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

• ClinicalTrials.gov Identifier: NCT03517085
• Recruitment Status: Active, not recruiting
• First Posted: May 7, 2018
• Last Update Posted: December 19, 2020
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Study Description

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.

Condition or disease	Intervention/treatment	Phase
GSD1	Genetic: DTX401	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: July 24, 2018
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: DTX401 Dose 1; DTX401 solution for intravenous (IV) infusion	Genetic: DTX401; DTX401 administered as a single peripheral IV infusion; Other Name: AAV8G6PC
Experimental: DTX401 Dose 2; DTX401 solution for intravenous (IV) infusion	Genetic: DTX401; DTX401 administered as a single peripheral IV infusion; Other Name: AAV8G6PC
Experimental: DTX401 Dose 3; DTX401 solution for intravenous (IV) infusion	Genetic: DTX401; DTX401 administered as a single peripheral IV infusion; Other Name: AAV8G6PC
Experimental: DTX401 Dose 4; DTX401 solution for intravenous (IV) infusion	Genetic: DTX401; DTX401 administered as a single peripheral IV infusion; Other Name: AAV8G6PC

Outcome Measures

Primary Outcome Measures :

1. Adverse Events (AEs), Treatment-emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs) [ Time Frame: Up to 52 Weeks ]

Secondary Outcome Measures :

1. 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Connecticut

UCONN Health

Farmington, Connecticut, United States, 06030-3213

United States, Michigan

Michigan Medicine University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Texas

UT Health - McGovern Medical School

Houston, Texas, United States, 77030

Canada, Quebec

Montreal Children Hospital, McGill University Health Centre

Montréal, Quebec, Canada, H4A3J1

Netherlands

University Medical Center Groningen

Groningen, Netherlands, 9700RB

Spain

Complejo Hospitalario Universitario de Santiago

Santiago De Compostela, A Coruna, Spain, 15706

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT03517085
• Other Study ID Numbers: 401GSDIA01; 1706-1617 ( Other Identifier: NIH Protocol Registration Number )
• First Posted: May 7, 2018
• Last Update Posted: December 19, 2020
• Last Verified: December 2020

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

Keywords provided by Ultragenyx Pharmaceutical Inc:

glycogen storage disorder Ia; AAV; gene therapy; von Gierke disease; glucose metabolism disorder

Additional relevant MeSH terms:

Glycogen Storage Disease; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases