%)
         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
    10 Jul 2015
    • To decrease the duration of follow up from 36mths to 12mths • To amend the exclusion criteria such that persons with positive serology for HIV, Hepatitis B and C, HTLV and Syphilis are excluded from the study • To amend the total number of skin biopsies to be taken at baseline (V1B) from 2 (1x6mm and 1x4mm punch) to 2-3 (1x6mm and 1-2x4mm punch). • To include two additional investigations on the skin biopsies; histology and RT-PCR to demonstrate the difference in COL7A1 gene expression between fibroblasts from treated versus untreated skin.
    25 Apr 2016
    The purpose of this amendment secondary endpoints. Amend inclusion/exclusion criteria. Amend IMP administration details to minimise the amount of tattooing to mark the injected sites.

    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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