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

OTC Deficiency Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05345171
• Other study ID #: DTX301-CL301
• Secondary ID: 2020-003384-25
• Status: Recruiting
• Phase: Phase 3
• Start date: October 18, 2022
• Est. completion date: December 2028

Study information

• Verified date: June 2024
• Source: Ultragenyx Pharmaceutical Inc
• Contact: Patients Contact: Trial Recruitment
• Phone: 1-888-756-8657
• Email: TrialRecruitment[@]ultragenyx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 2028
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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

Related Conditions & MeSH terms

• OTC Deficiency

Intervention

Genetic:
• DTX301
non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector

Other:
• Placebo
normal saline infusion

Drug:
• Oral Corticosteroids
Participants who receive DTX301 solution will receive oral corticosteroids.
• Placebo for oral corticosteroids
Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind
• Sodium Acetate
A tracer for the Ureagenesis Rate Test (URT)

Locations

Country	Name	City	State
Argentina	Hospital Italiano de Buenos Aires	Buenos Aires
Argentina	Clinica Universitaria Reina Fabiola	Córdoba
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre
Canada	The Hospital for Sick Children	Toronto	Ontario
France	Hopital Femme Mere Enfant	Bron
France	Necker-Enfants Maladas Hospital	Paris
Germany	Universitatsklinikum Heidelberg	Heidelberg
Italy	University of Naples Federico II	Napoli
Italy	University Hospital of Padova	Padova
Italy	Ospedale Infantile Regina Margherita	Torino
Japan	Kumamoto University Hospital	Kumamoto
Japan	Fujita Health University Hospital	Toyoake
Netherlands	Erasmus Universitair Medisch Centrum Rotterrdam	Rotterdam
Portugal	Centro Hospitalar Universitario de Sao Joao	Porto
Spain	Fundacio Hospital Universitari Vall D'Hebron-Institute de Recerca	Barcelona
Spain	Hospital Clinico Universitario de Santiago	Santiago De Compostela
United Kingdom	University Hospitals Birmingham NHS	Birmingham
United States	University of Colorado	Aurora	Colorado
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 Florida College of Medicine	Gainesville	Florida
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	University of California	Los Angeles	California
United States	Yale School of Medicine	New Haven	Connecticut
United States	University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Ultragenyx Pharmaceutical Inc

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  France,  Germany,  Italy,  Japan,  Netherlands,  Portugal,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma Ammonia as Measured by 24-hour Ammonia (AUC0-24)		Week 64
Primary	Percentage of Participants Who Have Achieved Complete Response		Week 64
Secondary	Percentage of Participants Who Have Achieved Complete Response, Response, or No Response		Week 64
Secondary	Patient Global Impression of Change (PGIC) Overall Change Score		Week 64
Secondary	Rate of Hyperammonemic Crises (HACs) from Baseline to Week 64 Compared to Pre-Enrollment		Pre-enrollment, Baseline, Week 64
Secondary	Change from Baseline in Plasma Ammonia (AUC0-24) After DTX301 Exposure		Baseline, Up to Week 64
Secondary	Change from Baseline in Plasma Ammonia (AUC0-24)		Baseline, Up to Week 64
Secondary	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
Secondary	Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, Physical Examination Results, and Vital Sign Measurements		Baseline, Up to Week 324
Secondary	Number of Participants With Anti-OTC Antibodies		Up to Week 324

External Links

•   Ultragenyx Patient Advocacy/OTC Disease Information