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    Summary
    EudraCT Number:2020-004184-12
    Sponsor's Protocol Code Number:DTX401-CL301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-09-15
    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 number2020-004184-12
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus Serotype 8-mediated Gene Transfer of Glucose-6-phosphatase in Patients With Glycogen Storage Disease Type Ia.

    EMA Decision number on PIP: EMA/PDCO/154270/2021
    Studio di fase 3, randomizzato, in doppio cieco, controllato con placebo sul trasferimento genico della glucosio-6-fosfatasi mediato dal virus adeno-associato sierotipo 8 in pazienti affetti da malattia da accumulo di glicogeno di tipo Ia

    Numero di decisione dell'EMA sul PIP: EMA/PDCO/154270/2021
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Phase 3 clinical study comparing a vector transferring the gene for Glucose-6-Phosphatase with placebo in adults with Glycogen Storage Disease Type Ia.
    Studio di Fase 3 che confronta un vettore che trasferisce il gene per la Glucosio-6-Fosfatasi con placebo negli adulti affetti da malattia da accumulo di glicogeno di tipo Ia
    A.3.2Name or abbreviated title of the trial where available
    na
    na
    A.4.1Sponsor's protocol code numberDTX401-CL301
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/278/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorULTRAGENYX PHARMACEUTICAL INC.
    B.1.3.4CountryUnited States
    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 supportUltragenyx Pharmaceutical Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUltragenyx Pharmaceutical Inc.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address60 Leveroni Court
    B.5.3.2Town/ cityNovato
    B.5.3.3Post codeCA 94949
    B.5.3.4CountryUnited States
    B.5.4Telephone number+14157204828
    B.5.5Fax number+16173008985
    B.5.6E-mailjsullivan@ultragenyx.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 Yes
    D.2.1.1.1Trade name Prednisolon STADA® 10 mg tablets
    D.2.1.1.2Name of the Marketing Authorisation holderSTADAPHARM GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namena
    D.3.2Product code [na]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPREDNISONE
    D.3.9.1CAS number 53-03-2
    D.3.9.2Current sponsor codena
    D.3.9.3Other descriptive nameprednisone
    D.3.9.4EV Substance CodeSUB10018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.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 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/3/16/1771
    D.3 Description of the IMP
    D.3.1Product nameDTX401
    D.3.2Product code [na]
    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.3.9.2Current sponsor codeDTX401
    D.3.9.4EV Substance CodeSUB192511
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number73 to 9
    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 numberClassified as gene therapy medicinal product, EMA/506999/2016.
    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 Yes
    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: 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 Prednisolon STADA® 5 mg tablets
    D.2.1.1.2Name of the Marketing Authorisation holderSTADAPHARM GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namena
    D.3.2Product code [na]
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPREDNISONE
    D.3.9.1CAS number 53-03-2
    D.3.9.2Current sponsor codena
    D.3.9.3Other descriptive nameprednisone
    D.3.9.4EV Substance CodeSUB10018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Glycogen Storage Disease Type Ia (GSDIa).
    Malattia da accumulo di glicogeno di tipo Ia (GSDIa).
    E.1.1.1Medical condition in easily understood language
    Inherited disorder causing decrease of glucose.
    Disturbo ereditario che causa diminuzione del glucosio.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10056911
    E.1.2Term Glycogen storage disease type IA
    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
    •To reduce or eliminate dependence on exogenous glucose replacement therapy to maintain euglycemia
    •To maintain or improve the quality of glucose control
    - Ridurre o eliminare la dipendenza dalla terapia sostitutiva con glucosio esogeno per mantenere l’euglicemia
    - Mantenere o migliorare la qualità del controllo glicemico
    E.2.2Secondary objectives of the trial
    •To evaluate the effect of DTX401 on glucose control
    •To evaluate the effect of DTX401 on reducing the frequency of exogenous glucose replacement therapy
    •To evaluate the effect of DTX401 on subject experience of disease
    •To evaluate the safety of DTX401
    - Valutare l’effetto di DTX401 sul controllo del glucosio
    - Valutare l’effetto di DTX401 sulle riduzione della frequenza della terapia sostitutiva con glucosio esogeno
    - Valutare l’effetto di DTX401 sull’esperienza della malattia da parte del soggetto
    - Valutare la sicurezza di DTX401
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female patients = 8 years of age at time of informed consent or assent.
