Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency
- Conditions
- OTC Deficiency
- Interventions
- Genetic: DTX301Other: PlaceboDrug: Oral CorticosteroidsDrug: Placebo for oral corticosteroids
- Registration Number
- NCT05345171
- Lead Sponsor
- Ultragenyx Pharmaceutical Inc
- Brief Summary
The primary objective is to evaluate the efficacy of DTX301 on the improvement of ornithine transcarbamylase (OTC) function by maintaining safe plasma ammonia levels with removal of dietary protein restriction and alternative pathway medication.
- Detailed Description
This study is a Phase 3, randomized, double-blind, placebo-controlled study of DTX301 in patients with late-onset OTC deficiency 12 years of age and older.
Participants will be randomized 1:1 to DTX301 or placebo group and followed closely for 64 weeks. At week 64 eligible patients will crossover and receive DTX301 if they had previously received placebo or placebo if they had previously received DTX301.
The planned study duration is up to 324 weeks. Upon completion of this study or early withdrawal, all participants who received DTX301 are invited to enroll in the Disease Monitoring Program (DMP) for follow-up for up to an additional 5 years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 50
- Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation by enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis)
- Free from symptomatic hyperammonemia and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline
- If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening
- If on a protein-restricted diet, must be on a stable total daily protein intake that does not vary more than 20% for ≥ 4 weeks prior to screening
- From the time written informed consent through Week 128, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not father a child or donate sperm
Key
- Significant hepatic inflammation or cirrhosis
- Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the 2021 CKD-EPI creatinine-based formula (Inker et al., 2021) for patients ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients < 18 years of age
- Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity
- Active infection (viral or bacterial)
- Detectable pre-existing antibodies to the AAV8 capsid
- Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
- Participation (current or previous) in another gene transfer study
Note: Additional inclusion/exclusion criteria may apply, per protocol
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Placebo, Then DTX301 DTX301 Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution. DTX301, Then Placebo DTX301 Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo. DTX301, Then Placebo Placebo Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo. Placebo, Then DTX301 Placebo Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution. DTX301, Then Placebo Oral Corticosteroids Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo. DTX301, Then Placebo Placebo for oral corticosteroids Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo. Placebo, Then DTX301 Oral Corticosteroids Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution. Placebo, Then DTX301 Placebo for oral corticosteroids Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution. DTX301, Then Placebo Sodium Acetate Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo. Placebo, Then DTX301 Sodium Acetate Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution.
- Primary Outcome Measures
Name Time Method Plasma Ammonia as Measured by 24-hour Ammonia (AUC0-24) Week 64 Percentage of Participants Who Have Achieved Complete Response Week 64
- Secondary Outcome Measures
Name Time Method Number of Participants With Anti-OTC Antibodies Up to Week 324 Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, Physical Examination Results, and Vital Sign Measurements Baseline, Up to Week 324 Rate of Hyperammonemic Crises (HACs) from Baseline to Week 64 Compared to Pre-Enrollment Pre-enrollment, Baseline, Week 64 Change from Baseline in Plasma Ammonia (AUC0-24) Baseline, Up to Week 64 Patient Global Impression of Change (PGIC) Overall Change Score Week 64 Percentage of Participants Who Have Achieved Complete Response, Response, or No Response Week 64 Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs, Related Serious TEAEs and Adverse Events of Special Interest (AESIs) Up to Week 324 Change from Baseline in Plasma Ammonia (AUC0-24) After DTX301 Exposure Baseline, Up to Week 64
Trial Locations
- Locations (25)
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
University of California
🇺🇸Los Angeles, California, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
Yale School of Medicine
🇺🇸New Haven, Connecticut, United States
University of Florida College of Medicine
🇺🇸Gainesville, Florida, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Hospital Italiano de Buenos Aires
🇦🇷Buenos Aires, Argentina
Clinica Universitaria Reina Fabiola
🇦🇷Córdoba, Argentina
Hospital de Clinicas de Porto Alegre
🇧🇷Porto Alegre, Brazil
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Hopital Femme Mere Enfant
🇫🇷Bron, France
Necker-Enfants Maladas Hospital
🇫🇷Paris, France
Universitatsklinikum Heidelberg
🇩🇪Heidelberg, Germany
University of Naples Federico II
🇮🇹Napoli, Italy
University Hospital of Padova
🇮🇹Padova, Italy
Ospedale Infantile Regina Margherita
🇮🇹Torino, Italy
Kumamoto University Hospital
🇯🇵Kumamoto, Japan
Fujita Health University Hospital
🇯🇵Toyoake, Japan
Erasmus Universitair Medisch Centrum Rotterrdam
🇳🇱Rotterdam, Netherlands
Centro Hospitalar Universitario de Sao Joao
🇵🇹Porto, Portugal
Fundacio Hospital Universitari Vall D'Hebron-Institute de Recerca
🇪🇸Barcelona, Spain
Hospital Clinico Universitario de Santiago
🇪🇸Santiago De Compostela, Spain
University Hospitals Birmingham NHS
🇬🇧Birmingham, United Kingdom