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    Summary
    EudraCT Number:2018-003842-18
    Sponsor's Protocol Code Number:OTL-103-4
    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:2018-11-19
    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 number2018-003842-18
    A.3Full title of the trial
    A Single Arm, Open Label Clinical Study of Haematopoietic Stem Cell Gene Therapy with Cryopreserved Autologous CD34+ Cells Transduced with Lentiviral Vector encoding WAS cDNA in Subjects with Wiskott-Aldrich Syndrome (WAS).
    Studio clinico a braccio singolo, in aperto, della terapia genica con cellule staminali ematopoietiche con cellule CD34+ autologhe crioconservate trasdotte con il vettore lentivirale codificante il cDNA del gene WAS in soggetti con Sindrome di Wiskott-Aldrich (WAS).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene therapy study using a frozen formulation of OTL-103 in patients with Wiskott-Aldrich Syndrome (WAS)
    Studio con terapia genica che utilizza una formulazione congelata di OTL-103 in pazienti con sindrome di Wiskott-Aldrich (WAS).
    A.3.2Name or abbreviated title of the trial where available
    Clinical study using cryopreserved OTL-103 for treatment of WAS.
    Studio clinico che utilizza OTL-103 crioconservato per il trattamento della WAS.
    A.4.1Sponsor's protocol code numberOTL-103-4
    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 SponsorOrchard Therapeutics Ltd.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOrchard Therapeutics Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOrchard Therapeutics Ltd.
    B.5.2Functional name of contact pointClinical
    B.5.3 Address:
    B.5.3.1Street Address108 Cannon Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC4N 6EU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+440203384 6700
    B.5.5Fax number+440203727 0797
    B.5.6E-mailclinical@orchard-tx.com
    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/3/12/998
    D.3 Description of the IMP
    D.3.1Product nameOTL-103 Dispersion for Infusion
    D.3.2Product code OTL-103
    D.3.4Pharmaceutical form Dispersion 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 INNOther hematological Agents
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameAutologous CD34+ enriched cell fraction that contains CD34+ cells transduced with lentiviral vector that encodes for the human Wiskott Aldrich Syndrome (WAS) cDNA sequence
    D.3.9.4EV Substance CodeSUB192087
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number10000000
    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 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.IMP: 2
    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 Yes
    D.2.1.1.1Trade name Busilvex
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Concentrate for 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 INNBUSULFAN
    D.3.9.1CAS number 55-98-1
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB05993MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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 Yes
    D.3.11.13.1Other medicinal product typechemotherapic agent
    D.IMP: 3
    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 Yes
    D.2.1.1.1Trade name Fludarabina Accord
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical form Concentrate for 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 INNFLUDARABINE
    D.3.9.1CAS number 21679-14-1
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB07678MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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 Yes
    D.3.11.13.1Other medicinal product typechemiotherapic agent
    D.IMP: 4
    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 Yes
    D.2.1.1.1Trade name MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Concentrate for 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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 Yes
    D.3.11.13.1Other medicinal product typeimmunologic
    D.IMP: 5
    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 Yes
    D.2.1.1.1Trade name Mozobil,
    D.2.1.1.2Name of the Marketing Authorisation holderGenzyme Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/11/931
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNplerixafor
    D.3.9.1CAS number 110078-46-1
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive namePLERIXAFOR
    D.3.9.4EV Substance CodeSUB28849
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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 Yes
    D.3.11.13.1Other medicinal product typeimmunostimolants
    D.IMP: 6
    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 Yes
    D.2.1.1.1Trade name MYELOSTIM
    D.2.1.1.2Name of the Marketing Authorisation holderItalfarmaco S.p.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namegranulocyte colony stimulating factor (G-CSF)
