A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 3
- 主要终点
- Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b
研究概览
简要总结
The purpose of this study is to evaluate the the safety and efficacy of the investigational product, fazirsiran (TAK-999, ARO-AAT), administered subcutaneously to patients with alpha-1 antitrypsin deficiency associated liver disease (AATD).
详细描述
Participants will be enrolled to receive multiple subcutaneous injections of fazirsiran (TAK-999, ARO-AAT). All eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. All participants will undergo an end of study (EOS) biopsy. Treated participants will be offered the opportunity to continue treatment in an open label extension during which they will undergo a final biopsy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of AATD
- •Liver biopsy indicating Metavir F1-F3 liver fibrosis based on local pathology read.
- •Women of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use contraception
- •Willing to provide written informed consent and to comply with study requirements
- •Non-smoker for at least 1 year
- •No abnormal finding of clinical relevance at screening
排除标准
- •Clinically significant health concerns other than AATD
- •Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis
- •Regular use of alcohol within one month prior to Screening
- •Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention
- •Use of illicit drugs within 1 year prior to Screening
- •Note: additional inclusion/exclusion criteria may apply, per protocol
研究组 & 干预措施
ARO-AAT 100 mg Cohort 1b
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous AROAAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W.
干预措施: ARO-AAT (Drug)
ARO-AAT 200 mg Cohort 1
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous AROAAT Q12W. Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W.
干预措施: ARO-AAT (Drug)
ARO-AAT 200 mg Cohort 2
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous AROAAT Q12W. Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W.
干预措施: ARO-AAT (Drug)
结局指标
主要结局
Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b
时间窗: Baseline, Week 24
Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2
时间窗: Baseline, Week 48
次要结局
- Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b(Baseline, Weeks 2, 4, 6, 16, 24)
- Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2(Baseline, Weeks 2, 4, 6, 16, 22, 28, 34, 40, 48)
- Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b(Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24)
- ALT Values Over Time: Cohort 2(Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48)
- Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b(Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24)
- GGT Values Over Time: Cohort 2(Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48)
- Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b(Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24)
- FIB4 Score Values Over Time: Cohort 2(Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 28 + 1 day, Week 34, Week 40, Week 48)
- Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b(Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24)
- APRI Values Over Time: Cohort 2(Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 34, Week 40, Week 48)
- N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b(Baseline, Weeks 4, 16, 24)
- PRO-C3 Values Over Time: Cohort 2(Baseline, Weeks 4, 16, 28, 40, 48)
- FibroScan® Values Over Time: Cohorts 1/1b(Baseline, Week 24)
- FibroScan® Values Over Time: Cohort 2(Baseline, Week 24)
- Portal Inflammation Over Time: Cohorts 1/1b(Baseline, Week 24)
- Portal Inflammation Over Time: Cohort 2(Baseline, Week 48)
- Interface Hepatitis Over Time: Cohorts 1/1b(Baseline, Week 24)
- Interface Hepatitis Over Time: Cohort 2(Baseline, Week 48)
- Lobular Inflammation Over Time: Cohorts 1/1b(Baseline, Week 24)
- Lobular Inflammation Over Time: Cohort 2(Baseline, Week 48)
- Hepatocyte Cell Death Over Time: Cohorts 1/1b(Baseline, Week 24)
- Hepatocyte Cell Death Over Time: Cohort 2(Baseline, Week 48)
- Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b(Baseline, Week 24)
- Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2(Baseline, Week 48)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(From first dose of study drug up to a maximum duration of study follow-up of 202 weeks.)