A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients With Late-onset OTC Deficiency
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 37
- 试验地点
- 32
- 主要终点
- Plasma Ammonia as Measured by 24-Hour Ammonia (AUC0-24)
研究概览
简要总结
The primary objective is to evaluate the efficacy of DTX301 on the improvement of ornithine transcarbamylase (OTC) function by maintaining safe plasma ammonia levels.
详细描述
This study is a Phase 3, randomized, double-blind, placebo-controlled study of DTX301 in patients with late-onset OTC deficiency 12 years of age and older.
Participants will be randomized 1:1 to DTX301 or placebo and followed closely for 36-64 weeks. Between Week 36 and Week 64, eligible participants will cross over and receive DTX301 if they had previously received placebo, and some who received DTX301 may receive placebo.
The planned study duration is up to 324 weeks. Upon completion of this study or early withdrawal, all participants who received DTX301 are invited to enroll in the Disease Monitoring Program (DMP) for follow-up for up to an additional 5 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation by enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis)
- •Free from symptomatic hyperammonemia and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline
- •If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening
- •If on a protein-restricted diet, must be on a stable total daily protein intake that does not vary more than 20% for ≥ 4 weeks prior to screening
- •From the time written informed consent through Visit 28, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not father a child or donate sperm
排除标准
- •Significant hepatic inflammation or cirrhosis
- •Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the 2021 CKD-EPI creatinine-based formula (Inker et al., 2021) for patients ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients < 18 years of age
- •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
- •Active infection (viral or bacterial)
- •Detectable pre-existing antibodies to the AAV8 capsid
- •Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
- •Participation (current or previous) in another gene transfer study
- •Note: Additional inclusion/exclusion criteria may apply, per protocol
研究组 & 干预措施
DTX301
Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may receive single peripheral IV infusion of placebo.
干预措施: Oral Corticosteroids (Drug)
DTX301
Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may receive single peripheral IV infusion of placebo.
干预措施: Placebo (Other)
Placebo, Then DTX301
Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.
干预措施: Placebo (Other)
Placebo, Then DTX301
Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.
干预措施: Oral Corticosteroids (Drug)
DTX301
Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may receive single peripheral IV infusion of placebo.
干预措施: Placebo for oral corticosteroids (Drug)
DTX301
Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may receive single peripheral IV infusion of placebo.
干预措施: Sodium Acetate (Drug)
Placebo, Then DTX301
Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.
干预措施: DTX301 (Genetic)
Placebo, Then DTX301
Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.
干预措施: Placebo for oral corticosteroids (Drug)
Placebo, Then DTX301
Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.
干预措施: Sodium Acetate (Drug)
DTX301
Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may receive single peripheral IV infusion of placebo.
干预措施: DTX301 (Genetic)
结局指标
主要结局
Plasma Ammonia as Measured by 24-Hour Ammonia (AUC0-24)
时间窗: Week 36
Complete Responder Rate at the Final Study Visit After DTX301 Exposure
时间窗: Up to 64 Weeks Post DTX301 Infusion
次要结局
- Number of Participants With Anti-OTC Antibodies(Up to Week 324)
- Change in Plasma Ammonia (AUC0-24) for Participants Who Have an Elevated Ammonia AUC0-24 at Baseline(Baseline, Up to 64 Weeks Post DTX301 Infusion)
- Percentage of Complete Responders or Responders After DTX301 Exposure(Up to 64 Weeks Post DTX301 Infusion)
- Annualized Event Rate of Hyperammonemic Crises (HACs) Pre-DTX301 Exposure vs Post-DTX301 Exposure(Pre-enrollment, Baseline, Up to 64 Weeks Post DTX301 Infusion)
- Annualized Event Rate of Interim Clinical Events (ICEs) Pre-DTX301 Exposure vs Post-DTX301 Exposure(Pre-enrollment, Baseline, Up to 64 Weeks Post DTX301 Infusion)
- Change from Baseline in Plasma Ammonia (AUC0-24)(Baseline, Up to Week 36)
- Change in Plasma Ammonia (AUC0-24) After DTX301 Exposure(Up to 64 Weeks Post DTX301 Infusion)
- Percentage of Participants Who Have Achieved Complete Management Response (CMR) or Management Response (MR) After DTX301 Exposure(Up to 64 Weeks Post DTX301 Infusion)
- Change in Baseline Disease Management (Dietary Protein and Total Scavenger Medication Use) With Plasma Ammonia (AUC0-24)(Up to 64 Weeks Post DTX301 Infusion)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs, Related Serious TEAEs and Adverse Events of Special Interest (AESIs)(Up to Week 324)
- Long-Term Durability of Response(Up to 64 Weeks Post DTX301 Infusion)