A Phase 1/2a Study Evaluating the Effects of ARO-MUC5AC Inhalation Solution in Healthy Subjects and Patients With Muco-Obstructive Lung Disease
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 78
- 试验地点
- 16
- 主要终点
- Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of ARO-MUC5AC in normal healthy volunteers (NHVs), patients with moderate-to-severe asthma and patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In part 1 NHVs will receive a single dose of ARO-MUC5AC or placebo. In part 2 of the study, NHVs, adult patients with asthma, and adult patients with COPD will receive 3 doses of ARO-MUC5AC or placebo.
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
- Triple (Participant, Care Provider, Investigator)
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
- 是
入选标准
- •Normal pulmonary function tests at Screening (NHVs only)
- •Confirmed diagnosis of asthma or COPD based on source verifiable medical record (asthma and COPD patients only)
- •No abnormal finding of clinical relevance at Screening (NHVs only)
- •Stable dose of asthma controller medications for at least 28 days prior to Screening (asthma patients only)
- •Documented treatment with an inhaled corticosteroid and at least 1 additional maintenance asthma controller medication for at least 3 months prior to Screening (asthma patients only)
- •Non-smoking (NHVs and asthma patients)
- •Current smoker or ex-smoker with smoking history of ≥ 10 pack-years (COPD patients only)
- •All COPD treatments have been stable for at least one month prior to Screening (COPD patients only)
- •Able to produce an induced sputum sample at Screening
- •Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding, and must be willing to use contraception. Males must not donate sperm during the study and for at least 90 days following the last dose of study drug
- •Willing to provide written informed consent and to comply with study requirements
排除标准
- •Acute lower respiratory infection within 30 days prior to first dose and/or acute upper respiratory infection within 7 days prior to first dose
- •Positive COVID-19 test during Screening window
- •Any history of chronic pulmonary disease (NHVs only)
- •Any concomitant pulmonary disease in asthma or COPD patients that could interfere with the evaluation of the study drug or interpretation of patient safety or study results
- •Use of theophylline within 30 days prior to first dose
- •History of lung volume reduction surgery or pneumonectomy (COPD patients)
- •Need for chronic oxygen support at Screening
- •Clinically significant health concerns (other than asthma in asthma patients)
- •Human immunodeficiency virus (HIV) infection, seropositive for hepatitis B virus (HBV), seropositive for hepatitis C virus (HCV)
- •Uncontrolled hypertension
- •Unwilling to limit alcohol consumption to within moderate limits for the duration of the study
- •Use of illicit drugs
- •Use of an investigational agent or device within 30 days prior to first dose
- •Note: additional inclusion/exclusion criteria may apply per protocol
研究组 & 干预措施
NHV (Single Ascending Dose [SAD]): Pooled Placebo
a single dose of placebo was administered once on Day 1
干预措施: Placebo (Drug)
NHV (Multiple Ascending Dose [MAD]): Pooled Placebo
3 total doses of placebo were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: Placebo (Drug)
Asthma Patients (MAD): Pooled Placebo
3 total doses of placebo were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: Placebo (Drug)
Asthma Patients (MAD): ARO-MUC5AC 56 mg
3 total doses of ARO-MUC5AC 56 mg were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: ARO-MUC5AC (Drug)
COPD Patients (MAD): Pooled Placebo
3 total doses of placebo were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: Placebo (Drug)
COPD Patients (MAD): 56 mg
3 total doses of ARO-MUC5AC 56 mg were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: ARO-MUC5AC (Drug)
NHV (SAD): ARO-MUC5AC 24 mg
a single dose of ARO-MUC5AC 24 mg was administered once on Day 1
干预措施: ARO-MUC5AC (Drug)
NHV (SAD): ARO-MUC5AC 56 mg
a single dose of ARO-MUC5AC 56 mg was administered once on Day 1
干预措施: ARO-MUC5AC (Drug)
Asthma Patients (MAD): ARO-MUC5AC 108 mg
3 total doses of ARO-MUC5AC 108 mg were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: ARO-MUC5AC (Drug)
NHV (SAD): ARO-MUC5AC 108 mg
a single dose of ARO-MUC5AC 108 mg was administered once on Day 1
干预措施: ARO-MUC5AC (Drug)
NHV (SAD): ARO-MUC5AC 232 mg
a single dose of ARO-MUC5AC 232 mg was administered once on Day 1
干预措施: ARO-MUC5AC (Drug)
NHV (MAD): ARO-MUC5AC 24 mg
3 total doses of ARO-MUC5AC 24 mg were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: ARO-MUC5AC (Drug)
NHV (MAD): ARO-MUC5AC 56 mg
3 total doses of ARO-MUC5AC 56 mg were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: ARO-MUC5AC (Drug)
NHV (MAD): ARO-MUC5AC 108 mg
3 total doses of ARO-MUC5AC 108 mg were administered, with 1 dose given on each of Days 1, 15, and 29
干预措施: ARO-MUC5AC (Drug)
结局指标
主要结局
Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
时间窗: single dose phase: up to Day 29; multiple dose phase: up to Day 85
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: From first dose of study drug up to Day 29 (single dose phase), and up to Day 85 (multiple dose phase)
An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with treatment. TEAEs will be defined as AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. A serious AE (SAE) is an AE occurring during any study phase, and at any dose of study drug that: results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above.
