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

• 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	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 establish a dose of DTX301 that has a clinically meaningful increase in the rate of ureagenesis. 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

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	9 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 2020
Estimated Study Completion Date :	December 2020

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.	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.	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.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Name: DTX301

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.
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

Layout table for eligibility information

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

Criteria

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 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

Exclusion Criteria:

1. Screening or Baseline (Day 0) ammonia level ≥100 µmol/L or signs and symptoms indicative of hyperammonemia during the 4-week period preceding Day 0
2. Liver transplant, including hepatocyte cell therapy/transplant.
3. History of liver disease
4. Serum creatinine >2.0 mg/dL.
5. Participation in another investigational medicine study (including another gene transfer trial) within 3 months of Screening
6. History of a malignancy for which the subject has received treatment in the past 2 years except for prostate cancer treated with watchful waiting or surgically removed non-melanoma skin cancer.

Contacts and Locations

Contacts

Layout table for location contacts

Contact: Patients Contact: Patient Advocacy	1-415-483-8800	patientadvocacy@ultragenyx.com
Contact: HCPs Contact: Medical Information	1-888-756-8657	medinfo@ultragenyx.com

Locations

Layout table for location information

United States, California
Ronald Reagan University of Califonria Los Angeles Medical Center	Recruiting
Los Angeles, California, United States, 90095
University of California San Francisco	Recruiting
San Francisco, California, United States, 94158
United States, Colorado
The Children's Hospital Colorado	Recruiting
Aurora, Colorado, United States, 80045
United States, Massachusetts
Boston Children's Hospital	Recruiting
Boston, Massachusetts, United States, 02115
United States, New York
Icahn School of Medicine at Mount Sinai	Recruiting
New York, New York, United States, 10029-6508
United States, Ohio
University Hospital Cleveland Medical Center/Case Western Reserve University	Recruiting
Cleveland, Ohio, United States, 44106
United States, Oregon
Oregon Health and Science University	Recruiting
Portland, Oregon, United States, 97239
Canada, Alberta
Alberta's Children's Hospital	Recruiting
Calgary, Alberta, Canada, T3B 6A8
Spain
Hospital Clinico Universitario de Santiago	Recruiting
Santiago de Compostela, A Coruna, Spain, 15706
Hospital Universitario de Cruzes	Recruiting
Barakaldo, Vizcaya, Spain, 48903
United Kingdom
National Hospital for Neurology & Neurosurgery	Recruiting
London, London City, United Kingdom, WC1N 3BG
Queen Elizabeth Hospital	Recruiting
Birmingham, United Kingdom, B15 2TH

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

Investigators

Layout table for investigator information

Study Director:	Medical Director	Ultragenyx Pharmaceutical Inc

More Information

Layout table for additonal information

Responsible Party:	Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier:	NCT02991144 History of Changes
Other Study ID Numbers:	301OTC01; 2016-001057-40 ( EudraCT Number )
First Posted:	December 13, 2016
Last Update Posted:	April 2, 2019
Last Verified:	April 2019

Keywords provided by Ultragenyx Pharmaceutical Inc:

Gene Transfer; OTC Deficiency; Urea Cycle Disorder

Additional relevant MeSH terms:

Layout table for 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