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    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 INNLENOGRASTIM
    D.3.9.1CAS number 135968-09-1
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive namerHuG-CSF
    D.3.9.4EV Substance CodeSUB02888MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number13400000
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    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
    Wiskott-Aldrich Syndrome
    Sindrome di Wiskott-Aldrich
    E.1.1.1Medical condition in easily understood language
    A rare genetic disease characterized by immune deficiency
    rara malattia genetica caratterizzata da deficit immunitario
    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 10061598
    E.1.2Term Immunodeficiency
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the engraftment and biological efficacy of the cryopreserved formulation of OTL-103 at 6 months
    valutare l’attecchimento e l’efficacia biologica della formulazione crioconservata di OTL-103 a 6 mesi
    E.2.2Secondary objectives of the trial
    • to evaluate the safety of treatment with OTL-103
    • to evaluate the biological efficacy of the cryopreserved formulation of OTL-103 at 12 months and 2 years
    • to evaluate the clinical efficacy of the cryopreserved formulation of OTL-103 at 2 years
    • to evaluate sustained engraftment of the cryopreserved formulation of OTL-103 at 2 years
    • to evaluate the immunological function after treatment with OTL-103 at 2 years
    • to evaluate the effect of OTL-103 on health-related quality of life at 2 years
    • valutare la sicurezza del trattamento con OTL-103
    • valutare l’efficacia biologica della formulazione crioconservata di OTL-103 a 12 mesi e a 2 anni
    • valutare l’efficacia clinica della formulazione crioconservata di OTL-103 a 2 anni
    • valutare l’attecchimento a lungo termine della formulazione crioconservata di OTL-103 a 2 anni
    • valutare la funzionalità immunologica dopo il trattamento con OTL-103 a 2 anni
    • valutare l’effetto di OTL-103 sulla qualità della vita correlata alla salute a 2 anni
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Age: up to 65 years.
    • Diagnosis of WAS defined by genetic mutation and at least one of the following criteria:
    Severe WASP mutation;
    Absent WASP expression;
    Severe clinical score (Zhu clinical score ≥ 3);
    Family member affected by WAS with life-threatening or fatal clinical events.
    • No human leukocyte antigen (HLA)-identical related donor available.
    • Parental/guardian/subject-signed informed consent, and subject assent (if appropriate).
    •For all subjects in the reproductive age range, agreement to use highly
    effective and adequate method of contraception (as detailed in Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information) while receiving treatment and for at least 12 months following drug administration.
    1. Età: fino a 65 anni.
    2. Diagnosi di WAS definita da mutazione genetica e almeno uno dei seguenti criteri:
    • Grave mutazione di WASP, definita dai dati della letteratura (studi di genotipo/fenotipo);
    • Espressione di WASP assente, valutata con citometria a flusso;
    • Grave punteggio clinico (punteggio clinico di Zhu ≥3);
    • Membro della famiglia affetto da WAS con eventi clinici potenzialmente letali o fatali.
    3. Nessun donatore HLA identico correlato disponibile per HSCT.
    4. Consenso informato firmato da genitore/tutore/soggetto, e assenso del soggetto (se pertinente).
    5. Per tutti i soggetti nella fascia di età riproduttiva, consenso a utilizzare metodi contraccettivi altamente efficaci e adeguati (come indicato in Appendice 4: “Guida alla contraccezione e raccolta di informazioni sulla gravidanza) mentre ricevono il trattamento e per almeno 12 mesi successivamente alla somministrazione del farmaco.
    E.4Principal exclusion criteria
    1. End-organ dysfunction, severe active infection not responsive to treatment or other severe disease or clinical condition which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    In addition to the potential infections tested per protocol, the PI should Tissue Directive as clinically appropriate and discuss the results with the medical monitor prior to cell harvest.
    Patients with ALT >2x upper limit of normal (ULN) or total bilirubin >1.5 x ULN may be included only after discussed and agreed with the medical monitor and considered in the context of the criterion for excluding patients with other severe disease.
    Isolated elevation of total bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35% of total.
    2. Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome . Patients with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the medical monitor.
    3. Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia , or other serious haematological disorders.
