E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Glycogen Storage Disease Type Ia (GSDIa). |
glucogenosis de tipo Ia (GSD-Ia) |
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E.1.1.1 | Medical condition in easily understood language |
Inherited disorder causing decrease of glucose. |
desorden hereditario causante de la disminución de glucosa |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056911 |
E.1.2 | Term | Glycogen storage disease type IA |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the safety of single IV doses of DTX401 in adults with GSDIa, including the incidence of dose-limiting toxicities (DLTs). |
Determinar la seguridad de distintas dosis intravenosas (IV) únicas de DTX401 en adultos con GSDIa, incluida la incidencia de toxicidades limitantes de la dosis (TLD). |
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E.2.2 | Secondary objectives of the trial |
To establish a dose of DTX401 that achieves symptom-free euglycemia (glucose >=60 mg/dL [>=3.33 mmol/L]) in a setting of a controlled fasting challenge to allow further clinical development. |
Determinar una dosis de DTX401 que logre la euglucemia asintomática (glucosa >= 60 mg/dl [>=3,33 mmol/l]) en el contexto de una prueba de provocación en ayunas controlada para poder continuar con el desarrollo clínico. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent. 2. Males and females >=18 years of age. 3. Documented GSDIa with confirmation by molecular testing. 4. Documented history of >=1 hypoglycemic event with glucose <60 mg/dL (<3.33 mmol/L). 5. Subject’s GSDIa disease is stable as evidenced by no hospitalization for severe hypoglycemia during the 4-week period preceding the screening visit. 6. Hematology and coagulation panel results are within the normal range or, if outside the normal range, are deemed not clinically significant in the opinion of the investigator. 7. No known allergic reaction to any component of DTX401. 8. Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalization, frequent blood collections, and 24-hour urine collection. 9. Males and females of childbearing potential must be willing to use effective contraception at the time of administration of DTX401 and for 52 weeks following administration of DTX401 to prevent the potential transmission of the AAV vector. |
1.Disposición y capacidad para otorgar el consentimiento informado por escrito. 2.Varones y mujeres de 18 años o más. 3.GSDIa documentada con confirmación por análisis molecular. 4.Antecedentes documentados de >= 1 episodio hipoglucémico con un valor de glucosa < 60 mg/dl (< 3,33 mmol/l). 5.GSDIa estable, demostrado por la ausencia de hospitalizaciones por hipoglucemia grave durante el periodo de 4 semanas previo a la visita de selección. 6.Resultados de las pruebas de hematología y coagulación dentro de la normalidad o, si están fuera del intervalo normal, sin significación clínica a juicio del investigador. 7.Ausencia de reacciones alérgicas conocidas a cualquiera de los componentes de DTX401. 8.Disposición y capacidad para cumplir los procedimientos y requisitos del estudio, incluidas las hospitalizaciones periódicas, las extracciones de sangre frecuentes y la obtención de muestras de orina de 24 horas. 9. Los varones y las mujeres potencialmente fértiles deben aceptar el uso de métodos anticonceptivos eficaces desde el momento de la administración de DTX401 y durante las 52 semanas siguientes para prevenir la posible transmisión del vector del AAV |
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E.4 | Principal exclusion criteria |
1. Screening or Baseline (Day 0) glucose level <60 mg/dL (<3.33 mmol/L); subjects may be rescreened after glucose is controlled and stable, at the discretion of the investigator. 2. Liver transplant, including hepatocyte cell therapy/transplant. 3. Presence of liver adenoma >5 cm in size. 4. Presence of liver adenoma >3 cm and <=5 cm in size that has 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: alanine aminotransferase (ALT) or aspartate aminotransferase > the upper limit of normal (ULN), total bilirubin >1.5 × ULN, or alkaline phosphatase >2.5 × ULN. Liver function tests may be repeated during the screening period at the investigator’s discretion. 6. Serum creatinine >2.0 mg/dL. 7. Triglycerides >=1000 mg/dL at the time of the screening visit. 8. Presence of active, or history of treatment for, hepatitis B virus or hepatitis C virus infection. 9. History of human immunodeficiency virus infection AND any of the following: CD4+ cell count <350 cells/mm3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or viral load >200 copies/mL, on 2 separate occasions, as measured by polymerase chain reaction. 10. History of a malignancy for which the subject has received treatment in the past 2 years except for prostate cancer treated with watchful waiting or surgically removed nonmelanoma skin cancer. 11. Active infection (viral or bacterial). 12. Anti-AAV8 neutralizing antibody titer >=1:5. 13. Participation (current or previous) in another gene transfer study. 14. Participation in another investigational product study within 3 months of Screening. 15. Has a positive serum pregnancy test at Screening (females of childbearing potential only), a positive urine pregnancy test at Baseline (Day 0; females of childbearing potential only), or is nursing. 16. Has any other significant medical condition that the investigator feels would be a risk to the subject or would impede the study. |
