Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency

A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients With Late-onset OTC Deficiency

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.

Study Overview

• Status: Recruiting
• Conditions: OTC Deficiency
• Intervention / Treatment: Genetic: DTX301; Other: Placebo; Drug: Oral Corticosteroids; Drug: Placebo for oral corticosteroids; Drug: Sodium Acetate

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Patients Contact: Trial Recruitment; Phone Number: 1-888-756-8657; Email: trialrecruitment@ultragenyx.com
• Study Contact Backup: Name: HCPs Contact: Medical Information; Phone Number: 1-888-756-8657; Email: medinfo@ultragenyx.com

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1199
    • Recruiting
    • Hospital Italiano de Buenos Aires
  • Córdoba, Argentina, X5004
    • Recruiting
    • Clinica Universitaria Reina Fabiola
• Australia
  • Sydney, Australia, 2145
    • Not yet recruiting
    • Westmead Hospital
• Brazil
  • Porto Alegre, Brazil, 90035-903
    • Recruiting
    • Hospital de Clínicas de Porto Alegre
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Recruiting
      • The Hospital for Sick Children
• France
  • Bron, France, 69500
    • Recruiting
    • Hopital Femme Mere Enfant
  • Paris, France, 75015
    • Recruiting
    • Necker-Enfants Maladas Hospital
• Germany
  • Heidelberg, Germany, 69120
    • Recruiting
    • Universitätsklinikum Heidelberg
• Italy
  • Napoli, Italy, 80138
    • Not yet recruiting
    • University of Naples Federico II
  • Padova, Italy, 35129
    • Not yet recruiting
    • University Hospital of Padova
  • Torino, Italy, 10126
    • Not yet recruiting
    • Ospedale Infantile Regina Margherita
• Japan
  • Kumamoto, Japan, 860-8556
    • Recruiting
    • Kumamoto University Hospital
  • Toyoake, Japan, 470-1192
    • Not yet recruiting
    • Fujita Health University Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015
    • Recruiting
    • Erasmus Universitair Medisch Centrum Rotterrdam
• Portugal
  • Porto, Portugal, 4200-319
    • Recruiting
    • Centro Hospitalar Universitário de São João
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Fundacio Hospital Universitari Vall D'Hebron-Institute de Recerca
  • Santiago De Compostela, Spain, 15706
    • Recruiting
    • Hospital Clinico Universitario de Santiago
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • Not yet recruiting
    • University Hospitals Birmingham NHS
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Recruiting
      • University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Not yet recruiting
      • Yale School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32603
      • Recruiting
      • University of Florida College of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• 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 Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DTX301, Then Placebo; Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo.	Genetic: DTX301; non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector; Other Names: avalotcagene ontaparvovec; Other: Placebo; normal saline infusion; Drug: Oral Corticosteroids; Participants who receive DTX301 solution will receive oral corticosteroids.; Other Names: Prednisolone; Drug: Placebo for oral corticosteroids; Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind; Drug: Sodium Acetate; A tracer for the Ureagenesis Rate Test (URT)
Experimental: Placebo, Then DTX301; Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution.	Genetic: DTX301; non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector; Other Names: avalotcagene ontaparvovec; Other: Placebo; normal saline infusion; Drug: Oral Corticosteroids; Participants who receive DTX301 solution will receive oral corticosteroids.; Other Names: Prednisolone; Drug: Placebo for oral corticosteroids; Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind; Drug: Sodium Acetate; A tracer for the Ureagenesis Rate Test (URT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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
Number of Participants With Anti-OTC Antibodies	Up to Week 324
Patient Global Impression of Change (PGIC) Overall Change Score	Week 64
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) After DTX301 Exposure	Baseline, Up to Week 64
Change from Baseline in Plasma Ammonia (AUC0-24)	Baseline, Up to Week 64
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, Physical Examination Results, and Vital Sign Measurements	Baseline, Up to Week 324

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Ultragenyx Patient Advocacy/OTC Disease Information

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: April 18, 2022
• First Submitted That Met QC Criteria: April 22, 2022
• First Posted (Actual): April 25, 2022

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Ornithine Carbamoyltransferase Deficiency Disease; 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: DTX301-CL301; 2020-003384-25 (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
• product manufactured in and exported from the U.S.: No