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    Summary
    EudraCT Number:2010-024253-36
    Sponsor's Protocol Code Number:10MI29
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-05-09
    Trial results View 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 number2010-024253-36
    A.3Full title of the trial
    Phase I/II, historical controlled, open-label, non-randomised, single-centre trial to assess the safety and efficacy of EF1αS-ADA lentiviral vector mediated gene modification of autologus CD34+ cells from ADA-deficient individuals
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to study the effects of genetically modified patients' CD34+ cells
    A.3.2Name or abbreviated title of the trial where available
    LV Gene Therapy for ADA Deficiency
    A.4.1Sponsor's protocol code number10MI29
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01380990
    A.5.4Other Identifiers
    Name:GTAC referenceNumber:GTAC178
    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 SponsorGreat Ormond Street Hospital for Children NHS Trust
    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 supportDepartment of Health, Internal Funder
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUCL Institute of Child Health & GOSH R&D Office
    B.5.2Functional name of contact pointAvani Shukla
    B.5.3 Address:
    B.5.3.1Street Address30 Guilford Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1N 1EH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02079052863
    B.5.5Fax number02079052201
    B.5.6E-mailAvani.Shukla@gosh.nhs.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 nameEF1αS-ADA lentiviral vector transduced patient CD34+ cells
    D.3.2Product code transduced patient CD34+ cells
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEF1αS-ADA lentiviral vector gene modified autologous CD34+ cells
    D.3.9.3Other descriptive nameAutologous CD34+ HSCs transduced ex vivo with EFS lentiviral vector encoding for the human ADA gene
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number500000
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adenosine deaminase (ADA) deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency (SCID). Children with SCID lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. If not treated in a way that restores immune function, children with SCID usually live only a year or two.
    E.1.1.1Medical condition in easily understood language
    Adenosine Deaminase (ADA) is an enzyme, needed by the body to develop lymphocytes of the immune system. Children who are born with mutations in ADA gene have severe combined immunodeficiency (SCID).
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10066372
    E.1.2Term ADA deficiency
    E.1.2System Organ Class 100000012248
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To examine the safety and efficacy of lentiviral vector mediated gene therapy for ADA-deficient SCID.
    2. To assess efficacy of treatment by measurement of ADA cDNA copy number in peripheral blood leukocytes using real-time PCR.
    3. To assess efficacy of treatment by measurement of cellular and humoral immune system recovery
    4. To assess efficacy of treatment by measurement of ADA activity and reduction in dATP in peripheral blood cells
    5. To assess safety of treatment by clinical, haematological and immunological monitoring of patients
    6. To assess safety of treatment by analysis of vector integration sites and analysis of clonal proliferation
    7. To compare outcomes between patients treated with gene therapy and patients treated with allogeneic HSCT
    E.2.2Secondary objectives of the trial
    1. To improve the overall health of the patient, including reduction in frequency of infections & promote growth.
    2. To evaluate the longitudinal clinical effect in terms of improved immunity.
    3. To evaluate tolerability of conditioning regimen
    4. To evaluate feasibility of the transduction procedure


    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients treated with Gene Therapy
    1. Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
    2. Patients who lack a fully HLA-matched family donor
    3. Patients (male or female) <5yrs of age OR
    Patients (male or female) >5yrs to 15 yrs of age who have preserved thymic function as evidenced by presence of >10 % naïve T cells (CD4+45RA+27+ cells)
    4. Parental/guardian signed informed consent

    Historical HSCT control group
    Inclusion criteria
    1. Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
    2. Patients (male or female) from all age
    3. Patient treated with allogeneic haematopoietic stem cell transplantation

    No exclusion criteria
    E.4Principal exclusion criteria
    1. Cytogenetic abnormalities on peripheral blood
    2. Evidence of active malignant disease
    3. Known sensitivity to busulfan
    4. If applicable, confirmed pregnancy (to be tested in patients above 12 years old)
    E.5 End points
    E.5.1Primary end point(s)
    1) Overall survival following gene therapy after 1 year post gene therapy

    2) Disease free survival as assessed by complete cessation of PEG-ADA 2 years post gene therapy

    3) Engraftment of genetically corrected haematopoietic progenitors and/or differentiated cells in peripheral blood and/or in bone marrow (as assessed by evidence of vector copy number or transgene expression in the cells)

    4) Reconstitution of cell mediated and humoral immunity 2 years post gene therapy (as assessed by evidence of changes in T cell function and circulating immunoglobulin levels).
    5) Correction of metabolic abnormalities (as assessed by dATP at levels comparable to published data from HSCT treated patients and by evidence of ADA activity in erythrocytes)
    6) Analysis of frequency of vector integration into known proto oncogene and analysis of frequency of clonal expansion associated with vector integration near proto oncogene
    7) To compare overall survival and event-free survival between patients treated with gene therapy and patients treated with allogeneic HSCT
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 years post-infusion of gene-modified cells.
    E.5.2Secondary end point(s)
    1) Reduction in frequency of infections (evaluated from 1 year after treatment by clinical history, complete physical examinations at 3 years post-gene therapy, haematological tests) and improved weight parameter
    2) Long term immune reconstitution as assessed by sustained improvement in thymic function assessed by TRECS after 2 years post-gene therapy
    3) Tolerability of conditioning regimen assessed by hematopoietic recovery within 6 weeks as assessed by absolute neutrophil count (ANC) above 0.5 x 109 cells/l
    4) Feasibility of the transduction procedure assessed by availability of greater than 0.5 x 106 CD34+ cells/kg after transduction; undetectable RCL (determined retrospectively); and CD45+ cell viability after transduction equal to or greater than 50%, in accordance with the final product release criteria
    E.5.2.1Timepoint(s) of evaluation of this end point
    3 years post-infusion of gene-modified cells.
    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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Historical control group
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    allogeneic haematopoietic stem cell transplantation control group
    E.8.2.4Number of treatment arms in the trial1
    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 No
    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 study is defined as the last patient’s last scheduled visit according to the protocol, which will be the 3 year follow-up visit of the last patient entered into the trial.
    In case the study is ended prematurely, the sponsor will notify GTAC and the MHRA within 15 days, including the reasons for the premature termination.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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 years10
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days2
    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: 10
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    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 Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    In this trial patients less than 5 years of age will be recruited who are incapable of giving consent personally, therefore Informed Consent will be obtained from Parents/Guardians.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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)
    The treatment is a one-off procedure and as such the issue of continued provision is not applicable. Patients will be monitored on study for 3 years but will remain under regular clinical follow up throughout childhood.
    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 Decision2012-08-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-12-23
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