1.Glucosa < 60 mg/dl (< 3,33 mmol/l) en la selección o en el momento basal (Día 0); los sujetos podrán repetir la selección una vez la glucosa esté controlada y estable, a criterio del investigador. 2.Trasplante de hígado, incluido el trasplante o tratamiento de hepatocitos. 3.Presencia de adenoma hepático con un tamaño > 5 cm. 4.Presencia de adenoma hepático con un tamaño > 3 cm y <= 5 cm, que tenga una tasa de crecimiento anual documentada >= 0,5 cm al año. 5.Inflamación hepática o cirrosis importantes demostradas mediante estudios de imagen o por alguna de los anomalías analíticas siguientes: alanina aminotransferasa (ALT) o aspartato aminotransferasa > el límite superior de la normalidad (LSN); bilirrubina total > 1,5 veces el LSN o fosfatasa alcalina > 2,5 veces el LSN. Durante el periodo de selección se podrán repetir las pruebas de la función hepática a criterio del investigador. 6.Creatinina sérica > 2,0 mg/dl. 7.Triglicéridos >= 1000 mg/dl en el momento de la visita de selección. 8.Presencia de infección activa o antecedentes de tratamiento para la infección por el virus de la hepatitis B o C. 9.Antecedentes de infección por el virus de la inmunodeficiencia humana Y cualquiera de los siguientes: Recuento de linfocitos CD4+ < 350 células/mm3, variación de pauta de tratamiento antirretroviral en los 6 meses anteriores al día 0 o viremia > 200 copias/ml documentada en dos ocasiones distintas mediante reacción en cadena de la polimerasa. 10.Antecedentes de neoplasia maligna para la que el sujeto haya recibido tratamiento en los 2 últimos años, excepto el cáncer de próstata tratado con espera vigilante o el cáncer de piel no melanomatoso extirpado quirúrgicamente. 11.Infección activa (vírica o bacteriana). 12.Título de anticuerpos neutralizantes frente al AAV8 >= 1:5. 13.Participación (actual o previa) en otro estudio de transferencia génica. 14.Participación en otro estudio con un producto en investigación en los 3 meses anteriores a la selección. 15.Resultado positivo en una prueba de embarazo en suero practicada en la selección (solo las mujeres potencialmente fértiles) o en una prueba de embarazo en orina practicada en el momento basal (Día 0; solo las mujeres potencialmente fértiles) o paciente en periodo de lactancia. 16.Cualquier otra condición médica de importancia que, en opinión del investigador suponga un riesgo para el sujeto o impida la realización del estudio |
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E.5 End points |
E.5.1 | Primary end point(s) |
The incidence of AEs, including the incidence of DLTs at each dose level, TEAEs, and SAEs for each dosing cohort, assessed by severity and relationship to study product. |
Incidencia de acontecimientos adversos (AA), incluida la incidencia de TLD en cada nivel de dosis, acontecimientos adversos de aparición durante el tratamiento (AAAT) y acontecimientos adversos graves (AAG) por cohorte de dosis, evaluados según la intensidad y la relación con el fármaco del estudio. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the time the subject signs the Informed Consent Form (ICF) and up to 30 days after the end of the study / early withdrawal visit. |
Desde la firma del consentimiento informado hasta 30 dias después de la visita de fin de estudio / retirada prematura. |
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E.5.2 | Secondary end point(s) |
The change from baseline in time (in minutes) to first hypoglycemic event (defined as glucose <60 mg/dL [<3.33 mmol/L]) during a controlled fasting challenge at 6, 12, 24, and 52 weeks after IV administration of DTX401. |
Variación con respecto al momento basal del tiempo (en minutos) hasta el primer episodio hipoglucémico (definido como un valor de glucosa < 60 mg/dl [< 3,33 mmol/l]) durante una prueba de provocación en ayunas controlada a las 6, 12, 24 y 52 semanas después de la administración IV de DTX401. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 0 and weeks 6, 12, 24 and 52. |
Día 0 y semanas 6, 12, 24 y 52 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Netherlands |
Spain |
United States |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 21 |