A Phase I, First-in-Human, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2373 Following Single Ascending Dose Administrations to Healthy Male Subjects of African Ancestry
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Number of subjects with adverse events and/or abnormal findings in vital signs, and/or clinical laboratory assessments and/or physical examination and/or electrocardiogram (ECG) evaluation and/or telemetry and/or injection site reactions
研究概览
简要总结
This is a Phase 1 study to assess the the safety, tolerability and pharmacokinetics (PK) of AZD2373, following subcutaneous (SC) administration of single ascending doses (SAD) of AZD2373 in healthy male subjects of African ancestry.
详细描述
This study will be conducted as a single-centre, randomised, placebo-controlled, single-blind study to assess the effect of AZD2373 following ascending dose sequential group design administrations to healthy male subjects of African ancestry. The study will include 6 single dose cohorts with the option to include 2 additional cohorts based on emerging data from preceding cohorts in the study.
Approximately 48 male subjects aged 18 to 55 years at the time of informed consent (inclusive) will be randomized with the aim to have 8 subjects participate in each cohort. Within each cohort, 6 subjects will receive AZD2373 and 2 subjects will receive placebo.
Sentinel dosing will be applied for each cohort and will be divided into 2 groups:
- Group 1 (sentinel group): 1 active, 1 placebo;
- Group 2 (the rest of the cohort): 5 active, 1 placebo. The safety data of up to 72 hours post-dose in Group 1 will be reviewed by the Principal Investigator (PI) before the subjects in Group 2 are dosed.
The study will comprise:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
This study is single-blind (in which the study center staff remain blinded during the clinical conduct of a given cohort) with regard to treatment (AZD2373 or placebo) at each dose level. Study subjects will be blinded to treatment allocation throughout the study.
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Provision of signed and dated, written informed consent prior to any study specific procedures.
- •Healthy male subjects of West African ancestry aged 18 to 55 years (inclusive, at time of informed consent) with suitable veins for cannulation or repeated venipuncture.
- •Have a body mass index (BMI) between 18 and 35 kg/m^2 (inclusive) and weigh at least 50 kg and no more than 120 kg (inclusive).
- •Provision of signed, written and dated informed consent for study participation which includes mandatory genotyping (study objective). NOTE: If a subject would decline to participate in the mandatory genotyping component of the study, the subject will not be included in the study.
排除标准
- •Subjects with known ancestry outside of West Africa.
- •History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
- •History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
- •Any clinically important illness, medical/surgical procedure or trauma within 4 weeks prior to administration of IMP on Study Day
- •Any laboratory values with the following deviations:
- •Alanine aminotransferase or aspartate aminotransferase greater than upper limit of normal and clinically significant as determined by the PI.
- •White blood cell (WBC) count < 3.0 x 10^9/L.
- •Hemoglobin (Hb) below lower limit normal .
- •Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results, other than those described above, as judged by the PI.
研究组 & 干预措施
Cohort 1
On Day 1, randomized subjects will receive a subcutaneous (SC) injection of AZD2373 dose 1 (6 subjects) or matching placebo (2 subjects).
干预措施: AZD2373 subcutaneous injection (Drug)
Cohort 1
On Day 1, randomized subjects will receive a subcutaneous (SC) injection of AZD2373 dose 1 (6 subjects) or matching placebo (2 subjects).
干预措施: Placebo (Drug)
Cohort 2
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 2 (6 subjects) or matching placebo (2 subjects).
干预措施: AZD2373 subcutaneous injection (Drug)
Cohort 2
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 2 (6 subjects) or matching placebo (2 subjects).
干预措施: Placebo (Drug)
Cohort 3
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 3 (6 subjects) or matching placebo (2 subjects).
干预措施: AZD2373 subcutaneous injection (Drug)
Cohort 3
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 3 (6 subjects) or matching placebo (2 subjects).
干预措施: Placebo (Drug)
Cohort 4
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 4 (6 subjects) or matching placebo (2 subjects).
干预措施: AZD2373 subcutaneous injection (Drug)
Cohort 4
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 4 (6 subjects) or matching placebo (2 subjects).
干预措施: Placebo (Drug)
Cohort 5
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 5 (6 subjects) or matching placebo (2 subjects).
干预措施: AZD2373 subcutaneous injection (Drug)
Cohort 5
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 5 (6 subjects) or matching placebo (2 subjects).
干预措施: Placebo (Drug)
Cohort 6
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 6 (6 subjects) or matching placebo (2 subjects).
干预措施: AZD2373 subcutaneous injection (Drug)
Cohort 6
On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 6 (6 subjects) or matching placebo (2 subjects).
干预措施: Placebo (Drug)
结局指标
主要结局
Number of subjects with adverse events and/or abnormal findings in vital signs, and/or clinical laboratory assessments and/or physical examination and/or electrocardiogram (ECG) evaluation and/or telemetry and/or injection site reactions
时间窗: Screening Visit to final Follow-up Visit (Week 10 post last dose)
To assess adverse events as a variable of safety and tolerability of subcutaneous (SC) single ascending dose (SAD) administrations of AZD2373
次要结局
- Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC (0-48)](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Time to reach peak or maximum observed concentration or response following drug administration (tmax)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point [fe(0-last)](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Area under the plasma concentration-time curve from time zero to 72 hours after dosing [AUC(0-72)](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Area under plasma concentration-time curve from time zero extrapolated to infinity (AUC)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Area under the plasma concentration curve from time zero to the time of last quantifiable analyte concentration (AUClast)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Mean residence time of the unchanged drug in the systemic circulation (MRT)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Apparent total body clearance of drug from plasma after extravascular administration [CL/F](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Time of the last quantifiable concentration [tlast Ae(0-last)](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Apolipoprotein L1 (APOL1) concentrations and change from baseline(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Terminal elimination rate constant (λz)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)](Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Observed maximum plasma concentration (Cmax)(Visit 2 to final Follow-up Visit (Week 10 post last dose))
- Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR)(Visit 2 to final Follow-up Visit (Week 10 post last dose))