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

Sponsor

Ultragenyx Pharmaceutical Inc (Industry)

Overall Status

Completed

CT.gov ID

NCT02991144

Collaborator

(none)

Enrollment

Locations

Arms

59.4

Duration (Months)

1.2

Patients Per Site

Patients Per Site Per Month

Study Details

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

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 :

Jan 1, 2017

Actual Primary Completion Date :

Dec 15, 2021

Actual Study Completion Date :

Dec 15, 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 Names: 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 Names: 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 Names: 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 Names: DTX301 Drug: Oral prednisone Initiated before dosing with DTX301, sustained for 4 weeks, followed by tapering Other Names: Oral prednisolone

Outcome Measures

Primary Outcome Measures

The incidence of treatment-related adverse events by dosing group [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

Change in baseline in ureagenesis rate [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.
Change in baseline 24 hour area under the curve of ammonia [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

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
Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L.
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.
On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks.
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:

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.
Liver transplant, including hepatocyte cell therapy/transplant.
History of liver disease
Significant hepatic inflammation or cirrhosis
Serum creatinine >2.0 mg/dL.
Participation in another investigational medicine study (including another gene transfer trial) within 3 months of Screening
Pregnant or nursing

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital Colorado	Aurora	Colorado	United States	80045
2	Boston Children's Hospital	Boston	Massachusetts	United States	02115
3	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029-6508
4	University Hospital Cleveland Medical Center/Case Western Reserve University	Cleveland	Ohio	United States	44106
5	Alberta's Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
6	Hospital Clinico Universitario de Santiago	Santiago de Compostela	A Coruna	Spain	15706
7	Hospital Universitario de Cruzes	Barakaldo	Vizcaya	Spain	48903
8	National Hospital for Neurology & Neurosurgery	London	London City	United Kingdom	WC1N 3BG
9	Queen Elizabeth Hospital	Birmingham		United Kingdom	B15 2TH