    2. Subject has a diagnosis of GSDIa confirmed by deficient enzymatic activity (on liver biopsy), or by molecular testing of G6PC gene revealing 2 pathogenic mutations. In the case where only a single pathogenic mutation is identified, clinical diagnosis is compatible with GSDIa and absence of characteristic features of GSDIb (ie, chronic neutropenia, inflammatory bowel disease).
    3. Subject is currently receiving a therapeutic regimen of cornstarch (or equivalent) and clinically stable as evidenced by no more than a 10% weekly change in cornstarch (or equivalent) regimen; no more than 15% variation in weekly average euglycemia (60-120 mg/dL) assessed by CGM and no hospitalization for hypoglycemia during the 4-week period preceding randomization and dosing.
    4. Subject is willing and able to comply with study procedures and requirements, including periodic inpatient hospitalization or admission in a research facility; CFC studies; frequent blood collection; wearing a CGM device for the duration of the study (and excluding the use of any non-study CGM or flash glucose device); performing capillary glucose measurements using a study-approved glucometer (and excluding the use of any other glucometer); completing an eDiary routinely throughout the study to track daily cornstarch, dietary intake, and reason for performing SMBG; and completing patient-reported questionnaires. If < 18 years (or as required by region), has a parent or legal guardian willing and able to assist with study requirements.
    5. From the period following informed consent through the duration of participation in the study, female subjects of childbearing potential and fertile male subjects must consent to use highly effective contraception as defined by the Food and Drug Administration (FDA) and Clinical Trial Facilitation Group Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials (Version 1.1 dated 21 Sep 2020). Female subjects must agree not to become pregnant and male subjects must agree not father a child or donate sperm for at least 48 weeks after the last dose of IP if they decide to withdraw early from the study.
    6. Subject is willing and able to provide written informed consent after the study has been explained and before any study-related procedures are performed. If < 18 years (or as required by region), willing and able to provide written assent and have a parent or legal guardian willing and able to provide written informed consent after the study has been explained and before any study-related procedures are performed.
    1. Il partecipante, uomo o donna, ha un’età =8 anni al momento del consenso informato o dell’assenso.
    2. Il soggetto presenta una diagnosi di GSDIa confermata da una scarsa attività enzimatica (su biopsia epatica), o mediante analisi molecolare del gene G6PC che rivela 2 mutazioni patogene. Nel caso in cui venga identificata solo una singola mutazione patogenetica, la diagnosi clinica è compatibile con GSDIa e assenza di caratteristiche tipiche di GSDIb (ovvero, neutropenia cronica, malattia infiammatoria intestinale).
    3. Il soggetto sta attualmente ricevendo un regime terapeutico di amido di mais (o equivalente) e clinicamente stabile, come evidenziato da una variazione settimanale non superiore al 10% nel regime di amido di mais (o equivalente), una variazione non superiore al 15% nel valore di euglicemia medio settimanale (60 120 mg/dl) valutata mediante CGM e nessun ricovero per ipoglicemia durante il periodo di 4 settimane precedente la randomizzazione e la somministrazione.
    4. Il soggetto è disposto e in grado di rispettare le procedure e i requisiti previsti dallo studio, tra cui ricovero periodico in ospedale o accesso a una struttura di ricerca, studi CFC, frequenti prelievi di sangue, uso di un dispositivo CGM per la durata dello studio (ed escludendo l’uso di qualsiasi dispositivo CGM non appartenente allo studio o dispositivo di misurazione flash del glucosio), esecuzione di misurazioni del glucosio capillare mediante un glucometro approvato per lo studio (ed escludendo l’uso di qualsiasi altro glucometro), compilazione dell’eDiary per tenere traccia della somministrazione giornaliera di amido di mais e dell’alimentazione, controllo SMBG di routine per tutta la durata dello studio e compilazione dei questionari con gli esiti riportati dal paziente. Se l’età è <18 anni (o come richiesto per regione), un genitore o tutore legale è disposto e in grado di fornire assistenza in merito ai requisiti dello studio.
    5. Dal periodo successivo al consenso informato per tutta la durata della partecipazione allo studio, i soggetti di sesso femminile in età fertile e i soggetti di sesso maschile fertili devono acconsentire a utilizzare una contraccezione altamente efficace, come definito dall’Ente statunitense preposto alla tutela di alimenti e medicinali (Food and Drug Administration, [FDA]) e dalle raccomandazioni del Gruppo di facilitazione delle sperimentazioni cliniche relative alla contraccezione e al test di gravidanza nelle sperimentazioni cliniche (Versione 1.1 datata 21 settembre 2020). I soggetti di sesso femminile devono acconsentire a non rimanere incinte e i soggetti di sesso maschile devono acconsentire a non procreare o donare sperma per almeno 48 settimane dopo l’ultima dose dell’IP se decidono di ritirarsi in anticipo dallo studio.
