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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
Study DTX401-CL301 is a phase 3, randomized, double-blind, placebo-controlled 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.

Official Title
-----------------
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

Conditions
-----------------
Glycogen Storage Disease Type IA

Intervention / Treatment
-----------------
* Genetic: DTX401
* Other: Placebo
* Drug: Oral corticosteroids
* Drug: Placebo for oral corticosteroids


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 8 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
glycogen storage disorder Ia, AAV, gene therapy, von Gierke disease, glucose metabolism disorder, GSDIa, GSD1