A Single-blind, Randomized, Placebo-controlled 3 Part Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Tolerability, and Pharmacokinetics of Inhaled AZD4604 Following Single and Multiple Ascending Doses and to Investigate the Anti-inflammatory Effect of Inhaled AZD4604
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 110
- 试验地点
- 1
- 主要终点
- Part 1b: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)
研究概览
简要总结
This is a first in human clinical study. Part 1 of the clinical study will assess the safety and tolerability, as well as the single dose pharmacokinetics (PK), of inhaled AZD4604 in healthy volunteers (Part 1a, single ascending dose [SAD]). The single dose administration will be performed with dry powder inhaler (DPI) formulation of AZD4604. When at least 4 cohorts of the SAD part of the study have been completed, AZD4604 will be administered as a single intravenous (IV) or oral (PO) dose to 2 different cohorts of healthy volunteers (Part 1b). The main purpose is to compare the PK between IV, oral and inhaled administration to further characterize the PK properties of AZD4604 by the various administration routes. The results will be used to improve future study design and interpretation. In Part 2 (Multiple ascending dose [MAD]), AZD4604 will be administered at multiple doses (twice daily [BID], 7 days) to healthy volunteers. In Part 3, AZD4604 will be administered at multiple doses to patients with mild asthma at dose levels assessed in Part 2. The multiple-dose administration will be performed with DPI-formulated AZD4604.
详细描述
Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study. Seven inhaled dose levels of AZD4604 are planned to be investigated in cohorts of 8 healthy volunteers, with 6 healthy volunteers randomly assigned to inhaled AZD4604 and 2 healthy volunteers randomly assigned to inhaled placebo in each cohort.
Part 1a will comprise of:
- A Screening Visit within 28 days before dosing.
- A Treatment Period (Day -1 to Day 7, in the Clinical Unit) with a single inhaled dose of AZD4604 or corresponding placebo on Day 1. Although the anticipated systemic exposure and risk for potential adverse systemic effects are considered to be low for AZD4604, healthy volunteers will remain resident at site for additional 6 days of monitoring.
- A Final Assessment on day of discharge.
In Part 1b, AZD4604 will be administered as a single IV or a PO dose to healthy volunteers in order to compare the PK between IV, PO and inhaled administration. Part 1b will be open-label and consist of 2 dose cohorts, IV and PO, with 6 healthy volunteers in each.
Part 1b will comprise of:
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
- Single (Participant)
盲法说明
Part 1a: Healthy volunteers will be blinded to treatment allocation (single-blind design) to minimize bias.
Part 1b: This part of the study is open-label and blinding is not applicable.
Part 2: Healthy volunteers will be blinded to treatment allocation (single-blind design) to minimize bias.
Part 3: Patients will be blinded to treatment allocation (single-blind design) to minimize bias
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 1)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 1 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 2)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 2 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI(Dose 3)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 3 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 4)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 4 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 5)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 5 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 6)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 6 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 10)
Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 7)
Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 7 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): AZD4604 for inhalation via DPI
An additional cohort of healthy volunteers will receive a single inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 1a (SAD): Placebo for AZD4604 for inhalation via DPI
Healthy volunteers will receive placebo administered with a DPI.
干预措施: Placebo for AZD4604 for inhalation via DPI (Drug)
Part 1b: AZD4604 for intravenous administration
Healthy volunteers will receive a single IV dose of AZD4604 administered as a 20 minute infusion.
干预措施: AZD4604 for IV administration (Drug)
Part 1b: AZD4604 for oral administration
Healthy volunteers will receive a single PO dose of AZD4604.
干预措施: AZD4604 for oral administration (Drug)
Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 8)
Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 9)
Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 2 (MAD): Placebo for AZD4604 for inhalation via DPI
Healthy volunteers will receive placebo administered with a DPI.
干预措施: Placebo for AZD4604 for inhalation via DPI (Drug)
Part 3 (MAD): AZD4604 for inhalation via DPI (Dose 9)
Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 3 (MAD): AZD4604 for inhalation via DPI (Dose 10)
Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
Part 3 (MAD): Placebo for AZD4604 for inhalation via DPI
Patients will receive placebo administered with a DPI.
干预措施: Placebo for AZD4604 for inhalation via DPI (Drug)
Part 3 (PoM): AZD4604 for inhalation via DPI (Dose 9 or Dose 10)
Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.
干预措施: AZD4604 for inhalation via DPI (Drug)
结局指标
主要结局
Part 1b: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)
时间窗: From Day 1 to Day 3
AUClast of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
时间窗: From Day 1 to Day 3
AUClast of AZD4604 following PO administration of a single dose to healthy volunteers.
