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    The EU Clinical Trials Register currently displays   44209   clinical trials with a EudraCT protocol, of which   7332   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2018-000673-68
    Sponsor's Protocol Code Number:16IC17
    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:2018-07-27
    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 number2018-000673-68
    A.3Full title of the trial
    Phase I/II study of lentiviral gene transfer for SCID-X1 with low dose targeted busulfan
    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 in patients with X-linked Severe Combined Immunodeficiency
    A.3.2Name or abbreviated title of the trial where available
    Lentiviral gene therapy for SCID-X1
    A.4.1Sponsor's protocol code number16IC17
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03601286
    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 supportBoston Children's Hospital
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportNIHR Biomedical Research Centres (BRCs)
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportHSS (NHS England)
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportSCIDNET
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUCL Great Ormond Street Institute of Child Health
    B.5.2Functional name of contact pointFiona Shepheard
    B.5.3 Address:
    B.5.3.1Street Address30 Guilford Street
    B.5.3.3Post codeWC1N 1EH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02077626058
    B.5.6E-mailf.shepheard@ucl.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 nameCryopreserved G2SCID lentiviral vector 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 INNCryopreserved G2SCID lentiviral vector transduced patient CD34+ cells
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number20 x10e6 cells
    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
    Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. Children with SCID lack virtually all immune protection from pathogens. They are prone to repeated and persistent infections that can be very serious or life threatening.
    E.1.1.1Medical condition in easily understood language
    Children who are born with mutations in the IL2RG gene which is located on the X chromosome 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 10069566
    E.1.2Term Severe combined immunodeficiency syndrome
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the research is to measure event-free survival and T cell immune reconstitution one year after gene therapy. Events include death, infusion of the patient's back-up cells (collected prior to gene therapy) for failure of blood cell recovery and bone marrow transplant from a donor due to poor immune system recovery. T cell reconstitution recovery 1 year after gene therapy will be evaluated by assessment of the patient's T cells and gene marking.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to measure overall survival, event-free survival, safety related to the procedure, clinical and laboratory measures of efficacy including blood immune reconstitution and gene marking after gene transfer.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All subjects must fulfill the following criteria to be included in the study:
    1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG
    2. Lack of an HLA identical (A, B, C, DR, DQ) related donor
    3. Age <5 years
    4. Signed informed consent
    5. Documentation of willingness to follow up for 15 years post-infusion
    6. If the patient has previously undergone allogeneic transplant, lack of donor T cell engraftment must be documented.
    7. Age at least 8 weeks of age by the time of busulfan administration
    E.4Principal exclusion criteria
    Subjects will not be eligible for the study if any of the following criteria is fulfilled:
    1. Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).
    a. Mechanical ventilation including continuous positive airway pressure
    b. Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL
    c. Shortening fraction on echocardiogram <25% or ejection fraction <50%
    d. Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence
    2. Uncontrolled seizure disorder
    3. Encephalopathy
    4. Documented coexistence of any disorder known to affect DNA repair
    5. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
    6. Patients with evidence of infection with HIV-1
    7. Previous allogeneic transplant with cytoreductive chemotherapy
    8. Major (life-threatening) congenital anomalies. Examples of “major (life-threatening) congenital anomalies” include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.
    9. Other conditions which in the opinion of the P.I. or Co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient’s inability to follow the protocol. These may include for example clinical ineligibility to receive anaesthesia, severe deterioration of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship.
    E.5 End points
    E.5.1Primary end point(s)
    Measure event-free survival and T cell immune reconstitution 1 year after gene transfer. Event-free Survival is defined as the time from the infusion to the first event, if an event occurred, or to the date of the last evaluation without an event if no event occurred. If no event occurred, the subject’s data will be considered censored at the last evaluation. An event is any of the following:
    • Death
    • Infusion of back-up product due to failure of haematopoietic recovery, or
    • Allogeneic transplant performed for poor immune reconstitution

    T cell reconstitution is defined as both:
    • CD3+ T cell count ≥300 cells/microliter in peripheral blood, and
    • Gene marking ≥0.1 copies/cell in sorted CD3+ T cells
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 year
    E.5.2Secondary end point(s)
    Secondary endpoints are enumeration of events related to survival, safety and measuring laboratory correlates of efficacy.
    1) Overall survival at 2 years post-infusion
    2) Event-free survival at 2 years post-infusion
    Events will include death, allogeneic transplant and development of insertional oncogenesis requiring treatment. Descriptive statistics and graphical techniques will be used to summarize overall and event-free survival. Given the trial’s nature with small numbers of infant and child subjects who require close medical supervision, and stringent screening requirements, loss to follow-up is not anticipated. Cumulative events will be reported and recorded into a database in real time. At scheduled investigations, absolute numbers of specific events will be tallied and, after several events have transpired, exact (binomial) confidence intervals of proportions will be computed. Over the 2-year period, monitoring will be continuous and individual patient timelines will be plotted (noting specific events and times), and a cumulative probability of the composite endpoint will be estimated.
    3) Incidence of adverse events related to gene therapy including:
    a. Detection of replication competent lentivirus (RCL)
    b. Clonal dominance
    c. Life-threatening adverse reactions related to the gene therapy procedure i.e. insertional oncogenesis
    Samples will be collected according to the monitoring schedule. RCL will be performed by the National Gene Vector Biorepository. Monitoring of clonal dominance will be performed in the laboratory of Frederic Bushman, University of Pennsylvania
    4) Clinical and laboratory correlates of efficacy including:
    a. Immune reconstitution
    This will include
    • enumeration of absolute lymphocyte count determined by routine complete blood counts (CBC)
    • absolute numbers of T, B and NK lymphocytes
    • percentage of naïve and memory T and B cell subsets
    • freedom from immunoglobulin substitution for at least 9 months measured at 2 years post-infusion
    • serum immunoglobulin levels (IgA, IgM and IgG at least 12 weeks without exogenous substitution)
    • antigen specific antibody titers to tetanus toxoid
    • proliferation of lymphocytes to phytohemagglutinin determined by tritiated thymidine incorporation
    • T cell receptor excision circles (TREC)
    • T cell receptor Vb family usage
    b. Frequency of gene marking in peripheral blood cells
    • To assess the efficacy of stem cell transduction/engraftment, we will obtain serial samples of peripheral blood and sort specific lineages including CD3+, CD19+, CD3- CD56+ and CD15+ cells. Genomic DNA isolated from each population will be assayed for vector copy number by quantitative PCR (qPCR).
    c. Clonal diversity of vector integrants
    • Clonal diversity will be quantitated and used to estimate the number of transduced HSC that have engrafted in the subjects. Number of sequence reads and unique integration sites will be assessed to quantify population clone diversity, distribution of integration sites and relative abundance.
    5) Haematopoietic recovery after receipt of busulfan
    Haematopoietic recovery is defined as absolute neutrophil count (ANC) above 0.5 x 109 /l for three consecutive days, achieved within 6 weeks following infusion.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoints will be measured over a series of timepoints throughout the study.
    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) 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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.4.1Number of sites anticipated in Member State concerned1
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    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) 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: 0
    F.1.1.6Adolescents (12-17 years) Yes
    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 No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    children
    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 5
    F.4.2.2In the whole clinical trial 5
    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 the study for 2 years. The patient will then be followed-up on a separate long-term follow-up protocol up until 15 years post gene therapy.

    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 Decision2018-10-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-09
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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