Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in Adults With Glycogen Storage Disease Type Ia (GSDIa)

• ClinicalTrials.gov Identifier: NCT03517085
• Recruitment Status: Completed
• First Posted: May 7, 2018
• Last Update Posted: November 23, 2021
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Tracking Information

• First Submitted Date: April 24, 2018
• First Posted Date: May 7, 2018
• Last Update Posted Date: November 23, 2021
• Actual Study Start Date: July 24, 2018
• Actual Primary Completion Date: November 2, 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 24, 2018): Adverse Events (AEs), Treatment-emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs) [ Time Frame: Up to 52 Weeks ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 18, 2021)

Change from Baseline in Time (Minutes) to First Hypoglycemic Event During a Controlled Fasting Challenge at Weeks 12, 24, and 52 [ Time Frame: Baseline and Weeks 12, 24, and 52 ]

The change from baseline in time (in minutes) to first hypoglycemic event (defined as glucose <54 mg/dL [<3.0 mmol/L]) during a controlled fasting challenge after IV administration of DTX401).

Original Secondary Outcome Measures (submitted: April 24, 2018)

Change from Baseline in Time (Minutes) to First Hypoglycemic Event During a Controlled Fasting Challenge at Weeks 6, 12, 24, and 52 [ Time Frame: Baseline and Weeks 6, 12, 24, and 52 ]

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 after IV administration of DTX401).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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: Subjects enrolled in the 401GSDIA01 study will be monitored for 52 weeks following DTX401 administration. Subjects in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible vector-induced hepatitis following treatment with DTX401. Subjects 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, subjects will be offered enrollment into a 4-year extension study.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: GSD1

Intervention

Genetic: DTX401

DTX401 administered as a single peripheral IV infusion

Other Name: AAV8G6PC

Study Arms

• Experimental: DTX401 Dose 1
  DTX401 solution for intravenous (IV) infusion
  Intervention: Genetic: DTX401
• Experimental: DTX401 Dose 2
  DTX401 solution for intravenous (IV) infusion
  Intervention: Genetic: DTX401
• Experimental: DTX401 Dose 3
  DTX401 solution for intravenous (IV) infusion
  Intervention: Genetic: DTX401
• Experimental: DTX401 Dose 4
  DTX401 solution for intravenous (IV) infusion
  Intervention: Genetic: DTX401

Publications *

• 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.
• Zhang L, Cho JH, Arnaoutova I, Mansfield BC, Chou JY. An evolutionary approach to optimizing glucose-6-phosphatase-α 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 19, 2020): 12
• Original Estimated Enrollment (submitted: April 24, 2018): 9
• Actual Study Completion Date: November 2, 2021
• Actual Primary Completion Date: November 2, 2021 (Final data collection date for primary outcome measure)

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 × ULN, alkaline phosphatase >2.5 × ULN

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT03517085
• Other Study ID Numbers: 401GSDIA01; 1706-1617 ( Other Identifier: NIH Protocol Registration Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ultragenyx Pharmaceutical Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Ultragenyx Pharmaceutical Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

• PRS Account: Ultragenyx Pharmaceutical Inc
• Verification Date: November 2021