Clinical trial NCT05345171: Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: OTC Deficiency
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2022-04-25
Enrollment: 32
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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 and followed closely for 36-64 weeks. Between Week 36 and Week 64, eligible participants will cross over and receive DTX301 if they had previously received placebo, and some who received DTX301 may receive placebo.

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.

Eligibility criteria: 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 Visit 28, 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

Primary outcomes:
measure: Plasma Ammonia as Measured by 24-Hour Ammonia (AUC0-24)
timeFrame: Week 36
measure: Complete Responder Rate at the Final Study Visit After DTX301 Exposure
timeFrame: Up to 64 Weeks Post DTX301 Infusion
Secondary outcomes:
measure: Percentage of Complete Responders or Responders After DTX301 Exposure
timeFrame: Up to 64 Weeks Post DTX301 Infusion
measure: Annualized Event Rate of Hyperammonemic Crises (HACs) Pre-DTX301 Exposure vs Post-DTX301 Exposure
timeFrame: Pre-enrollment, Baseline, Up to 64 Weeks Post DTX301 Infusion
measure: Annualized Event Rate of Interim Clinical Events (ICEs) Pre-DTX301 Exposure vs Post-DTX301 Exposure
timeFrame: Pre-enrollment, Baseline, Up to 64 Weeks Post DTX301 Infusion
measure: Change from Baseline in Plasma Ammonia (AUC0-24)
timeFrame: Baseline, Up to Week 36
measure: Change in Plasma Ammonia (AUC0-24) After DTX301 Exposure
timeFrame: Up to 64 Weeks Post DTX301 Infusion
measure: Percentage of Participants Who Have Achieved Complete Management Response (CMR) or Management Response (MR) After DTX301 Exposure
timeFrame: Up to 64 Weeks Post DTX301 Infusion
measure: Change in Baseline Disease Management (Dietary Protein and Total Scavenger Medication Use) With Plasma Ammonia (AUC0-24)
timeFrame: Up to 64 Weeks Post DTX301 Infusion
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs, Related Serious TEAEs and Adverse Events of Special Interest (AESIs)
timeFrame: Up to Week 324
measure: Number of Participants With Anti-OTC Antibodies
timeFrame: Up to Week 324
measure: Long-Term Durability of Response
timeFrame: Up to 64 Weeks Post DTX301 Infusion
measure: Change in Plasma Ammonia (AUC0-24) for Participants Who Have an Elevated Ammonia AUC0-24 at Baseline
timeFrame: Baseline, Up to 64 Weeks Post DTX301 Infusion
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Córdoba
country: Argentina
facility: Clinica Universitaria Reina Fabiola
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Bron
country: France
facility: Hopital Femme Mere Enfant
city: Paris
country: France
facility: Necker-Enfants Maladas Hospital
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus Universitair Medisch Centrum Rotterrdam
city: Porto
country: Portugal
facility: Centro Hospitalar Universitario de Sao Joao
city: Barcelona
country: Spain
facility: Fundacio Hospital Universitari Vall D'Hebron-Institute de Recerca
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References: