NCT07227207招募中1 期
A Phase 1/2, Open-Label, Multi-Center, Dose Escalation, Dose Expansion, and Single Repeat Dose Study of TSRA-196 in Adults With the PiZZ Genotype Who Have Lung and/or Liver Disease Associated With Severe Alpha-1 Antitrypsin Deficiency
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 72
- 试验地点
- 7
- 主要终点
- Part 1 (Dose Escalation): Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
研究概览
简要总结
This is a Phase 1/2, open-label, multi-center, dose escalation (Part 1), dose expansion (Part 2), and single repeat dose (Part 3) study to evaluate the safety, tolerability, efficacy, and PK/PD parameters of TSRA-196 in adults with the PiZZ genotype who have lung and/or liver disease associated with severe alpha-1 antitrypsin deficiency (AATD)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males or females who are 18 to 70 years of age, inclusive, at the time of signing the informed consent
- •Body mass index of 18 to 37 kg/m2, inclusive
- •Confirmed diagnosis of AATD and PiZZ genotype
- •At least one previous measure of blood total AAT level <11 µmol/L
- •Nonsmoker for at least 6 months before screening and must remain nonsmoking for the entire study duration
- •Either AAT treatment-naïve or washed out of all investigational or approved treatments that modify AAT levels for 5 half-lives or at least 4 weeks, whichever is longer, before TSRA-196 administration
- •Parts 1A and 2A (AATD lung disease with no or minimal liver fibrosis)
- •Clinically significant lung disease, defined as 1) evidence of emphysema or bronchiectasis by computed tomography or 2) DLCO <70% of the predicted value or 3) ppFEV1 <80%
- •ppFEV1 ≥35%
- •METAVIR fibrosis score F0 or F1 confirmed by liver biopsy at screening, or a liver stiffness measure by FibroScan ≤7 kPa at screening
- •FIB-4 index score ≤3.25 at screening
- •ALT and/or AST \7 and ≤15 kPa at screening
- •ALT and/or AST <2 x ULN at screening
排除标准
- •Presence of genetic variation in SERPINA1 gene that may disrupt the function of TSRA-196, determined by screening genotyping
- •History of liver disease unrelated to AATD, or history of or clinical signs of cirrhosis
- •Significant lung disease not attributable to manifestations of AATD, as determined by the investigator
- •History of one or more hospitalizations due to severe exacerbation of underlying lung disease during the year before screening or received IV antibiotics for treatment of a pulmonary infection within 6 months before screening
- •Unstable AATD-related COPD, as determined by the investigator, or severe bronchiectasis
- •Lung volume reduction surgery within 1 year before screening or plan to receive lung volume reduction surgery during the study period
- •Documented chronic need for positive airway pressure therapy beyond nocturnal use
- •Seropositive for human immunodeficiency virus (HIV) (HIV-1 or HIV-2)
- •Seropositive for hepatitis B (hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb] positive) with detectable HBV DNA
- •Hepatitis C virus (HCV) RNA positive at screening (Parts 1A and 2A), or HCV RNA positive and/or HCV antibody positive at screening (Parts 1B and 2B)
- •Has received an organ transplant or is on a waiting list for an organ transplant
- •Prior treatment with gene therapy using viral vectors or intended to permanently change the patient's DNA
- •Any investigational products within 30 days before dosing or plan to take an investigational product before the end of study
研究组 & 干预措施
TSRA-196 Drug Product
Experimental
干预措施: TSRA-196 (Drug)
结局指标
主要结局
Part 1 (Dose Escalation): Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
时间窗: 1 Year
Part 2 (Dose Expansion): Proportion of participants who have serum levels of total alpha-1 antitrypsin (AAT) greater than or equal to Lower Limit of Normal (LLN) after TSRA-196 treatment
时间窗: 1 Year
Part 3 (Single Repeated Dose): Proportion of participants who have serum levels of total alpha-1 antitrypsin (AAT) greater than or equal to Lower Limit of Normal (LLN) after a second dose of TSRA-196
时间窗: 1 Year
次要结局
- Part 2 (Dose Expansion): Incidence of TEAEs and SAEs(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Proportion of participants who have serum levels of total AAT greater than or equal to 11 μM after TSRA-196 treatment(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change in serum levels of total AAT from baseline over time(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Incidence of Adverse Event of Special Interest (AESI) from day of dosing through end of study(1 Year)
- Part 1 (Dose Escalation): Proportion of participants who have serum levels of total AAT greater than or equal to LLN after TSRA-196 treatment(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change over time in safety measures, including clinical laboratory parameters, vital signs, and ECG parameters(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Pharmacokinetic (PK) parameter: Area under the blood concentration time curves (AUC) of TSRA-196(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Maximum observed blood concentration (Cmax) of TSRA-196(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Time to Cmax (tmax) of TSRA-196(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Half-life (t1/2) of TSRA-196(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Clearance (CL) of TSRA-196(1 Year)
- Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: The volume of distribution at terminal stage (Vz) of TSRA-196(1 Year)
研究者
研究点 (7)
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