    4. Prior allogeneic hematopoietic stem cell transplantation, with evidence of residual cells of donor origin.
    5. Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
    6. Current participation in other interventional clinical trials.
    7. Previous gene therapy.
    8. Symptomatic herpes zoster, not responsive to specific treatment.
    Patients with a recent history of herpes zoster may be included in the study. In such cases, inclusion, additional monitoring and treatment of the condition must be discussed and approved by the medical monitor.
    9. Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON®-TB Gold test and microbiological evidence.
    Patients with latent TB, as documented by medical history and/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such patients must be discussed and approved by the medical monitor.
    10. Acute or chronic stable Hepatitis B as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to start of conditioning and/or positive HBV DNA.
    Patients with positive Hepatitis B core antibody due to prior resolved disease may be eligible to be included, only if a confirmatory negative HBsAg and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such patients must be discussed and approved by the medical monitor.
    11. Presence of positive Hepatitis C RNA test result at screening. Patients who have previously tested positive for HCV can be treated, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of ≤15 international units/mL.
    Negative test results are required on at least 3 sequential occasions over a period of at least 4 weeks, after completion of treatment for hepatitis C, with the final test conducted no more than 3 days prior to cell harvest.
    Inclusion, monitoring and treatment of hepatitis in such subjects must be discussed and approved by the medical monitor.
    12. Patients that are not eligible for mobilisation protocols in order to obtain CD34+ cells for DP manufacture.
    1. Disfunzione degli organi bersaglio, grave infezione attiva che non risponde al trattamento, o altra grave malattia o condizione clinica che, a giudizio dello sperimentatore, renderebbe il paziente inadatto all’ingresso nello studio.
    Oltre alle potenziali infezioni testate come da protocollo, il PI deve testare altri agenti infettivi trasmissibili elencati nella Direttiva UE sulle cellule e sui tessuti come clinicamente appropriato e discutere i risultati con il medical monitor prima della raccolta delle cellule.
    I pazienti con ALT >2x limite superiore della norma (upper limit of normal, ULN) o bilirubina totale >1,5 x ULN possono essere inclusi solo dopo averne discusso e concordato con il medical monitor ed essere stati considerati nel contesto del criterio di esclusione dei pazienti con altre malattie gravi.
    Elevazione isolata della bilirubina totale >1,5 x ULN è accettabile se la bilirubina è frazionata e la bilirubina diretta è <35% del totale.
    2. Neoplasia maligna (fatta eccezione per il carcinoma cutaneo locale) o un’anamnesi documentata di sindrome ereditaria da tumore. I pazienti con un tumore maligno precedentemente trattato con successo e un follow-up sufficiente per escludere la recidiva (in base al parere dell’oncologo) possono essere inclusi dopo discussione e approvazione del medical monitor.
    3. Mielodisplasia, alterazioni citogenetiche caratteristiche della sindrome mielodisplastica e leucemia mieloide acuta, o altri disturbi ematologici seri.
    4. Precedente trapianto allogenico di cellule staminali ematopoietiche, con evidenza di cellule residue provenienti da donatore.
    5. Infezione documentata da HIV (RNA positivo a HIV e/o anticorpi anti-p24).
    6. Attuale partecipazione ad altre sperimentazioni cliniche interventistiche.
    7. Precedente terapia genica.
    8. Herpes zoster sintomatico, che non risponde a trattamento specifico.
    I pazienti con recente anamnesi di herpes zoster possono essere inclusi nello studio. In tali casi, l’inclusione, l’ulteriore monitoraggio e trattamento della patologia devono essere discussi e approvati dal medical monitor.
    9. Evidenza di tubercolosi attiva (TBC) in base a esame medico, a diagnostica per immagini del torace e al test della TBC ad es. QuantiFERON®-TB Gold e a evidenza microbiologica.