次要结局
- Change Over Time from Baseline in Forced Expiratory Volume (FEV1)(single dose phase: up to Day 29; multiple dose phase: up to Day 85)
- PK of ARO-MUC5AC: Terminal Elimination Half-Life (t1/2)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Apparent Terminal-Phase Volume of Distribution (VZ/F)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Recovery of Unchanged Drug in Urine Over 24 Hours (Amount Excreted; Ae)(through 24 hours post-dose)
- PK of ARO-MUC5AC: Percentage of Administered Drug Recovered in Urine Over 0-24 Hours(through 24 hours post-dose)
- PK of ARO-MUC5AC: Maximum Observed Plasma Concentration (Cmax)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Area Under the Plasma Concentration versus Time Curve From Zero to 24 Hours (AUC0-24)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Area Under the Plasma Concentration versus Time Curve From Zero to Infinity (AUCinf)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- Change Over Time from Baseline in Forced Vital Capacity (FVC)(single dose phase: up to Day 29; multiple dose phase: up to Day 85)
- PK of ARO-MUC5AC: Area Under the Plasma Concentration versus Time Curve From Zero to the Last Quantifiable Plasma Concentration (AUClast)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Apparent Systemic Clearance (CL/F)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Renal Clearance (CLr)(single dose phase: up to 48 Hours; multiple dose phase: up to 6 hours post-dose on Days 1 and 29 for NHVs; and up to 6 hours post-dose on Days 1 and 29, and up to 24 hours post-dose on Days 2 and 30 for participants with asthma or COPD)
- PK of ARO-MUC5AC: Time to Cmax (Tmax), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Renal Clearance (CLr), SAD Cohorts Only(Day 1: Predose and cumulatively from 0 to 6 hours and 6 to 24 hours postdose.)
- PK of ARO-MUC5AC: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC0-t), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours (AUC0-24), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose (based on start of inhalation))
- Change Over Time From Baseline in Forced Expiratory Volume (FEV1), SAD Cohorts(Baseline, Day 1: 15, 60, 120 minutes (mins) post-dose, Days 2,3, 8, 15, 22, 29 (end of study [EOS]))
- Change Over Time From Baseline in FEV1, MAD Cohorts(Baseline, Day 1 (15, 60, 120 mins post-dose), Days 2, 3, 8, 15 (15, 60, 120 mins post-dose), 22, 29 (15, 60, 120 mins post-dose), 30, 35, 36, 43, 50, 57, 71, 85 (EOS))
- Change Over Time From Baseline in Forced Vital Capacity (FVC), SAD Cohorts(Baseline, Day 1: 15, 60, 120 minutes (mins) post-dose, Days 2, 3, 8, 15, 22, 29 (end of study [EOS]))
- Change Over Time From Baseline in FVC, MAD Cohorts(Baseline, Day 1 (15, 60, 120 mins post-dose), Days 2, 8, 15 (15, 60, 120 mins post-dose), 22, 29 (15, 60, 120 mins post-dose), 30, 35, 36, 43, 50, 57, 71, 85 (EOS))
- Pharmacokinetics (PK) of ARO-MUC5AC: Maximum Observed Plasma Concentration (Cmax), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUCinf), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Terminal Elimination Half-Life (t1/2), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Apparent Systemic Clearance (CL/F), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Apparent Terminal-Phase Volume of Distribution (Vz/F), SAD Cohorts(Day 1: Predose, at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (based on start of inhalation); Day 2: 24 hours postdose; Day 3: 48 hours postdose)
- PK of ARO-MUC5AC: Recovery of Unchanged Drug in Urine Over 24 Hours (Amount Excreted; Ae), SAD Cohorts Only(Day 1: Predose and cumulatively from 0 to 6 hours and 6 to 24 hours postdose.)
- PK of ARO-MUC5AC: Fraction of Respirable Delivered Dose (RDD) Excreted Unchanged in Urine Over 24 Hours Postdose, as a Percentage (Fe), SAD Cohorts Only(Day 1: Predose and cumulatively from 0 to 6 hours and 6 to 24 hours postdose.)
- PK of ARO-MUC5AC: Maximum Observed Plasma Concentration (Cmax), MAD Cohorts(NHV Cohorts: Day 1: Predose, 0.5, 1, 2, 4, and 6 hours postdose (based on start of inhalation); Day 15: Predose; Day 29: Predose, 0.5, 1, 2, 4, and 6 hours postdose.)
- PK of ARO-MUC5AC: Tmax, MAD Cohorts(NHV Cohorts: Day 1: Predose, 0.5, 1, 2, 4, and 6 hours postdose (based on start of inhalation); Day 15: Predose; Day 29: Predose, 0.5, 1, 2, 4, and 6 hours postdose.)
- PK of ARO-MUC5AC: AUC0-t, MAD Cohorts(NHV Cohorts: Day 1: Predose, 0.5, 1, 2, 4, and 6 hours postdose (based on start of inhalation); Day 15: Predose; Day 29: Predose, 0.5, 1, 2, 4, and 6 hours postdose.)