A Study of Adeno-Associated Virus Serotype 8-Mediated Gene Transfer of Glucose-6-Phosphatase in Patients With Glycogen Storage Disease Type Ia (GSDIa)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Adeno-Associated Virus Serotype 8-Mediated Gene Transfer of Glucose-6-Phosphatase in Patients With Glycogen Storage Disease Type Ia

The primary objectives of this study are to evaluate the efficacy of DTX401 to reduce or eliminate dependence on exogenous glucose replacement therapy to maintain euglycemia and to maintain or improve the quality of glucose control.

Study Overview

• Status: Active, not recruiting
• Conditions: Glycogen Storage Disease Type IA
• Intervention / Treatment: Genetic: DTX401; Other: Placebo; Drug: Oral corticosteroids; Drug: Placebo for oral corticosteroids

Detailed Description

Study DTX401-CL301 is a phase 3 study to determine the efficacy and confirm the safety of DTX401 in patients 8 years and older with glycogen storage disease type Ia (GSDIa).

Participants will be randomized 1:1 to DTX401 or placebo group, and followed closely for 48 weeks. At week 48 eligible participants will cross over and receive DTX401 if they had previously received placebo or placebo if they had previously received DTX401, and will be followed closely for an additional 96 weeks. After completion of week 144 or early withdrawal, participants will be offered enrollment into a Disease Monitoring Program (DMP) where they will be followed for at least 10 years post DTX401 infusion.

In Japan, there will be a single open label study arm and all participants will be treated with DTX401. At week 48, Japanese participants will be offered enrollment into a Disease Monitoring Program (DMP) where they will be followed for at least 10 years post DTX401 infusion.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre
• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3H 1P3
      • McGill University
• Denmark
  • Capital
    • Kopenhagen, Capital, Denmark, 2100
      • Righospitalet
• Germany
  • Hamburg, Germany, 20251
    • University Medical Center Eppendorf
• Italy
  • Naples, Italy, 80131
    • University of Naples
  • Linguria
    • Genova, Linguria, Italy, 16147
      • Istituto Giannina Gaslini
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • Groningen University
• Spain
  • A Coruna
    • Santiago De Compostela, A Coruna, Spain, 15706
      • Hospital Clinico Universitario De Santiago
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • New York
    • Bronx, New York, United States, 10467
      • Mount Sinai
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Primary Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Documented GSDIa with confirmation by molecular testing or enzymatic activity on liver biopsy
• Currently receiving a therapeutic regimen of cornstarch (or equivalent), following international guidance/recommendations with stable nutrition, glycemic, and clinical status.
• Willing and able to complete the informed consent process and to comply with study procedures and visit schedule
• Females of childbearing potential and fertile males must consent to use highly effective contraception from the period following informed consent through the duration of the 144-week study and in cases of early withdrawal at least 48 weeks after the last dose of investigational product (IP). Female subjects must agree not to become pregnant. Male subjects must agree not to father a child or donate sperm

Key Exclusion Criteria:

• Detectable pre-existing antibodies to the AAV8 capsid
• History of liver transplant, including hepatocyte cell therapy/ transplant
• History of liver disease
• 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
• Non-fasting triglycerides ≥1000 mg/dL
• Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study.
• Current or previous participation in another gene transfer study
• History of illicit drug use within 60 days prior to screening or positive results from an 8-panel urine drug screen during the Screening Period completed at 2 time points at least 4 weeks apart

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DTX401, Then Placebo; Participants receive single peripheral intravenous (IV) infusion of DTX401 in solution. At week 48 participants receive single peripheral IV infusion of Placebo.	Genetic: DTX401; nonreplicating, recombinant, adeno-associated virus (AAV) serotype 8 (AAV8); Other: Placebo; Normal Saline infusion; Drug: Oral corticosteroids; Participants who receive DTX401 solution will receive oral corticosteroids; Other Names: prednisolone; Drug: Placebo for oral corticosteroids; Participants who receive Placebo will receive placebo oral corticosteroids to maintain the study blind
Placebo Comparator: Placebo, Then DTX401; Participants receive single peripheral IV infusion of Placebo. At week 48 eligible participants receive single peripheral IV infusion of DTX401 solution.	Genetic: DTX401; nonreplicating, recombinant, adeno-associated virus (AAV) serotype 8 (AAV8); Other: Placebo; Normal Saline infusion; Drug: Oral corticosteroids; Participants who receive DTX401 solution will receive oral corticosteroids; Other Names: prednisolone; Drug: Placebo for oral corticosteroids; Participants who receive Placebo will receive placebo oral corticosteroids to maintain the study blind
Experimental: DTX401 (Japan Only); Participants receive single peripheral intravenous (IV)infusion of DTX401 in solution.	Genetic: DTX401; nonreplicating, recombinant, adeno-associated virus (AAV) serotype 8 (AAV8); Drug: Oral corticosteroids; Participants who receive DTX401 solution will receive oral corticosteroids; Other Names: prednisolone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change from Baseline to Week 48 in Daily Cornstarch Intake	Baseline, Week 48

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline to Week 48 in Number of Total Daily Doses of Cornstarch in DTX401 Group Compared to Placebo Group	Baseline, Week 48
Change from Baseline to Week 48 in Percentage of Glucose Values in Hypoglycemic Range (<70mg/dL [3.9 mmol/L])	Baseline, Week 48
Patient Global Impression of Change (PGIC) Assessment Score at Week 48	Baseline, Week 48
Change from Baseline to Week 48 in Time to Hypoglycemia (<54 mg/dL [3.0 mmol/L]) During a Controlled Fasting Challenge	Baseline, Week 48
Change from Baseline to Week 48 in Percentage of Glucose Values in the Range of 70-120 mg/dL (3.9-6.7 mmol/L)	Baseline, Week 48
Number of Treatment Emergent Adverse Events (TEAEs), TEAEs of Special Interest, Serious TEAEs, Related TEAEs, Discontinuations From Study or Investigational Product Due to Adverse Events (AEs), and Fatal AEs	up to 144 weeks

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc
• Investigators: Study Director: Medical Director, Ultragenyx Pharmaceutical Inc

Publications and helpful links

Helpful Links

• Ultragenyx Patient Advocacy/GSDIA Disease Information

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2021
• Primary Completion (Actual): February 20, 2024
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: July 14, 2021
• First Submitted That Met QC Criteria: November 17, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: gene therapy; AAV; glycogen storage disorder Ia; von Gierke disease; glucose metabolism disorder; GSDIa; GSD1
• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Disease; Metabolic Diseases; Glycogen Storage Disease; Glycogen Storage Disease Type I; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: DTX401-CL301; 2020-004184-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No