EUCTR2016-001057-40-ES进行中（未招募）1 期
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.
适应症
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 12
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
- 性别
- All
入选标准
- •1. Willing and able to provide written informed consent.
- •2. 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. This may include identification of a pathogenic mutation, pedigree analysis, liver OTC activity that is <20% of normal activity, or elevated urinary orotate (>20 µmol/mmol creatinine) after an allopurinol challenge test.
- •3. Documented history of =1 symptomatic hyperammonemia event with ammonia =100 µmol/L.
- •4. 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.
- •5. Subject’s ammonia level on Day 1 (predose) is <100 µmol/L and is within the range of historical ammonia levels obtained when the subject was clinically stable. If the Day 1 (predose) ammonia is >100 µmol/L and the subject is clinically stable, the ammonia level may be repeated and DTX301 administered if the investigator determines that the repeat
- •ammonia is within the subject’s normal range. NOTE: If the subject is deemed clinically unstable, dosing will be held and the subject can be rescreened once the subject is determined to be clinically stable.
- •6. On stable dose of ammonia scavenger therapy for =4 weeks.
- •7. Willing to taper or discontinue ammonia scavengers during the study if deemed safe by the investigator.
- •8. No known allergic reaction to any component of DTX301.
- •9. Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalizations, frequent blood draws, and urine collections over a 24-hour period.
- •10. Hematology and coagulation panel results are within the normal range or, if outside the normal range, deemed not clinically significant in the opinion of the investigator.
- •11. 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 to prevent the potential transmission of the AAV vector. For male subjects, appropriate contraceptive methods include the use of a condom with spermicide. For female subjects, appropriate contraceptive methods include the use of a condom with spermicide plus at least 1 of the following:
- •a. Oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device;
- •b. Use of a diaphragm or cervical/vault cap;
- •c. Previous female sterilization (surgical bilateral oophorectomy [with or without hysterectomy] or tubal ligation) at least 6 weeks prior to DTX301 administration. In case of an oophorectomy alone, the reproductive status of the subject must have been confirmed by follow-up hormone level assessment.
- •NOTE: Abstinence is an acceptable form of birth control; however, appropriate contraception must be used if the subject becomes sexually active. A condom with spermicide is required to be used by all sexually active vasectomized males in the study in order to prevent potential transmission of the vector via seminal fluid.
- •NOTE: Females of childbearing potential are defined as all females physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for the duration of the study. Females are consi
排除标准
- •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; subjects may be rescreened once after their ammonia is controlled and stable for at least 28 days, at the discretion of the investigator.
- •2. Liver transplant, including hepatocyte cell therapy/transplant.
- •3. History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.
- •4. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase or aspartate aminotransferase >2.0 × upper limit of normal (ULN), total bilirubin >1.5 × ULN, alkaline phosphatase >2.5 × ULN.
- •5. Serum creatinine >2.0 mg/dL.
- •6. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity.
- •NOTE: Subjects with a history of HCV infection must have documentation of 2 negative viral assays by polymerase chain reaction (PCR), collected at least 6 months apart, to be considered negative for HCV. Subjects with a history of HCV infection who test positive for HCV RNA at Screening can be rescreened once, after they have been treated and have documentation of at least 2 negative samples collected at least 6 months apart.
- •7. History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count <350 cells/mm3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or plasma viral load >200 copies/mL, documented on 2 separate occasions, as measured by PCR.
- •8. Active infection (viral or bacterial).
- •9. Anti-AAV8 neutralizing antibody titer >1:5.
- •10. Participation (current or previous) in another gene transfer study.
- •11. Participation in another investigational medicine study within 3 months of Screening.
- •12. 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.
- •13. Has a positive serum pregnancy test at screening (females of childbearing potential only), a positive urine pregnancy test at Baseline (Day 0; females of childbearing potential only), or is nursing.
- •14. Has any other significant medical condition that the investigator feels would be a risk to the subject or would impede the study.
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