Clinical trial NCT03517085: Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in Adults With Glycogen Storage Disease Type Ia (GSDIa)
Official title: A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Glucose-6- Phosphatase (G6Pase) in Adults With Glycogen Storage Disease Type Ia (GSDIa)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: GSD1
Keywords: glycogen storage disorder Ia
AAV
gene therapy
von Gierke disease
glucose metabolism disorder
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2018-05-07
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to determine the safety of single doses of DTX401, including the incidence of dose-limiting toxicities (DLTs) at each dose level.

Detailed description: Participants enrolled in the 401GSDIA01 study will be monitored for 52 weeks following DTX401 administration. Participants in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible vector-induced hepatitis following treatment with DTX401. Participants in Cohort 4 will receive prophylactic oral steroid treatment to prevent possible vector-induced hepatitis. After completion of the Week 52 visit or early withdrawal, participants will be offered enrollment into a 4-year extension study.

Eligibility criteria: Key Inclusion Criteria:

* Males and females ≥18 years of age
* Documented GSDIa with confirmation by molecular testing
* Documented history of ≥1 hypoglycemic event with blood glucose \<60 mg/dL (\<3.33 mmol/L)
* Patient's GSDIa disease is stable as evidenced by no hospitalization for severe hypoglycemia during the 4-week period preceding the screening visit

Key Exclusion Criteria:

* Anti-AAV8 neutralizing antibody titer ≥1:5
* Screening or Baseline (Day 0) blood glucose level \<60 mg/dL (\<3.33 mmol/L)
* Liver transplant, including hepatocyte cell therapy/transplant
* Presence of liver adenoma \>5 cm in size
* Presence of liver adenoma \>3 cm and ≤5 cm in size that has a documented annual growth rate of ≥0.5 cm per year
* Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> upper limit of normal (ULN), total bilirubin \> 1.5 x ULN, or alkaline phosphatase \> 2.5 x ULN

Note additional inclusion/exclusion criteria may apply, per protocol.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs)
timeFrame: AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug through the End of Study (EOS)/Early Withdrawal visit (up to Week 52) plus 30 days.
Secondary outcomes:
measure: Change From Baseline in Time to First Hypoglycemic Event Over Time
timeFrame: Baseline, Weeks 12, 24, 52
Other outcomes:
Locations:
city: Farmington
country: United States
facility: UCONN Health
state: Connecticut
city: Ann Arbor
country: United States
facility: Michigan Medicine University of Michigan
state: Michigan
city: Houston
country: United States
facility: UT Health - McGovern Medical School
state: Texas
city: Montréal
country: Canada
facility: Montreal Children Hospital, McGill University Health Centre
state: Quebec
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
state: A Coruna
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Zhang L, Lee C, Arnaoutova I, Anduaga J, Starost MF, Mansfield BC, Chou JY. Gene therapy using a novel G6PC-S298C variant enhances the long-term efficacy for treating glycogen storage disease type Ia. Biochem Biophys Res Commun. 2020 Jun 30;527(3):824-830. doi: 10.1016/j.bbrc.2020.04.124. Epub 2020 May 16.
citation: Zhang L, Cho JH, Arnaoutova I, Mansfield BC, Chou JY. An evolutionary approach to optimizing glucose-6-phosphatase-alpha enzymatic activity for gene therapy of glycogen storage disease type Ia. J Inherit Metab Dis. 2019 May;42(3):470-479. doi: 10.1002/jimd.12069. Epub 2019 Feb 22.