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

Ornithine Transcarbamylase (OTC) Deficiency Clinical Trial

— CAPtivate  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02991144
• Other study ID #: 301OTC01
• Secondary ID: 2016-001057-40
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 31, 2017
• Est. completion date: December 16, 2021

Study information

• Verified date: January 2023
• Source: Ultragenyx Pharmaceutical Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: December 16, 2021
• Est. primary completion date: December 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Ornithine Transcarbamylase (OTC) Deficiency

Intervention

Genetic:
• scAAV8OTC
non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC)

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
Canada	Alberta's Children's Hospital	Calgary	Alberta
Spain	Hospital Universitario de Cruzes	Barakaldo	Vizcaya
Spain	Hospital Clinico Universitario de Santiago	Santiago de Compostela	A Coruna
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	National Hospital for Neurology & Neurosurgery	London	London City
United States	The Children's Hospital Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University Hospital Cleveland Medical Center/Case Western Reserve University	Cleveland	Ohio
United States	Icahn School of Medicine at Mount Sinai	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Ultragenyx Pharmaceutical Inc

Countries where clinical trial is conducted

United States,  Canada,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation	AE: any untoward medical occurrence regardless of its causal relationship to study product. TEAE: any event not present before exposure to study product or any event already present that worsens in either intensity or frequency after exposure to study product. SAE: any event that results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; is an important medical event, according to the investigator. AE intensity was rated as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life threatening), or 5 (death) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The relationship or association of the study product in causing or contributing to the AE was characterized as: unrelated; possible; probably; definite.	AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug up to End of Study (Week 52).
Secondary	Change From Baseline Over Time in Rate of Ureagenesis	The change from baseline in the rate of ureagenesis (as measured by the generation of [13C]urea over 4 hours) as determined by gas chromatography mass spectrometry over time to 52 weeks after the IV administration of DTX301. Sodium acetate was used as a tracer to measure the rate of ureagenesis.; Rate of ureagenesis was derived in the following manner: Derive area under the curve from time zero to 240 minutes (AUC0-240min) of absolute 13C-urea (µmol/l/min) estimated by the linear trapezoidal rule; Derive percent of normal AUC0-240min of absolute 13C-urea by dividing AUC0-240min of absolute 13C-urea (µmol*min/L) by 669.56 µmol*min/L (i.e. the AUC0-240min of absolute 13C-urea for an adult control); Derive rate of ureagenesis by multiplying % of normal AUC0-240min of absolute 13C-urea by 300 µmol*h/kg (i.e. the approximate rate of ureagenesis in healthy adults).	Baseline (Day 0), Weeks 6, 12, 20, 24, End of Study (Week 52). AUC was derived based on the following time points: 0.5, 1, 1.5, 2, 3, and 4 hours postdose.
Secondary	Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia		Baseline (Day 0), Weeks 6, 12, 24, End of Study (Week 52). AUC was derived based on predose (time 0) and approximately 2, 4, 8, 12, 16, 20, 24 hours (±5 minutes) postdose.