Phase I/II Open-Label Safety and Dose Finding Study of Adeno-Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 18
- 主要终点
- Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)
研究概览
简要总结
A Phase 1/2, open-label, dose-finding safety study of single ascending doses of DTX101 in adult males with moderate/severe to severe hemophilia B.
详细描述
Hemophilia B is an X-linked recessive genetic bleeding disorder caused by mutations in the factor IX (FIX) gene. FIX is produced in the liver and is critical for fibrin clot formation. Hemophilia B is characterized by frequent, spontaneous internal bleeding that can lead to chronic arthropathy (joint damage), intracranial hemorrhage, and even death. In patients with moderate/severe to severe hemophilia B, the majority of bleeding episodes occur in the joints and, if not treated, lead to debilitating damage and a decreased quality of life.
This study will evaluate the safety and efficacy of the adeno-associated virus (AAV) to deliver human factor IX (hFIX) gene, the healthy gene necessary to make FIX, to the liver where FIX is normally produced. This study will determine if AAVrh10 can produce clinically meaningful FIX levels in patients with moderately/severe or severe hemophilia B.
This study was previously posted by Dimension Therapeutics, which has been acquired by Ultragenyx in November 2017.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male ≥ 18 years of age.
- •Moderate/severe or severe hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%).
- •At least 3 bleeding episodes per year that require on-demand treatment with FIX OR are treated with a prophylactic regimen of FIX.
- •At least 100 days exposure history to FIX.
- •No documented history of inhibitors (neutralizing antibodies) to exogenous FIX.
- •No known allergic reaction to exogenous FIX or any component of DTX
- •Willing to stop prophylactic treatment with recombinant FIX at specified time points during the study.
排除标准
- •History of significant liver disease (ie, portal hypertension).
- •Significant hepatic inflammation or cirrhosis.
- •Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- •History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm^3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or plasma viral load > 200 copies/mL, on 2 separate occasions, as measured by polymerase chain reaction.
- •Anti-AAVrh10 neutralizing antibody titer > 1:
- •Participation (current or previous) in another gene therapy study.
- •Participation in another investigational medicine study within 3 months before screening.
- •NOTE: Other protocol defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
DTX101, Cohort 1
a single peripheral intravenous (IV) infusion of 1.6 x 10^12 genome copies (GC)/kg DTX101
干预措施: DTX101 (Genetic)
DTX101, Cohort 2
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
干预措施: DTX101 (Genetic)
结局指标
主要结局
Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)
时间窗: up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2)
An AE was defined as any untoward medical occurrence in a participant enrolled into this study (from the time the participant signed the informed consent form until his or her exit from the study), regardless of its causal relationship to study treatment. A TEAE was defined as any event not present before exposure to study product or any event already present that worsened in severity or increased in frequency after exposure to study product.
Change From Baseline in FIX Activity at Week 6
时间窗: Baseline, Week 6
Peak plasma level of FIX after IV administration as determined by the activated partial thromboplastin time (aPTT) clot-based assay. Change from baseline: postbaseline value - baseline value. For the change from baseline, only participants with a value at both baseline visit and the specific postbaseline visit were included.
次要结局
- Change From Baseline in FIX Activity Over Time(Baseline, Weeks 2, 4, 6, 8, 12, 16, 24, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal)
- Number of Participants With Cell-Mediated Immune Response to FIX(Day 0 (predose), Weeks 6, 8, 12, 16, 32, 40, 48, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal)
- Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire(Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52))
- Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire(Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52))
- Annualized Bleeding Rate(Week 0 to Week 52)
- Annualized FIX Replacement Therapy(Week 0 to Week 52)
- Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors)(Day 0 (predose), Weeks 6, 8, 16, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal)
- Average Weekly Use of FIX Replacement Therapy(Baseline (Screening), Week 0 through Week 52)