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

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ClinicalTrials.gov Identifier: NCT02991144
Recruitment Status : Recruiting
First Posted : December 13, 2016
Last Update Posted : May 31, 2018
Sponsor:
Information provided by (Responsible Party):
Dimension Therapeutics

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.


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 2019
Estimated Study Completion Date : December 2019


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




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



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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02991144


Contacts
Contact: Julie Lin, MD MPH FASN 617-714-0706 julie.lin@dimensiontx.com

Locations
United States, California
Ronald Reagan University of Califonria Los Angeles Medical Center Recruiting
Los Angeles, California, United States, 90095
Contact: Gerald Lipshutz, MD    310-267-9592    glipshutz@mednet.ucla.edu   
Contact: Maggie Lindenbaum    (310) 794-3788    mlindenbaum@mednet.ucla.edu   
University of California San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Renata Gallagher, MD, PhD    415-476-3572    renata.gallagher@ucsf.edu   
Contact: Emma Canepa    (415) 476-5360    emma.canepa@ucsf.edu   
United States, Colorado
The Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Janet A Thomas, MD    303-724-2334    janet.thomas@childrenscolorado.org   
Contact: Laurel Ware    (720) 777-5378    laurel.ware@childrenscolorado.org   
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Wen-Hann Tan, MD    617-355-6000    wen-hann.tan@childrens.harvard.edu   
Contact: Vera Anastasoaie    617-355-7346    vera.anastasoaie@childrens.harvard.edu   
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029-6508
Contact: George Diaz, MD    212-241-6947    george.diaz@mssm.edu   
Contact: Luca Ferro    212 659-1477    luca.ferro@mssm.edu   
United States, Ohio
University Hospital Cleveland Medical Center/Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Shawn E McCandless, MD    216-844-3936    shawn.mccandless@case.edu   
Contact: Audrey Lynn    (216) 844-7124    audrey.lynn@UHhospitals.org   
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Cary O Harding, MD    503-494-7608    hardingc@ohsu.edu   
Contact: Julie Martin, RN    503-494-5313    martijul@ohsu.edu   
Canada, Alberta
Alberta's Children's Hospital Recruiting
Calgary, Alberta, Canada, T3B 6A8
Contact: Aneal Khan, MSc MD, FRCP(C), FCCMG    (403) 955-7587    khaa@ucalgary.ca   
Contact: Connie Mohan    (403) 955-3091    connie.mohan@albertahealthservices.ca   
Spain
Hospital Clinico Universitario de Santiago Recruiting
Santiago de Compostela, A Coruna, Spain, 15706
Contact: Maria Luz Couce Pico, MD, PhD    +34981950162    maria.luz.couce.pico@sergas.es   
Contact: Sofia Gouveia    +34981950162    sofiabsg@gmail.co   
Hospital Universitario de Cruzes Recruiting
Barakaldo, Vizcaya, Spain, 48903
Contact: Luis Jose Aldamiz-Echevarria, MD, PhD    +34946006239    luisjose.aldamiz-echevarazuara@osakidetza.eus   
Contact: Marta Llarena Fernandez    +34946006327    marta.llarenafernandez@osakidetza.eus   
United Kingdom
National Hospital for Neurology & Neurosurgery Recruiting
London, London City, United Kingdom, WC1N 3BG
Contact: Robin Lachman, MB BChir, MA, MRCP, PhD    +4402034484778    robin.lachmann@uclh.nhs.uk   
Contact: Elaine Murphy       elaine.murphy@uclh.nhs.uk   
Queen Elizabeth Hospital Recruiting
Birmingham, United Kingdom, B15 2TH
Contact: Tarekegn Hiwot, MD, MS, PhD    +441213716982    tarekegn.geberhiwot@uhb.nhs.uk   
Contact: Vishy Veeranna    +4401213716694    vishy.veeranna@uhb.nhs.uk   
Sponsors and Collaborators
Dimension Therapeutics
Investigators
Study Director: Julie Lin, MD MPH FASN Dimension Therapeutics, Inc.

Responsible Party: Dimension Therapeutics
ClinicalTrials.gov Identifier: NCT02991144     History of Changes
Other Study ID Numbers: 301OTC01
2016-001057-40 ( EudraCT Number )
First Posted: December 13, 2016    Key Record Dates
Last Update Posted: May 31, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Dimension Therapeutics:
Gene Transfer
OTC Deficiency
Urea Cycle Disorder

Additional relevant 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