Part 2: Number of healthy volunteers with AEs
时间窗: From screening (SAEs only) up to Final assessment (Day 13)
Safety and tolerability of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.
Part 1b: Maximum observed plasma (peak) drug concentration (Cmax)
时间窗: From Day 1 to Day 3
Cmax of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Time to reach peak or maximum observed concentration or response following drug administration (tmax)
时间窗: From Day 1 to Day 3
tmax of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Time of last observed (quantifiable) concentration (tlast)
时间窗: From Day 1 to Day 3
tlast of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 3: Number of patients with AEs
时间窗: From Screening (SAEs only) up to Final Assessment (Day 16)
Safety and tolerability of AZD4604 following inhaled administration of multiple ascending doses to patients.
Part 1a: Number of healthy volunteers with adverse events (AEs)
时间窗: From screening (SAEs only) up to Final assessment (Day 7)
Safety and tolerability of AZD4604 following inhaled administration of single ascending doses to healthy volunteers.
Part 1b: Partial area under the plasma concentration time curve from time 0 to time 12 (AUC [0 - 12])
时间窗: From Day 1 to Day 3
AUC (0 - 12) of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Total body clearance of drug from plasma after intravascular administration (CL)
时间窗: From Day 1 to Day 3
CL of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 1b: Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F)
时间窗: From Day 1 to Day 3
Vz/F of AZD4604 following PO administration of a single dose to healthy volunteers.
Part 1b: Dose normalized AUCinf, derived by AUCinf divided by the dose administered (AUCinf/D)
时间窗: From Day 1 to Day 3
AUCinf/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Area under plasma concentration-time curve from zero to infinity (AUCinf)
时间窗: From Day 1 to Day 3
AUCinf of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Dose normalized Cmax, derived by Cmax divided by the dose administered (Cmax/D)
时间窗: From Day 1 to Day 3
Cmax/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz)
时间窗: From Day 1 to Day 3
λz of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz)
时间窗: From Day 1 to Day 3
t1/2λz of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Partial area under the plasma concentration time curve from time 0 to time 24 (AUC [0 - 24])
时间窗: From Day 1 to Day 3
AUC (0 - 24) of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Volume of distribution following intravascular administration (based on terminal phase) (Vz)
时间窗: From Day 1 to Day 3
Vz of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 1b: Dose normalized AUClast, derived by AUClast divided by the dose administered (AUClast/D)
时间窗: From Day 1 to Day 3
AUClast/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
次要结局
- Part1b: Number of healthy volunteers with AEs(From screening (only SAEs) to follow-up end of treatment visit (6 ± 1 day post-dose))
- Part 1a and Part 2: tmax(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
- Part1a: AUC (0 - 12)(From Day 1 to Day 7)
- Part 1a and Part 2: λz(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
- Part 1a and Part 2: t1/2λz(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
- Part 1a and Part 2: AUC (0 - 24)(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
- Part 2: Area under plasma concentration-time curve in the dose interval (AUCτ)(From Day 1 to Day 13)
- Part 1a and Part 2: Cmax(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
- Part 1a and Part 2: AUClast(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
- Part 1a: AUCinf(From Day 1 to Day 7)
- Part 1a and Part 2: Cmax/D(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
- Part1a: AUCinf/D(From Day 1 to Day 7)
- Part 2: Dose normalized AUCτ, derived by AUCτ divided by the dose administered (AUCτ/D)(From Day 1 to Day 13)
- Part 1a and Part 2: CL/F(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
- Part 1a and Part 2: Vz/F(From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2))
- Part 1a and Part 2: AUClast/D(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
- Part 1a and Part 2: tlast(From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2))
- Part 2: Accumulation ratio for Cmax (Rac Cmax)(On Day 7)
- Part 2: Accumulation ratio for AUCτ (Rac AUC)(On Day 7)
- Part 1b: Renal clearance of drug from plasma (CLR)(From Day 1 to Day 2)
- Part 1b: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae [t1 - t2])(From Day 1 to Day 2)
- Part 1b: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe [t1 - t2])(From Day 1 to Day 2)
- Part 3: AUC(From Days 1 to 16)
- Part 3: Cough severity self-assessment (Visual analog scale)(From Day -3 to -1, and Days 1 to 10)
- Part 2: Cough severity self-assessment (Visual analog scale)(Day-1 to Day 7 (Pre-dose) and Day 8 (Post -dose))
- Part 3: Cmax(From Days 1 to 16)
- Part 3: AUCτ(From Days 1 to 16)
- Part 3: Change from baseline in Fractional exhaled nitric oxide (FeNO) levels(From Day 1 to 10)