Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset OTC Deficiency (CAPtivate)

• ClinicalTrials.gov Identifier: NCT02991144
• Recruitment Status: Active, not recruiting
• First Posted: December 13, 2016
• Last Update Posted: February 17, 2021
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Study Description

Brief Summary:

A Phase 1/2, open-label dose-finding safety study of single ascending doses of DTX301 in adults with late-onset OTC Deficiency

Condition or disease	Intervention/treatment	Phase
Ornithine Transcarbamylase (OTC) Deficiency	Genetic: scAAV8OTC; Drug: Oral prednisone	Phase 1; Phase 2

Detailed Description:

This is a Phase 1/2, open-label, single arm, multicenter, safety and dose finding study of DTX301 in adults with late-onset OTC deficiency. The primary objective of the study is to determine the safety of single IV doses of DTX301.

Eligible subjects will receive a single IV infusion of DTX301. Dose escalation will be conducted according to a model that uses the collected data to predict the safety profile of the dose in order to determine the optimal biological dose (OBD). The decision to proceed to the next dose cohort will be made after the data monitoring committee (DMC) has evaluated the safety data for all subjects in a dosing cohort.

Subjects will be followed for 52 weeks after dosing. After completion of this study, subjects will be asked to enroll in a 4-year extension study to evaluate the long term (a total of 5 years) safety and efficacy of DTX301.

This study was previously posted by Dimension Therapeutics, which has been acquired by Ultragenyx.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 11 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Adults With Late-Onset OTC Deficiency
• Study Start Date: January 2017
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose 1: 2.0 × 10^12 GC/kg; DTX301 (scAAV8OTC) will be administered as a single peripheral IV infusion. Sodium acetate is used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Name: DTX301
Experimental: Dose 2: 6.0 × 10^12 GC/kg; DTX301 (scAAV8OTC) will be administered as a single peripheral IV infusion. Sodium acetate is used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Name: DTX301
Experimental: Dose 3: 1.0 × 10^13 GC/kg; DTX301 (scAAV8OTC) will be administered as a single peripheral IV infusion. Sodium acetate is used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Name: DTX301
Experimental: Dosing Process Optimization at Optical Biological Dose (OBD); Oral prednisone (or prednisolone), 60 mg tapered over 9 weeks, initiated before dosing with DTX301. DTX301 (scAAV8OTC; optimal biologic dose) will be administered as a single peripheral IV infusion. Sodium acetate is used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Name: DTX301; Drug: Oral prednisone; Initiated before dosing with DTX301, sustained for 4 weeks, followed by tapering; Other Name: Oral prednisolone

Outcome Measures

Primary Outcome Measures :

1. The incidence of treatment-related adverse events by dosing group [ Time Frame: 52 weeks ]
   The incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) for each dosing cohort, assessed by severity and relationship to study product.

Secondary Outcome Measures :

1. Change in baseline in ureagenesis rate [ Time Frame: 52 weeks ]
   The change from baseline in the rate of ureagenesis (as measured by the generation of [13C]urea) as determined over time to 52 weeks after the IV administration of DTX301. Sodium acetate is used as a tracer to measure the rate of ureagenesis.
2. Change in baseline 24 hour area under the curve of ammonia [ Time Frame: 52 weeks ]
   The change from baseline (Day 0) in area under the curve from time zero to 24 hours (AUC0 24) for serum ammonia over time to 52 weeks after IV administration of DTX301

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

1. Males and females ≥18 years of age with documented diagnosis of late onset (defined as first manifestation of signs and symptoms at ≥1 month of age) OTC deficiency, confirmed via enzymatic, biochemical, or molecular testing
2. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L.
3. Subject's OTC deficiency is stable as evidenced by either a) no clinical symptoms of hyperammonemia OR b) an ammonia level <100 µmol/L within the 4 week period preceding the Screening visit.
4. On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks.
5. Males and all females of childbearing potential must be willing to use effective contraception at the time of administration of gene transfer and for the 52 weeks following administration of DTX301

Key Exclusion Criteria:

1. At Screening or Baseline (Day 0), plasma ammonia level ≥ 100 μmol/L for patients who historically maintain normal ammonia levels; OR plasma ammonia level ≥ 200 μmol/L for patients who historically are not able to fully control ammonia levels with baseline management; OR signs and symptoms of hyperammonemia.
2. Liver transplant, including hepatocyte cell therapy/transplant.
3. History of liver disease
4. Significant hepatic inflammation or cirrhosis
5. Serum creatinine >2.0 mg/dL.
6. Participation in another investigational medicine study (including another gene transfer trial) within 3 months of Screening
7. Pregnant or nursing

Note additional inclusion/exclusion criteria may apply, per protocol.

Contacts and Locations

Locations

United States, California

Ronald Reagan University of Califonria Los Angeles Medical Center

Los Angeles, California, United States, 90095

University of California San Francisco

San Francisco, California, United States, 94158

United States, Colorado

The Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029-6508

United States, Ohio

University Hospital Cleveland Medical Center/Case Western Reserve University

Cleveland, Ohio, United States, 44106

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

Canada, Alberta

Alberta's Children's Hospital

Calgary, Alberta, Canada, T3B 6A8

Spain

Hospital Clinico Universitario de Santiago

Santiago de Compostela, A Coruna, Spain, 15706

Hospital Universitario de Cruzes

Barakaldo, Vizcaya, Spain, 48903

United Kingdom

National Hospital for Neurology & Neurosurgery

London, London City, United Kingdom, WC1N 3BG

Queen Elizabeth Hospital

Birmingham, United Kingdom, B15 2TH

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

More Information

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02991144
• Other Study ID Numbers: 301OTC01; 2016-001057-40 ( EudraCT Number )
• First Posted: December 13, 2016
• Last Update Posted: February 17, 2021
• Last Verified: February 2021

Keywords provided by Ultragenyx Pharmaceutical Inc:

Gene Transfer; OTC Deficiency; Urea Cycle Disorder

Additional relevant MeSH terms:

Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Prednisone; Prednisolone; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents