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

Primary Purpose

GSD1

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

DTX401

steroid regimen

About this trial

This is an interventional treatment trial for GSD1 focused on measuring glycogen storage disorder Ia, AAV, gene therapy, von Gierke disease, glucose metabolism disorder

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

UCONN Health
Michigan Medicine University of Michigan
UT Health - McGovern Medical School
Montreal Children Hospital, McGill University Health Centre
University Medical Center Groningen
Complejo Hospitalario Universitario de Santiago

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

DTX401 Cohort 1

DTX401 Cohort 2

DTX401 Cohort 3

DTX401 Cohort 4

Arm Description

Dose 1 (2.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after alanine aminotransferase [ALT] elevation)

Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

Dose 2 (6.0 × 10^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)

Dose 2 (6.0 × 10^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs)

An AE is defined as any untoward medical occurrence, regardless of its causal relationship to study product. An SAE is defined as any event that: results in death; is immediately life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or an important medical event, in the opinion of the investigator. The relationship to study drug was categorized as unrelated, possible, probable or definite. A DLT is defined as any AE/SAE ≥ Grade 3 that is considered by the Investigator and/or Sponsor to be related to DTX401, based on the Nation Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 or later version. Per protocol, SAEs that occurred > 30 days after EOS or Early withdrawal visit, did not need to be reported unless Investigator considered them related to study product.

Secondary Outcome Measures

Change From Baseline in Time to First Hypoglycemic Event Over Time

The change from baseline in time (in hours) to first hypoglycemic event (defined as glucose < 54 mg/dL [< 3.0 mmol/L]) during a controlled fasting challenge at 12, 24, and 52 weeks after IV administration of DTX401. A positive change from baseline is favorable.

Full Information

NCT ID

NCT03517085

First Posted

April 24, 2018

Last Updated

October 25, 2022

Sponsor

Ultragenyx Pharmaceutical Inc

1. Study Identification

Unique Protocol Identification Number

NCT03517085

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)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Completed

Study Start Date

May 18, 2018 (Actual)

Primary Completion Date

November 2, 2021 (Actual)

Study Completion Date

November 2, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ultragenyx Pharmaceutical Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

GSD1

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DTX401 Cohort 1

Arm Type

Experimental

Arm Description

Dose 1 (2.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after alanine aminotransferase [ALT] elevation)

Arm Title

DTX401 Cohort 2

Arm Type

Experimental

Arm Description

Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

Arm Title

DTX401 Cohort 3

Arm Type

Experimental

Arm Description

Dose 2 (6.0 × 10^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)

Arm Title

DTX401 Cohort 4

Arm Type

Experimental

Arm Description

Dose 2 (6.0 × 10^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

Intervention Type

Genetic

Intervention Name(s)

DTX401

Other Intervention Name(s)

AAV8G6PC, Pariglasgene brecaparvovec

Intervention Description

DTX401 administered as a single peripheral intravenous (IV) infusion

Intervention Type

Drug

Intervention Name(s)

steroid regimen

Intervention Description

prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs)

Description

Time Frame

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 Outcome Measure Information:

Title

Change From Baseline in Time to First Hypoglycemic Event Over Time

Description

Time Frame

Baseline, Weeks 12, 24, 52

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Ultragenyx Pharmaceutical Inc

Official's Role

Study Director

Facility Information:

Facility Name

UCONN Health

City

Farmington

State/Province

Connecticut

ZIP/Postal Code

06030-3213

Country

United States

Facility Name

Michigan Medicine University of Michigan

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

UT Health - McGovern Medical School

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Montreal Children Hospital, McGill University Health Centre

City

Montréal

State/Province

Quebec

ZIP/Postal Code

H4A3J1

Country

Canada

Facility Name

University Medical Center Groningen

City

Groningen

ZIP/Postal Code

9700RB

Country

Netherlands

Facility Name

Complejo Hospitalario Universitario de Santiago

City

Santiago De Compostela

State/Province

A Coruna

ZIP/Postal Code

15706

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

32430177

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.

Results Reference

derived

PubMed Identifier

30714174

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.

Results Reference

derived

Learn more about this trial

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

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