    6. Il soggetto è disposto e in grado di fornire il consenso informato scritto dopo che lo studio è stato spiegato e prima che sia eseguita qualsiasi procedura correlata allo studio. Se l’età è <18 anni (o come richiesto per regione), è disposto e in grado di fornire l’assenso scritto e ha un genitore o tutore legale disposto e in grado di fornire il consenso informato scritto dopo che lo studio è stato spiegato e prima che sia eseguita qualsiasi procedura correlata allo studio.
    E.4Principal exclusion criteria
    1. Detectable pre-existing antibodies to the AAV8 capsid.
    2. History of liver transplant, including hepatocyte cell therapy/transplant.
    3. History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage III fibrosis.
    4. Presence of liver adenoma > 5 cm in size or presence of liver adenoma > 3 cm and = 5 cm in size with a documented annual growth rate of = 0.5 cm per year.
    5. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities:
    - ALT or aspartate aminotransferase > 2.5 × the ULN
    - Total bilirubin > 2.0 × ULN (except if patient has documented Gilbert’s syndrome)
    - Alkaline phosphatase > 2.5 × ULN
    6.Non-fasting triglycerides = 1000 mg/dL. For the purposes of this study, non-fasting refers to the longest fasting period that each individual subject is able to tolerate. Depending on the meal and cornstarch schedule, the blood draw could occur in the morning before breakfast or before the first dose of cornstarch.
    7. Presence or history of hepatitis B virus infection, hepatitis C virus infection, or both.
    8. Human immunodeficiency virus infection AND any of the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy regimen within 6 months before baseline, or plasma viral load > 200 copies/mL on 2 separate occasions as measured by polymerase chain reaction.
    9. Presence or history of any disease or condition that, in the Investigator’s opinion, would interfere with the subject’s safety or ability to participate in the study or would significantly affect interpretation of study results. This includes any intercurrent febrile or nonfebrile illness including common viral infections, epidemic influenza, and coronavirus disease 2019 (COVID-19) until full clinical recovery.
    10. Female subjects of childbearing potential who have a positive serum pregnancy test at screening or a positive urine pregnancy test at baseline or who are unwilling to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have not experienced menarche, are postmenopausal (defined as having no menses for at least 12 months without an alternative medical cause), or are permanently sterile due to having total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
    11. Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study.
    12. Presence or history of any hypersensitivity to the excipients of DTX401 or placebo or to prednisolone, or inability to swallow capsules that, in the judgment of the Investigator, places the subject at increased risk for adverse effects.
    13. Current or previous participation in another gene transfer study.
    14. Use of any IP or investigational medical device within 3 months preceding screening or planning to use at any time during the study.
    15. History of illicit drug use within 60 days prior to screening or positive results from a 9-panel urine drug screen during the Screening Period completed at 2 time points at least 4 weeks apart. Positive results that are due to a prescribed medication may be allowed if not impacting glycemic control and liver function and after agreement with the Sponsor. For the purposes of this protocol, the use of recreational cannabis products is not allowed, even if legal in the region where the patient lives.
    1. Anticorpi preesistenti rilevabili contro il capside di AAV8.
    2. Anamnesi di trapianto di fegato, compresa terapia/trapianto di cellule epatocitarie.
    3. Anamnesi di epatopatia, evidenziata da una qualsiasi delle seguenti condizioni: ipertensione portale, ascite, splenomegalia, varici esofagee, encefalopatia epatica o biopsia epatica con evidenza di fibrosi in stadio III.
    4. Presenza di adenomi epatici di dimensioni >5 cm o di adenomi epatici >3 cm e =5 cm con un tasso di crescita annuale documentato =0,5 cm all’anno.
    5. Infiammazione epatica o cirrosi significativa, evidenziata mediante diagnostica per immagini o una qualsiasi delle seguenti anomalie di laboratorio:
    - ALT o aspartato aminotransferasi > 2,5 volte l’ULN
    - Bilirubina totale >2,0 × ULN (eccetto se il paziente presenta sindrome di Gilbert documentata)
    - Fosfatasi alcalina >2,5 × ULN
    6. Trigliceridi non a digiuno =1.000 mg/dl. Per le finalità del presente studio, per digiuno si intende il periodo a digiuno più lungo che ogni singolo soggetto è in grado di tollerare. In base alla programmazione dei pasti e dell’amido di mais, il prelievo di sangue potrebbe avvenire al mattino prima di colazione o prima della prima dose di amido di mais.
    7. Presenza o anamnesi di infezione da virus dell’epatite B, infezione da virus dell’epatite C o entrambi.
    8. Anamnesi di infezione da virus dell’immunodeficienza umana (HIV) E uno qualsiasi dei seguenti: Conta delle cellule CD4+ <350 cellule/mm3, variazioni nel regime di terapia antiretrovirale entro i 6 mesi precedenti il basale o una viremia >200 copie/ml in 2 diverse occasioni misurata mediante reazione a catena della polimerasi (Polymerase Chain Reaction, [PCR]).
    9. Presenza o anamnesi di qualsiasi malattia o condizione che, nell’opinione dello sperimentatore, interferirebbe con la sicurezza o la capacità del soggetto di partecipare allo studio o influirebbe significativamente sull’interpretazione dei risultati dello studio. Ciò comprende qualsiasi malattia febbrile o non febbrile intercorrente, comprese le infezioni virali comuni, l’influenza epidemica e la malattia da coronavirus 2019 (COVID-19) fino al completo recupero clinico.
    10. Soggetti di sesso femminile in età fertile che presentano un test di gravidanza sul siero positivo allo screening o un test di gravidanza sulle urine positivo al basale o che non desiderano sottoporsi a test di gravidanza aggiuntivi durante lo studio. Le donne considerate non potenzialmente fertili comprendono quelle che non hanno manifestato menarca, sono in post-menopausa (definita come assenza di mestruazioni da almeno 12 mesi senza una causa medica alternativa) o sono permanentemente sterile a causa di isterectomia totale, salpingectomia bilaterale o ooforectomia bilaterale.
    11. Donna in gravidanza, in allattamento o con intenzione di rimanere incinta (sé stessa o la partner) in qualsiasi momento durante lo studio.
    12. Presenza o anamnesi di ipersensibilità agli eccipienti di DTX401 o del placebo oppure al prednisolone, o incapacità di deglutire le capsule che, a giudizio dello sperimentatore, espone il soggetto a un rischio maggiore di effetti avversi.
    13. Partecipazione attuale o precedente a un altro studio di trasferimento genico.
    14. Uso di qualsiasi IP o dispositivo medico sperimentale nei 3 mesi precedenti lo screening o che prevede di utilizzare in qualsiasi momento durante lo studio.
    15. Anamnesi di uso di sostanze stupefacenti illecite nei 60 giorni precedenti lo screening o risultati positivi da uno screening tossicologico delle urine a 9 pannelli durante il periodo di screening completato almeno in 2 momenti definiti a 4 settimane di distanza. I risultati positivi dovuti a un farmaco prescritto sono consentiti se non influiscono sul controllo glicemico e sulla funzionalità renale, previa consultazione dello sponsor. Per le finalità del presente protocollo, i prodotti a base di cannabis per uso ricreativo non sono consentiti,anche se legalizzati nel paese in cui vive il paziente.
    E.5 End points
    E.5.1Primary end point(s)
    1. Percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 Group compared with the Placebo Group for superiority.
    2. Change from Baseline to Week 48 in the percentage of time spent in normal glucose control (60 to 120 mg/dL [3.3 to 6.7 mmol/L]) for the DTX401 Group compared with the Placebo Group, as measured by CGM for noninferiority.
    1. variazione percentuale dal basale alla Settimana 48 nell’assunzione giornaliera di amido di mais per il gruppo DTX401 rispetto al gruppo placebo per la superiorità.
    2. variazione dal basale alla Settimana 48 nella percentuale di tempo trascorso nel normale controllo glicemico (da 60 a 120 mg/dl [da 3,3 a 6,7 mmol/l]) per il gruppo DTX401 rispetto al gruppo placebo, come misurato mediante CGM per la non inferiorità
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Baseline, week 12, week 24, week 30, week 36, week 42, week 48.
    2. Baseline, day 1 to 12, week 12, week 24, week 30, week 36, week 48.
    1. Basale, settimana 12, settimana 24, settimana 30, settimana 36, ¿¿settimana 42, settimana 48.
    2. Basale, giorno da 1 a 12, settimana 12, settimana 24, settimana 30, settimana 36, ¿¿settimana 48.
    E.5.2Secondary end point(s)
    1. Change from Baseline to Week 48 in time to hypoglycemia (< 54 mg/dL [3.0 mmol/L]) during a CFC
    2. Change from Baseline to Week 48 in percentage of time spent in normal glucose control (60 to 120 mg/dL [3.3 to 6.7 mmol/L]), as measured by CGM for superiority.
