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

Sponsor

Ultragenyx Pharmaceutical Inc (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05139316

Collaborator

(none)

Enrollment

Locations

Arms

28.7

Anticipated Duration (Months)

1.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glycogen Storage Disease Type IA	Genetic: DTX401 Other: Placebo Drug: Oral corticosteroids Drug: Placebo for oral corticosteroids	Phase 3

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 48 weeks. After completion of week 96 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 8, 2021

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Apr 1, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Percent Change from Baseline to Week 48 in Daily Cornstarch Intake [Baseline, Week 48]
Change from Baseline to Week 48 in the Percentage of Time Spent in Normal Glucose Control (60 to 120 mg/dL [3.3 to 6.7 mmol/L]) as Measured by Continuous Glucose Monitoring (CGM) for Noninferiority [Baseline, Week 48]

Secondary Outcome Measures

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 Time Spent in Normal Glucose Control (60 to 120 mg/dL [3.3 to 6.7 mmol/L]) as Measured by CGM for Superiority [Baseline, Week 48]
Change from Baseline to Week 48 in Number of Total Daily Doses of Cornstarch [Baseline, Week 48]
Change from Baseline to Week 48 in the Glycogen Storage Disease Functional Assessment Diary (GSD FAD) Signs and Symptoms Scale [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 96 weeks]
Number of Participants with Clinically Relevant Changes in Standard Chemistry [up to 96 weeks]
Number of Participants with Clinically Relevant Changes in Hematology [up to 96 weeks]
Number of Participants with Clinically Relevant Changes in Urinalysis [up to 96 weeks]
Number of Participants with Clinically Relevant Changes in Physical Exams [up to 96 weeks]
Number of Participants with Clinically Relevant Changes in Vital Signs [up to 96 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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) and is clinically stable as evidenced by no more than a 10% change in cornstarch (or equivalent) regimen and no hospitalization for hypoglycemia over a 4 week period
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 96-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 6 weeks apart

Note additional inclusion/exclusion criteria may apply, per protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Orange County	Orange	California	United States	92868
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	University of Connecticut Health Center	Farmington	Connecticut	United States	06030
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	University of Michigan	Ann Arbor	Michigan	United States	48109
6	Mount Sinai	Bronx	New York	United States	10467
7	Duke University	Durham	North Carolina	United States	27710
8	Cleveland Clinic	Cleveland	Ohio	United States	44195
9	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
10	University of Texas	Houston	Texas	United States	77030
11	Primary Children's Hospital	Salt Lake City	Utah	United States	84132
12	Hospital de Clinicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90035-903
13	BC Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
14	McGill University	Montréal	Quebec	Canada	H3H 1P3
15	Righospitalet	Kopenhagen	Capital	Denmark	2100
16	Hopital Antoine Beclere	Clamart	Hauts-de-Seine	France	92140
17	Hopital Femme Mere Enfant	Bron	Rhone	France	69500
18	University Medical Center of Freiburg	Freiburg		Germany	79106
19	University Medical Center Eppendorf	Hamburg		Germany	20251
20	Istituto Giannina Gaslini	Genova	Linguria	Italy	16147
21	University of Naples	Naples		Italy	80131
22	Kumamoto University	Kumamoto		Japan	860-85555
23	Osaka City General Hospital	Osaka		Japan	534-0021
24	Yonsei University Wonju Severance Christian Hospital	Wŏnju	Gangwon-do	Korea, Republic of	26426
25	Groningen University	Groningen		Netherlands	9700 RB
26	Hospital de Santa Maria (Adult)	Lisboa		Portugal	1649-035
27	Hospital de Santa Maria (Pediatric)	Lisboa		Portugal	1649-035
28	Hospital Clinico Universitario de Santiago	Santiago De Compostela	A Coruna	Spain	15706
29	Hospital Universitario 12 de Octubre	Madrid	Community Of Madrid	Spain	28041