    I pazienti con TBC latente, come documentata da anamnesi medica e/o test per la TBC possono essere inclusi nello studio se hanno ricevuto una profilassi antibiotica (per es., isoniazid). L’inclusione, il monitoraggio e il trattamento della TBC in tali pazienti devono essere discussi e approvati dal medical monitor.
    10. Epatite B acuta o cronica stabile, come dimostrato dal risultato del test dell’antigene di superficie (HBsAg) positivo dell’epatite B allo screening o entro 3 mesi prima dell’inizio di condizionamento e/o DNA positivo all’HBV.
    I pazienti con anticorpi verso l’antigene core dell’epatite B positivi a causa di una precedente malattia risolta possono essere idonei all’inclusione solo se si ottengono un test confermativo dell’HBsAg negativo e un test del DNA negativo all’epatite B. L’inclusione, il monitoraggio e il trattamento dell’epatite in tali pazienti devono essere discussi e approvati dal medical monitor.
    11. Presenza del risultato del test dell’RNA positivo all’epatite C allo screening.
    I pazienti che sono risultati precedentemente positivi all’HCV possono essere trattati, a condizione che dimostrino l’assenza di infezione in corso mediante un test dell’acido nucleico con un limite di quantificazione di ≤15 unità internazionali/ml.
    Sono necessari risultati del test negativi in almeno 3 occasioni consecutive nell’arco di un periodo di almeno 4 settimane, dopo il completamento del trattamento per l’epatite C, con test finale eseguito non più di 3 giorni prima della raccolta delle cellule.
    L’inclusione, il monitoraggio e il trattamento dell’epatite in tali soggetti devono essere discussi e approvati dal medical monitor.
    12. Pazienti che non sono idonei ai protocolli di mobilizzazione al fine di ottenere cellule CD34+ per la produzione del DP
    E.5 End points
    E.5.1Primary end point(s)
    • Evaluation of engraftment and biological efficacy at 6 months:
    1) haematological reconstitution at 60 days post treatment (absolute neutrophil count >500 cells/μL);
    2) vector copy number (VCN)/cell of >0.1 in peripheral blood (PB)-derived CD3+ cells at 6 months;
    3) WAS protein (WASP) expression increased from pretreatment levels in lymphocytes and platelets at 6 months.
    Valutare l’attecchimento e l’efficacia biologica a 6 mesi:
    1) ricostituzione ematologica a 60 giorni successivamente al trattamento (conta assoluta dei neutrofili >500 cellule/μl);
    2) numero di copie del vettore (vector copy number, VCN)/cellula >0,1 nelle cellule CD3+ derivate dal sangue periferico (peripheral blood, PB) a 6 mesi;
    3) espressione della proteina WAS (WAS protein, WASP) aumentata dai livelli di pretrattamento in linfociti e piastrine a 6 mesi.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months and 60 days post treatment.
    6 mesi e 60 giorni dopo il trattamento
    E.5.2Secondary end point(s)
    Evaluation of the safety of treatment
    1) safety and tolerability as measured by adverse event (AE) reporting;
    2) absence of malignancy or abnormal clonal proliferation (ACP) development due to insertional oncogenesis;
    3) absence of replication-competent lentivirus (RCL).

    • Evaluation of biological correlates of efficacy at 12 months and 2 years:
    1) VCN/cell of >0.1 in PB-derived CD3+ cells;
    2) WASP expression increased from pretreatment levels in lymphocytes and platelets.
    • Evaluation of clinical efficacy at 2 years:
    1) reduction in the annualised rate of severe infections from 6 months to 2 years after gene therapy (GT) compared with 1 year prior to GT;
    2) reduction in the annualised rate of severe bleeding episodes from 6 months to 2 years after GT compared with 1 year prior to GT;
    3) improved platelet count compared with baseline;
    4) normalised mean platelet volume (MPV);
    5) reduction of eczema severity compared with baseline;
    6) reduction of autoimmunity phenomena compared with baseline;
    7) reduction in the annualised rate of hospitalisation due to infections or bleeding episodes from 6 months to 2 years after GT compared with 1 year prior to GT.