    3. Change from Baseline to Week 48 in number of total daily doses of cornstarch.
    4. Change from Baseline to Week 48 in the GSD FAD Signs and Symptoms Scale for the DTX401 Group compared with the Placebo Group.
    5. Incidence, severity, and relationship to investigational product of TEAEs, TEAEs of special interest, serious TEAEs, related TEAEs, discontinuations from study or investigational product due to AEs, and fatal AEs.
    6. Clinically relevant changes in standard chemistry, hematology, urinalysis panels, physical exams, and vital signs.
    1. Variazione dal basale alla Settimana 48 nel tempo di insorgenza dell’ipoglicemia (<54 mg/dl [3,0 mmol/l]) durante un test CFC
    2. Variazione dal basale alla Settimana 48 nella percentuale di tempo trascorso nel normale controllo del glucosio (da 60 a
    120 mg/dl [da 3,3 a 6,7 mmol/l]), misurata mediante CGM per superiorità
    3. Variazione dal basale alla Settimana 48 nel numero di dosi giornaliere totali di amido di mais
    4. Variazione dal basale alla Settimana 48 nella Scala dei segni e sintomi della GSD FAD per il gruppo DTX401 rispetto al gruppo placebo
    5. Incidenza, gravità e relazione con il prodotto sperimentale di TEAE, TEAE di particolare interesse, TEAE seri, TEAE correlati, interruzioni dello studio o del prodotto sperimentale a causa di EA ed EA fatali
    6. Variazioni clinicamente rilevanti in chimica standard, ematologia, analisi delle urine, esami obiettivi e segni vitali
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Baseline, week 12, week 24, week 36, week 48.
    2. Baseline, day 1 to 12, week 12, week 24, week 30, week 36, week 48.
    3. Baseline, week 12, week 24, week 30, week 36, week 42, week 48.
    4. Baseline, week 12, week 24, week 30, week 36, week 42, week 48.
    5. From the time the subject signs the Informed Consent Form (ICF) and up to 30 days after the End of Study Visit or Early Withdrawal/Termination Visit.
    6. From the time the subject signs the ICF and up to 30 days after the End of Study Visit or Early Withdrawal/Termination Visit
    1. Basale, settimana 12, settimana 24, settimana 36, ¿¿settimana 48.
    2. Basale, giorno da 1 a 12, settimana 12, settimana 24, settimana 30, settimana 36, ¿¿settimana 48.
    3. Basale, settimana 12, settimana 24, settimana 30, settimana 36, ¿¿settimana 42, settimana 48.
    4. Basale, settimana 12, settimana 24, settimana 30, settimana 36, ¿¿settimana 42, settimana 48.
    5. Dal momento in cui il soggetto firma il Modulo di Consenso Informato (ICF) e fino a 30 giorni dopo la Visita di Fine Studio o la Visita di Prelievo/Terminata.
    6. Dal momento in cui il soggetto firma l'ICF e fino a 30 giorni dopo la visita di fine studio o la visita di ritiro/terminazione anticipata
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Brazil
    Canada
    Japan
    United States
    Denmark
    France
    Germany
    Italy
    Netherlands
    Portugal
    Spain
    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 date of the Week 96 Visit (or Early Withdrawal Visit, if applicable) for the last participant enrolled in the study.
    La data della visita della settimana 96 (o della visita di ritiro anticipato, se applicabile) per l'ultimo partecipante iscritto allo studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 years1
    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) No
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 Yes
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 23
    F.4.2.2In the whole clinical trial 50
    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)
    After patients have ended their participation in the trial, they will be treated according to the normal standard of care. Upon completion of this study, all subjects who receive DTX401 are expected to enroll in a long-term follow-up study to evaluate safety and effectiveness of DTX401 via the DMP for at least 10 years after DTX401 administration. The DMP for GSDIa will be conducted under a separate protocol.
    Dopo che i pazienti hanno terminato la loro partecipazione allo studio, saranno trattati secondo il normale standard di cura. Al completamento di questo studio, tutti i soggetti che ricevono DTX401 dovrebbero iscriversi a uno studio di follow-up a lungo termine per valutare la sicurezza e l'efficacia di DTX401 tramite DMP per almeno 10 anni dopo la somministrazione di DTX401. Il DMP per GSDIa sarà condotto secondo un protocollo separato.
    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 Decision2022-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-17
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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