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    Summary
    EudraCT Number:2019-001825-28
    Sponsor's Protocol Code Number:R119513
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-07-29
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-001825-28
    A.3Full title of the trial
    Mesoangioblast-mediated exon 51 skipping for genetic correction of dystrophin, based upon a single injection in individual skeletal muscles of five non ambulant patients affected by Duchenne Muscular Dystrophy: a non randomized, open label, phase I/IIa study.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Mesoangioblast-based gene therapy for Duchenne Muscular Dystrophy:
    a phase I/IIa study / DMD04
    A.3.2Name or abbreviated title of the trial where available
    Mesoangioblast-based gene therapy for Duchenne Muscular Dystrophy
    A.4.1Sponsor's protocol code numberR119513
    A.5.4Other Identifiers
    Name:Funders Reference Number:WT200134/Z15/Z
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of Sponsor The University of Manchester
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportThe Wellcome Trust, Health Innovation Challenge Fund grant
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe University of Manchester
    B.5.2Functional name of contact pointMohammed Zubair
    B.5.3 Address:
    B.5.3.1Street AddressResearch Governance, Ethics and Integrity Team, Christie Building
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM139PL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01612752725
    B.5.6E-mailMohammed.Zubair@manchester.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLentiviral Vector Trans-Skip gene modified Autologous Mesoangioblasts
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Duchenne Muscular Dystrophy
    E.1.1.1Medical condition in easily understood language
    Duchenne Muscular Dystrophy
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10013801
    E.1.2Term Duchenne muscular dystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We want to test whether is possible to prepare genetically corrected cells from DMD patients and administer the cells to few muscles of the same patients to verify how much dystrophin is produced.
    We want to test whether the treatment is safe.
    E.2.2Secondary objectives of the trial
    In case of positive results (i.e. dystrophin produced at 10% or more of the level of a healthy muscle) we want to know whether this is sufficient to improve/stabilise the force of contraction of the thumb.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age between 12 and 16 years at time of study entry, provided that participants matching the eligibility criteria can be identified. Otherwise patients of progressively younger age may be recruited up to a minimum age of 8 years.
    2. Non-ambulant at the time of recruitment.
    3. Confirmed diagnosis of DMD with documented exon 51 skippable mutations in dystrophin gene.
    4. Progression of muscle degeneration ≤ to 50% reduction of muscle mass as determined by quantitative MRI (grade 2: Kinali et al. 2011).
    5. Written informed consent of caregivers of DMD patients and patient’s assent.
    E.4Principal exclusion criteria
    1. Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test.
    2. Presence of immune deficiency, neoplastic or autoimmune disease (based on clinical history).
    3. Bleeding disorder.
    4. Any known allergies to products likely to be used in the study.
    5. Prior or ongoing medical condition (e.g. concomitant illness, psychiatric condition, behavioural disorder, drug abuse), medical history, physical findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
    6. Ongoing participation in any other therapeutic clinical trial or treatment with exon skipping oligonucleotides. Use of steroids is considered standard care, as well as concomitant medications (e.g. B blockers, ACEI, ARBs, vitamin D, bisphosphonates) and therefore permitted.
    7. FS (fraction shortening) < 28% or ECG finding significant for underlying cardiac impairment.
    8. Pulmonary function tests assessed by spirometry (if cooperative) of FEV1 and FVC <30% of the predicted values. If unable, pulse oximetry < 95 % in room air.
    9. Change of medication related to DMD within last 3 months with the exception of adjustment based on weight gain of current medications.
    10. Presence of severe scoliosis (curve >50°).
    11. Presence of significant impairment of renal or hepatic function.
    E.5 End points
    E.5.1Primary end point(s)
    We will test safety of treatment and efficacy in restoring synthesis of dystrophin in the injected muscle.

    Safety: To assess the incidence of adverse events (any grade) in DMD patients treated with intra muscular foot injections of auto-MABS after genetic correction with a lentiviral vector expressing a small
    nuclear RNA engineered to skip exon 51 of the dystrophin gene.
    Note: In vitro/in vivo pre-clinical safety assessments will be performed on IMP prior to injection, as described in the IMPD.

    Efficacy: To determine cell engraftment and dystrophin expression after a single intramuscular injection into the foot medial Extensor Digitorum Brevis (EDB) of genetically corrected auto-MABS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Monitoring for SAE will be carried out throughout the trial.
    Evaluation of dystrophin expression will be carried out three months after IMP injection.
    E.5.2Secondary end point(s)
    Safety: Incidence and severity of local and systemic adverse events (any grade) in DMD patients treated with intramuscular injections of genetically corrected auto-MABS for one year from the injection.

    Efficacy: Enhancement, stabilization or decrease of the thumb muscle strength in DMD patients treated with injections of genetically corrected auto-MABS, evaluated periodically (starting at recruitment) up to 1 year from the last injection and in comparison with contralateral non injected thumb.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation will be carried out throughout the trial.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is tentatively planned after the final visit of the last patient (12-18 months after the last patient receives the foot injection). In case of a SAE, linked to the trial, the trial may end prematurely.
    On the other hand, should the clinical benefit persist up to completion, a new observational study may be planned to monitor the force of contraction of the transplanted hand until it remains constant (± 10 % of the average values recorded in the previous years).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days28
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 5
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There will be no continued interventions on patients after study closure. In case of a positive outcome and increased/stabilised force of contraction, an observational study may be designed to test for how long the benefit may last. This will have to involve adult neurologists as patients will likely by older than 16 by then.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-09-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-15
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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