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Completed

NCT Number: NCT02991144

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

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.

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Key information

Conditions

Ornithine Transcarbamylase (OTC) Deficiency Amino Acid Metabolism, Inborn Errors Brain Diseases Brain Diseases, Metabolic Brain Diseases, Metabolic, Inborn Central Nervous System Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Genetic Diseases, X-Linked Metabolic Diseases Metabolism, Inborn Errors Nervous System Diseases Nutritional and Metabolic Diseases Ornithine Carbamoyltransferase Deficiency Disease Urea Cycle Disorders, Inborn

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Alberta's Children's Hospital, Calgary, Alberta, Canada

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

scAAV8OTC

Genetic

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

Other names: DTX301

Reactive Corticosteroid Taper Regimen

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.

Prophylactic Corticosteroid Taper Regimen

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.

Primary outcomes

  1. Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation

    Time frame: 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).

    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.

Secondary outcomes

  1. Change From Baseline Over Time in Rate of Ureagenesis

    Time frame: 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.

    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).

  2. Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Ultragenyx Pharmaceutical Inc

Industry

Registry information

Official study 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

Acronym: CAPtivate

Important dates

Study start
2017
Primary completion
2021
Study completion
2021
First posted
Dec 13, 2016
Registry last updated
Jan 26, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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