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    Summary
    EudraCT Number:2019-002343-14
    Sponsor's Protocol Code Number:RAG1-2019-01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-03-15
    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 ConcernedItaly - Italian Medicines Agency
    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
    STUDIO CLINICO DI FASE I/II SULLA TERAPIA GENICA CON CELLULE STAMINALI EMATOPOIETICHE AUTOLOGHE PER L'IMMUNODEFICIENZA COMBINATA GRAVE CON DEFICIT DI RAG1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TERAPIA GENICA IN BAMBINI CON IMMUNODEFICIENZA COMBINATA GRAVE CON DEFICIT DI RAG1
    GENE THERAPY IN CHILDREN WITH RAG1 - DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY
    A.3.2Name or abbreviated title of the trial where available
    na
    na
    A.4.1Sponsor's protocol code numberRAG1-2019-01
    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 SponsorLeids Universitair Medisch Centrum
    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 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 code2333 - ZA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31715262806
    B.5.6E-mailrialbureauwakz@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+ cellule
    D.3.2Product code [RAG1-LV-CD34+ cellule]
    D.3.4Pharmaceutical form Suspension for injection
    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.3.9.2Current sponsor codeRAG1-LV-CD34+ cellule
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number25
    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)
    Pazienti con immunodeficienza combinata grave (SCID) basata su un difetto genetico nel gene attivante la ricombinasi 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
    Bambini con immunodeficienza combinata grave dovuta ad una mutazione nel gene RAG1
    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 PT
    E.1.2Classification code 10010099
    E.1.2Term Combined immunodeficiency
    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
    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.
    Gli obiettivi primari dello studio sono dimostrare la fattibilità e la sicurezza della terapia con cellule staminali ematopoietiche autologhe selezionate CD34+ con correzione genica, utilizzando un vettore SIN lentivirale che codifica il cDNA RAG1 umano ottimizzato per il codone, in pazienti con SCID con deficit di RAG1.
    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 IMP, b) persistence of gene marking in myeloid and lymphoid cell lineages in blood and marrow and c) recovery from failure to thrive and/or serious/invasive infections.
    Dimostrare l'efficacia di questo intervento terapeutico sulla base di a) ricostituzione delle cellule T e B a un anno dall'infusione del medicinale in fase di sperimentazione (IMP), b) persistenza della marcatura genica nei lignaggi delle cellule mieloidi e linfoidi nel sangue e nel midollo e c) recupero dall'insufficienza di crescita e/o da infezioni gravi/invasive.
    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/pL and/or naïve T cells < 1/pL
    3. Age < 2 years
    4. Age at least 8 weeks by the time of busulfan and fludarabine 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.
    Per essere idoneo a partecipare a questo studio, un soggetto deve soddisfare tutti i seguenti criteri:
    1. SCID con deficit di RAG1, come confermato dall'analisi genetica
    2. Cellule T del sangue periferico < 300/µL e/o cellule T naïve < 1/µL
    3. Età < 2 anni
    4. Età minima di 8 settimane al momento della somministrazione di busulfan e fludarabina.
    5. Mancanza di un donatore HLA compatibile (fratello HLA identico o donatore 10/10 (A, B, C, DR, DQ) con allele corrispondente).
    6. Consenso informato firmato (genitori o tutore).
    7. In grado di tornare al centro HSCT locale per il follow-up (come da protocollo) durante i 2 anni di studio e la revisione a lungo termine a 15 anni fuori dallo studio.
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Availability of an HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
    2. RAG1 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 medical condition which, in the opinion of the treating physician, would interfere with the good conduction of the clinical trial (e.g. contraindications for stem cell harvest or administration of conditioning medication)
    7. Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection
    Un potenziale soggetto che soddisfi uno dei seguenti criteri sarà escluso dalla partecipazione a questo studio:
    1. Disponibilità di un donatore HLA-matched (fratello HLA-identico o donatore 10/10 (A, B, C, DR, DQ) allele-matched (non) correlato)
    2. Deficit di RAG1 con cellule T del sangue periferico > 300/µL e/o cellule T naïve > 1/µL
    3. Sindrome di Omenn
    4. Precedente HSCT allogenico
    5. Disfunzione d'organo significativa/co-morbilità (incluse, ma non solo, quelle elencate di seguito)
    a. Ventilazione meccanica
    b. Frazione di accorciamento all'ecocardiogramma <25
    c. Insufficienza renale definita come dipendenza da dialisi
    d. Disturbo convulsivo non controllato

    6. qualsiasi altra condizione medica che, a giudizio del medico curante, potrebbe interferire con la buona conduzione dello studio clinico (ad esempio, controindicazioni per il prelievo di cellule staminali o la somministrazione di farmaci condizionanti)
    7. Infezione da virus dell'immunodeficienza umana (HIV) o infezione da virus della leucemia a cellule T umane (HTLV)
    E.5 End points
    E.5.1Primary end point(s)
    - 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.
