An Open-label, Non-randomized, Multiple-dose Study to Assess the Knockdown of Hepatic HSD17B13 mRNA Expression, Pharmacokinetics, Safety, and Tolerability Following Administration of AZD7503 in Participants With Non-alcoholic Fatty Liver Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Number of participants with Adverse Events (AEs).
研究概览
简要总结
This is a two-part study. In Part A, eligible participants will undergo a baseline diagnostic liver biopsy to determine non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage, but will not receive study intervention. In Part B, participants with histologically confirmed NAFLD or non-alcoholic steatohepatitis (NASH) will receive study intervention.
详细描述
This is a single center, open-label Phase I study to assess knockdown of hepatic HSD17B13 mRNA pharmacokinetics (PK), safety, and tolerability following multiple doses of AZD7503 in male and/or female participants of non-childbearing status with NAFLD or NASH.
In Part A, participants at high risk for NAFLD/NASH meeting inclusion criteria for Part A (Section 5.1) and none of the exclusion criteria noted in Section 5.2 will undergo a diagnostic, baseline liver biopsy per standard clinical care. Participants will be consented for the liver biopsy as a first step to determine eligibility for Part B. In Part B, participants will be consented for study intervention administration and repeat liver biopsy at the end-of-treatment (EOT). Eligible participants will be assigned to 1 study intervention cohort. Two additional cohorts may be added based on data from the FiH study (D9230C00001) and emerging data from this study.
Participants who are selected for Part B based on histopathology evaluation (NAFLD or NASH with NAS of ≥3) will have an assessment of the hepatic HSD17B13 mRNA expression from both the liver biopsy obtained in Part A and the liver biopsy obtained at the end of study intervention administration in Part B. The assessments for hepatic HSD17B13 mRNA expression will be performed after each dose cohort is treated and before moving to the next dose cohort.
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
- Other
- 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
- 未提供
排除标准
- •History or presence of hepatic disease (with the exception of hepatic steatosis, NASH) or evidence of other known forms of known chronic liver
- •History of liver transplant, evidence of cirrhosis, or current placement on a liver transplant
- •Positive results for HIV antigen and hepatitis B surface antigen If a participant has a positive result at the screening visit for hepatitis C antibody, the investigator will document that the participant has hepatitis C RNA below the limit of detection and has not received curative treatment in the last 3 years.
- •History of alcohol abuse or excessive intake of alcohol as judged by the investigator.
- •Uncontrolled blood pressure, defined as any of the following during pre-screening and/or Day -1 (mean of 3 measurements):
- •Systolic blood pressure >160 mmHg.
- •Diastolic blood pressure >100 mmHg.
- •Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG.
- •Any clinically important abnormalities in clinical chemistry, hematology, or urinalysis results,
- •Known or suspected history of drug abuse as judged by the investigator.
- •Positive screen for drugs of abuse at screening or admission to the study site prior to the administration of the study intervention.
- •Changes to any concomitant medication (initiation, dose change, or cessation) within one month prior to the screening visit.
- •Any laboratory values with following deviations at screening (one re-test allowed):
- •(a) ALT >3X ULN
- •(b) AST >3X ULN
- •(c) TBL >ULN or INR ≥1.3
- •(d) ALP >1.5X ULN
- •(e) eGFR <60 mL/min/1.73 m2 (calculated using CKD Epidemiology Collaboration
- •[CKD-EPI] formula) and applying the standard correction factor for African
- •American to the (CKD-EPI) by multiplying the GFR estimate by 1.159 and
- •(f) Platelets <150 × 109/L
研究组 & 干预措施
Intervention/ Drug
Investigation of the knockdown of hepatic HSD17B13 mRNA expression, PK, safety, and tolerability following multiple dose administration of AZD7503 in male participants and female participants of non-childbearing potential with NAFLD or NASH
干预措施: AZD7503 Intervention (Drug)
结局指标
主要结局
Number of participants with Adverse Events (AEs).
时间窗: 99 days
To assess adverse events as a variable of safety and tolerability of AZD7503.
次要结局
- Maximum observed plasma (peak) drug concentration (Cmax) of AZD7503(99 days)
- Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD7503(99 days)
- Apparent volume of distribution at steady state following extravascular administration based on terminal phase(Vz/F) of AZD7503(99 days)
- Change in HSD17B13 mRNA Expression(31 days)
- Number of participants with positive anti-drug antibodies to AZD7503(99 days)
- Area under plasma concentration time-curve from zero to infinity (AUCinf) of AZD7503(99 days)
- Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of AZD7503(99 days)
- Lowest observed drug concentration (Ctrough) before next dose of AZD7503(99 days)
- Apparent volume of distribution at steady state following extravascular administration (Vss/F) of AZD7503(99 days)
- Accumulation ratio for AUC of AZD7503.(99 days)
- Accumulation ratio for Cmax (Rac Cmax) of AZD7503(99 days)
- Partial area under plasma concentration-time-curve from time 0 to time t (AUC(0-t)) of AZD7503(99 days)
- Time to reach peak or maximum observed concentration or responsefollowing drug administration (tmax) of AZD7503(99 days)
- Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t½λz) of AZD7503(99 days)
- Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD7503(99 days)
- Time of last observed (quantifiable) concentration (tlast) of AZD7503(99 days)