    • Evaluation of sustained engraftment at 2 years
    1) >10% lentiviral vector (LV)-positive clonogenic progenitors in bone marrow;
    2) VCN/cell of >0.04 in BM-derived CD34+ cells;
    3) VCN/cell of >0.1 in PB-derived CD3+ cells.
    • Evaluation of immunological function at 2 years
    1) T cell function (proliferation to stimuli);
    2) response to vaccination, only if performed
    • Evaluation of the effect of treatment on health-related quality of life at 2 years
    1) Improvement from baseline in Paediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scale scores
    • Valutazione della sicurezza del trattamento
    1) sicurezza e tollerabilità misurate mediante la segnalazione degli eventi avversi (EA);
    2) assenza di sviluppo di tumore maligno o proliferazione clonale anomala (abnormal clonal proliferation, ACP) a causa di oncogenesi da inserzione;
    3) assenza di lentivirus competenti per la replicazione (replication-competent lentivirus, RCL).

    • Valutazione di tests biologici di efficacia a 12 mesi e a 2 anni:
    1) VCN/cellula >0,1 nelle cellule CD3+ da sangue periferico (PB);
    2) Espressione di WASP aumentata rispetto ai livelli di pretrattamento in linfociti e piastrine.
    • Valutazione dell’efficacia clinica a 2 anni:
    1) riduzione del tasso annualizzato di infezioni gravi dai 6 mesi ai 2 anni successivi alla terapia genica (gene therapy, GT) rispetto a 1 anno prima della GT;
    2) riduzione del tasso annualizzato di episodi di sanguinamento gravi dai 6 mesi ai 2 anni successivi alla GT rispetto a 1 anno prima della GT;
    3) miglioramento della conta piastrinica rispetto al basale;
    4) normalizzazione del volume piastrinico medio (mean platelet volume, MPV);
    5) riduzione della gravità dell’eczema rispetto al basale;
    6) riduzione dei fenomeni autoimmuni rispetto al basale;
    7) riduzione del tasso annualizzato di ospedalizzazioni a causa di infezioni o episodi di sanguinamento dai 6 mesi ai 2 anni successivi alla GT rispetto a 1 anno prima della GT.
    • Valutazione dell’attecchimento a lungo termine a 2 anni
    1) >10% progenitori clonogenici positivi al vettore lentivirale (lentiviral vector, LV) nel midollo osseo;
    2) VCN/cellula >0,04 nelle cellule CD34+ da midollo osseo (bone marrow, BM);
    3) VCN/cellula >0,1 nelle cellule CD3+ da PB.
    • Valutazione della funzionalità immunologica a 2 anni
    1) Funzionalità delle cellule T (proliferazione allo stimolo);
    2) risposta alla vaccinazione, solo se eseguita
    • Valutazione dell’effetto del trattamento sulla qualità della vita correlata alla salute a 2 anni
    1) Miglioramento del generic core scale dal basale nei punteggi del Questionario pediatrico sulla qualità della vita (Paediatric Quality of Life Inventory, PedsQL) 4.0
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months, 12 months and 2 years
    6 mesi, 12 mesi e 2 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) No
    E.7.1.1First administration to humans No
    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) Yes
    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.8.2.4Number 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 6
    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: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    F.1.3Elderly (>=65 years) No
    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
    Minors
    Minori
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 6
    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)
    Normal standard of care; After completion of the 2-year follow up, subjects will be enrolled in a long-term follow up study or in a registry, to monitor long term safety and efficacy
    Normale standard di cura; Dopo il completamento del follow di 2 anni, i soggetti saranno arruolati in uno studio di follow-up a lungo termine o in un registro, per monitorare la sicurezza e l'efficacia a lungo termine
    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 Decision2019-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-08
    P. End of Trial
    P.End of Trial StatusOngoing
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