    - Safety of the procedure based on overall survival and event-free survival (EFS) after infusion of the IMP with events defined as o a) death (of any cause) o b) failure of engraftment (neutrophils > 500/µL on three consecutive time points) within six weeks requiring infusion of the autologous unmanipulated backup stem cell product and/or a conventional allogeneic HSCT procedure o c) insufficient immune reconstitution within one year after RAG1 LV CD34+ cells infusion requiring allogeneic HSCT o d) occurrence of insertional mutagenesis presenting as malignant disease
    - Fattibilità basata sulla generazione di successo di un IMP (cellule RAG1 LV CD34+) per pazienti SCID con deficit di RAG1 che soddisfi i criteri di rilascio definiti nell'IMPD.
    - Sicurezza della procedura basata sulla sopravvivenza globale e sulla sopravvivenza libera da eventi (EFS) dopo l'infusione dell'IMP con eventi definiti come o a) morte (di qualsiasi causa) o b) fallimento dell'attecchimento (neutrofili > 500/µL per tre volte consecutive) entro sei settimane che richiede l'infusione di un prodotto di riserva di cellule staminali non manipolate e/o una procedura HSCT allogenica convenzionale o c) immunoricostituzione insufficiente entro un anno dopo RAG1 LV CD34+ infusione di cellule che richiedono HSCT allogenico o d) comparsa di mutagenesi inserzionale che si presenta come malattia maligna
    E.5.1.1Timepoint(s) of evaluation of this end point
    within six weeks and one year
    entro 6 settimane e un anno
    E.5.2Secondary end point(s)
    - T cell reconstitution (CD3 T cells > 300/µL blood) at 1 year
    - CD4 reconstitution (CD4 > 200/µL) at 1 year
    - Thymic function (TREC analysis, 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 at six months and one year and in bone marrow at one year
    - Frequency of serious/invasive infections
    - Recovery from failure to thrive
    - Quality of life at 2 years (assessed using PedsQL by proxy).
    - ricostituzione delle cellule T (cellule T CD3 > 300/µL di sangue) ad un anno
    - ricostituzione del CD4 (CD4 > 200/µL) ad un anno
    - la funzione timica (presenza di cellule T CD4 naïve) ad un anno
    - il repertorio molecolare dei recettori delle cellule T e B a un anno
    - indipendenza dalla sostituzione delle immunoglobuline a due anni
    - Persistenza della marcatura genica nelle linee mieloidi e linfoidi nel sangue a sei mesi e un anno e nel midollo osseo a un anno
    - Frequenza di infezioni serie
    - Recupero dall’insufficienza di crescita
    - Qualità di vita a due anni
    E.5.2.1Timepoint(s) of evaluation of this end point
    At six months, one year, two years
    a 6 mesi, un anno, due anni
    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 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.8.2.4Number of treatment arms in the trial0
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    Germany
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    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 2 years after administration of the IMP to the last subject in the trial. The two years timepoint is the last study visit of the last subject included in the trial
    La sperimentazione termina 2 anni dopo la somministrazione dell'IMP all'ultimo soggetto della sperimentazione. Il timepoint di due anni è l'ultima visita di studio dell'ultimo soggetto incluso nello studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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
    La popolazione target dei pazienti con SCID è tipicamente limitata a lattanti e bambini piccoli
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    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
    Il trattamento e il follow-up saranno simili al normale trattamento previsto per la 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 Decision2024-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-22
    P. End of Trial
    P.End of Trial StatusOngoing
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