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    Summary
    EudraCT Number:2019-002343-14
    Sponsor's Protocol Code Number:RAG1-2019-01
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-09-05
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2019-002343-14
    A.3Full title of the trial
    PHASE I/II CLINICAL TRIAL OF AUTOLOGOUS HEMATOPOIETIC STEM CELL GENE THERAPY FOR RAG1-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    GENE THERAPY IN CHILDREN WITH RAG1-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY
    A.4.1Sponsor's protocol code numberRAG1-2019-01
    A.5.4Other Identifiers
    Name:Clinicaltrials.govNumber:NCT04797260
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    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 supportZonMw (The Netherlands Organisation for Health Research and Development)
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportEU/H2020
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointTrialbureau Dep of Pediatrics
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2300
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31715262806
    B.5.6E-mailtrialbureauwakz@lumc.nl
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1257
    D.3 Description of the IMP
    D.3.1Product nameRAG1 LV CD34+ cells
    D.3.2Product code RAG1 LV CD34+ cells
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation Yes
    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 INNNot obtained
    D.3.9.3Other descriptive nameAutologous CD34+ cells transduced with a lentiviral vector containing the human RAG1 gene
    D.3.9.4EV Substance CodeSUB213607
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number3-25x10e6
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberEU/3/14/1257
    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 Yes
    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
    Patients with severe combined immunodeficiency (SCID) based on a genetic defect in the Recombinase Activating Gene 1 (RAG1)
    E.1.1.1Medical condition in easily understood language
    Children with a severe combined immunodeficiency due to a mutation in the RAG1 gene
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    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 objectives of the study are to demonstrate feasibility and safety of gene corrected autologous CD34+-selected hematopoietic stem cell therapy using a lentiviral SIN vector encoding codon-optimized human RAG1 cDNA in patients with RAG1-deficient SCID.
    E.2.2Secondary objectives of the trial
    To demonstrate efficacy of this therapeutic intervention based on a) T and B cell reconstitution at one year after infusion of the investigational medicinal product, b) event free survival of the patient, and c) persistence of gene marking in myeloid and lymphoid cell lineages in blood and marrow
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. RAG1 deficient SCID as confirmed by genetic analysis
    2. Peripheral blood T cells < 300/µL and/or naïve T cells < 1/µL
    3. Age < 2 years
    4. Age at least 8 weeks by the time of busulfan administration
    5. lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
    6. signed informed consent (parental or guardian)
    7. able to return to the local HSCT centre for follow-up (per protocol) during the 2-year study and the 15-year long-term off study review
    E.4Principal exclusion criteria
    1. availability of a HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
    2. RAG 1 deficiency with peripheral blood T cells > 300/µL and/or naïve T cells > 1/µL
    3. Omenn syndrome
    4. Previous allogeneic HSCT
    5. Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below)
    a. Mechanical ventilation
    b. Shortening fraction on echocardiogram <25%
    c. Renal failure defined as dialysis dependence
    d. Uncontrolled seizure disorder
    6. Any other condition that the investigator considers is a contraindication to collection and/or infusion of transduced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication to busulfan, major congenital abnormalities, ineligible to receive anesthesia, or documented refusal or inability of the family to return for scheduled visits
    7. HIV infection or HTLV infection
    E.5 End points
    E.5.1Primary end point(s)
    1. Feasibility of successful generation of an IMP (RAG1 LV CD34+ cells) for RAG1 deficient SCID patients that meets the release criteria as defined in the IMPD.
    2. Event free survival (EFS) after infusion of the IMP with events defined as
    a) failure of engraftment (neutrophils > 500/µL on three consecutive timepoints) within six weeks requiring infusion of the autologous unmanipulated backup stem cell product
    b) insufficient immune reconstitution within one year after RAG1 LV CD34+ cells infusion requiring allo-SCT
    c) occurrence of insertional mutagenesis presenting as malignant disease.
    E.5.1.1Timepoint(s) of evaluation of this end point
    ad 1. After producing the first three and after all five IMPs
    ad2. At one year after IMP infusion in the first three and at one after infusion of the fifth patient
    E.5.2Secondary end point(s)
    - Overall survival (at 2 years)
    - T cell reconstitution (CD3 T cells > 300/μL blood) at 1 year
    - CD4 reconstitution (CD4 > 200/μL) at 1 year
    - Thymic function (presence of naïve CD4 T cells) at 1 year
    - T and B cell receptor molecular repertoire at 1 year
    - immunoglobulin substitution independence at 2 years
    - Persistence of gene marking in myeloid and lymphoid lineages in blood and mar-row at six months and one year (> 0.1 VCN)
    - Frequency of serious/invasive infections
    - Recovery from failure to thrive
    - Quality of life at 2 years (assessed using PedQual by proxy).
    E.5.2.1Timepoint(s) of evaluation of this end point
    see time points in 5.2 per item
    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 No
    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 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Israel
    United Kingdom
    Germany
    Italy
    Netherlands
    Poland
    Spain
    Türkiye
    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 trial ends 5 years after administration of the IMP to the last subject in the trial. The 5 years timepoint is the last study visit of the last
    subject included in the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days30
    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.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    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
    The target population of SCID patients is typically restricted to infants
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 4
    F.4.2.2In the whole clinical trial 10
    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)
    Treatment and follow-up will be similar to the expected normal treatment of SCID
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-04-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-19
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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