Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4076 Following Multiple Ascending Dose Administration to T2DM Subjects 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
- 14
- 主要终点
- The safety and tolerability of AZD4076 by assessment of blood pressure
研究概览
简要总结
This is a phase I/IIa, randomized, single-blind, placebo-controlled, multiple-ascending dose study conducted at a single site. The study plans to include up to approximately 46 evaluable subjects with Type 2 Diabetes Mellitus (HbA1c 7-11%) and Non-Alcoholic Fatty Liver disease (liver fat content > = 8%) on metformin monotherapy.
Three initial cohorts are planned:
- Cohort 1: 6 subjects receiving AZD4076 and 4 subjects receiving placebo
- Cohort 2: 12 subjects receiving AZD4076 and 10 subjects receiving placebo
- Cohort 3: 10 subjects receiving AZD4076 and 10 subjects receiving placebo, with the possibility to add additional subjects if drop-out rates are higher than expected
Pending review by SRC, an additional 2 cohorts, each consisting of 18 evaluable subjects may be included in the study.
The primary objectives of this clinical trial are to investigate the safety and tolerability of AZD4076 following subcutaneous administration of multiple ascending doses; to assess the effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp with tracer technique; and to assess the effect of AZD4076 on liver fat content using magnetic resonance imaging. Secondary objectives of this trial are to characterize multiple dose PK of AZD4076 and its longmer and shortmer metabolites and assess the time required to reach steady state and the degree of accumulation; to assess the efficacy of AZD4076 on 24-hour glucose; and to assess the effect of AZD4076 on homeostatic model assessment insulin resistant (HOMA-IR) and Matsuda index.
详细描述
This is a phase I/IIa, randomized, single-blind, placebo-controlled, multiple-ascending dose study conducted at a single site. The study plans to include up to approximately 46 evaluable subjects with Type 2 Diabetes Mellitus (HbA1c 7-11%) and Non-Alcoholic Fatty Liver disease (liver fat content > = 8%) on metformin monotherapy
Three initial cohorts are planned:
- Cohort 1: 6 subjects receiving AZD4076 and 4 subjects receiving placebo
- Cohort 2: 12 subjects receiving AZD4076 and 10 subjects receiving placebo
- Cohort 3: 10 subjects receiving AZD4076 and 10 subjects receiving placebo, with the possibility to add additional subjects if drop-out rates are higher than expected.
Pending review by SRC, an additional 2 cohorts, each consisting of 18 evaluable subjects may be included in the study.
The planned study consists of a screening visit, followed by 12 subsequent study visits. There will be a total of three residential periods: (1) Loading phase of the treatment (visit 2, days -4 to 14), (2) maintenance phase of treatment (visit 6, days 42-43), and (3) 8 weeks post-first dose of study drug (visit 9, days 53-56). Dosing of study drug will take place on days 1, 3, 5, 7, and 9 in the loading phase; and on days 14, 21, 28, 35, and 42 during the maintenance phase. Following the maintenance phase, subjects will have four follow-up visits.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
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
- 未提供
研究组 & 干预措施
Treatment
Subjects in this arm will receive AZD4076
干预措施: AZD4076 (Drug)
Control
Subjects in this arm will receive placebo
干预措施: Placebo (Drug)
结局指标
主要结局
The safety and tolerability of AZD4076 by assessment of blood pressure
时间窗: From screening until 26 weeks post first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessment of pulse
时间窗: From screening until 26 weeks post first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
Reduction in liver fat content (%) per MRI
时间窗: Screening and 54 days post first dose
To assess the effect of AZD4076 on liver fat content using magnetic resonance imaging
The safety and tolerability of AZD4076 by assessing the number of participants with adverse events
时间窗: From screening until 26 weeks post first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessment of oral temperature
时间窗: From day -2 until day 42
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessing clinical chemistry
时间窗: From screening until 26 weeks post first dose
Percentage of patients with clinically significant changes in laboratory tests.
The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings
时间窗: From predose until 24 hours post-dose on days 1 and 42
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability AZD4076 by assessment of physical examination
时间窗: From screening until 26 weeks post first dose
Percentage of patients with abnormal physical examination
The safety and tolerability of AZD4076 by assessing the injection site
时间窗: From day 1 until day 42
Percentage of patients with dermatological adverse events
The safety and tolerability of AZD4076 by assessing the number of adverse events
时间窗: From screening until 26 weeks post first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessing urinalysis
时间窗: From screening until 26 weeks post-first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessing hematology
时间窗: From screening until 26 weeks post first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessment of electrocardiogram readings
时间窗: From screening until 26 weeks post first dose
To assess the safety and tolerability of multiple ascending doses of AZD4076
Glucose infusion rate at hyperinsulinemic clamp
时间窗: Day -1 and 56 days post first dose
To assess the effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp with tracer technique
次要结局
- Cmax of AZD4076 and longmer and shortmer metabolites(Dosing day 1 and day 42)
- Fasting Endogenous Glucose Production(Day -1 and day 56)
- AUC0-24 of AZD4076 and longmer and shortmer metabolites(Dosing day 1 and day 42)
- 24 hour glucose area under the curve(Day -2 and day 55)
- Matsuda Index(Day -2 and day 55)
- Tmax of AZD4076 and longmer and shortmer metabolites(Dosing day 1 and day 42)
- Ae of AZD4076 and longmer and shortmer metabolites(Dosing day 1 and day 42)
- AUCt of AZD4076 and longmer and shortmer metabolites(Dosing day 1 and day 42)
- HOMA-IR(Day -2 and day 55)
- CLR of AZD4076 and longmer and shortmer metabolites(Day 1 and 42)
- fe% of AZD4076 and longmer and shortmer metabolites(Dosing day 1 and day 42)