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

NCT ID: NCT02991144

Last Updated: 2023-01-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-31
• Study Completion Date: 2021-12-16

Brief Summary

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 intravenous (IV) doses of DTX301.

Detailed Description

Eligible participants 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 participants in a dosing cohort. Participants will be followed for 52 weeks after dosing. After completion of this study, participants 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.

Conditions

Ornithine Transcarbamylase (OTC) Deficiency

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1: DTX301 2.0 × 10^12 GC/kg

DTX301 (scAAV8OTC) 2.0 × 10\^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.

Group Type: EXPERIMENTAL

scAAV8OTC

Intervention Type: GENETIC

non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Reactive Corticosteroid Taper Regimen

Intervention Type: DRUG

Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels.

Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.

Cohort 2: DTX301 6.0 × 10^12 GC/kg

DTX301 (scAAV8OTC) 6.0 × 10\^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.

Group Type: EXPERIMENTAL

scAAV8OTC

Intervention Type: GENETIC

non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Reactive Corticosteroid Taper Regimen

Intervention Type: DRUG

Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels.

Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.

Cohort 3: DTX301 1.0 × 10^13 GC/kg

DTX301 (scAAV8OTC) 1.0 × 10\^13 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.

Group Type: EXPERIMENTAL

scAAV8OTC

Intervention Type: GENETIC

non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Reactive Corticosteroid Taper Regimen

Intervention Type: DRUG

Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels.

Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.

Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids

A prophylactic corticosteroid taper regimen (oral prednisone \[or prednisolone\], 60 mg tapered over 9 weeks) will be administered before dosing with DTX301 (scAAV8OTC) to prevent or minimize transient vector-induced hepatic effects. DTX301 (scAAV8OTC) 1.0x10\^13 GC/kg administered as a single peripheral IV infusion. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.

Group Type: EXPERIMENTAL

scAAV8OTC

Intervention Type: GENETIC

non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Prophylactic Corticosteroid Taper Regimen

Intervention Type: DRUG

Oral prednisone [or oral prednisolone] 60 mg/day at least 5 days prior to DTX301 administration, tapered over 9 weeks.

A prophylactic corticosteroid taper regimen will be administered to prevent or minimize transient vector-induced hepatic effects.

Interventions

scAAV8OTC

non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Intervention Type: GENETIC

Reactive Corticosteroid Taper Regimen

Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels.

Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.

Intervention Type: DRUG

Prophylactic Corticosteroid Taper Regimen

Oral prednisone [or oral prednisolone] 60 mg/day at least 5 days prior to DTX301 administration, tapered over 9 weeks.

A prophylactic corticosteroid taper regimen will be administered to prevent or minimize transient vector-induced hepatic effects.

Intervention Type: DRUG

Other Intervention Names

DTX301

Eligibility 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 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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ultragenyx Pharmaceutical Inc

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Ultragenyx Pharmaceutical Inc

Locations

The Children's Hospital Colorado

Aurora, Colorado, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

University Hospital Cleveland Medical Center/Case Western Reserve University

Cleveland, Ohio, United States

Alberta's Children's Hospital

Calgary, Alberta, Canada

Hospital Clinico Universitario de Santiago

Santiago de Compostela, A Coruna, Spain

Hospital Universitario de Cruzes

Barakaldo, Vizcaya, Spain

National Hospital for Neurology & Neurosurgery

London, London City, United Kingdom

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Countries

United States; Canada; Spain; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-001057-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

301OTC01

Identifier Type: -

Identifier Source: org_study_id