A Sequential, Phase 1a/1b, Double-blind, 2-part Study to Investigate the Safety, Tolerability, Microbiological Response, and Pharmacokinetics of Rev-56 for Inhalation Compared With Placebo in Healthy Adult Participants and Adult Non-cystic Fibrosis Bronchiectasis (NCFB) Patients With Chronic Pseudomonas Aeruginosa
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 64
- 试验地点
- 2
- 主要终点
- Incidence and severity of treatment-emergent adverse events (AEs)
研究概览
简要总结
This is a Phase 1a/1b study to test the safety, tolerability, microbiological response, and pharmacokinetics of inhaled Rev-56 compared to placebo in adult healthy participants and non-cystic fibrosis bronchiectasis (NCFB) patients with P. aeruginosa, respectively.
Phase 1a (Part A) will evaluate single doses of inhaled Rev-56 in adult healthy participants and includes up to 5 cohorts. Eligible participants will be randomized to active treatment or placebo in a 3:1 randomization scheme.
Phase 1b (Part B) will evaluate the safety, tolerability, microbiological response, and pharmacokinetics of multiple doses of inhaled Rev-56 in NCFB patients with P. aeruginosa and includes 2 cohorts evaluating once daily dosing and twice daily dosing, respectively. Eligible participants will be randomized to active treatment or placebo in a 2:1 randomization scheme.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •(Healthy Participants):
- •Healthy male and female participants aged 18 to 55 years, inclusive
- •Body mass index > 18 to ≤ 32 kg/m^2
- •Forced expiratory volume in 1 second (FEV1) ≥ 80%
- •Creatinine clearance ≥ 90 mL/min
- •Normal laboratory values and physical exam at screening, or Grade 1 abnormalities that are not clinically significant
- •Inclusion Criteria (NCFB Patients with P. aeruginosa):
- •Male and female NCFB patients aged 18 to 80 years, inclusive
- •Bronchiectasis confirmed by prior computerized tomography (CT) scan
- •Chronic P. aeruginosa infection (≥ 2 positive cultures within prior 12 months)
- •Screening sputum culture positive for P. aeruginosa at ≥ 10^4 CFU/mL
- •FEV1 ≥ 50% (post bronchodilator)
排除标准
- •(Healthy Participants):
- •Clinically significant medical history
- •Acute illness within 4 weeks of screening
- •Current smoker or nicotine user
- •History of alcohol abuse (within prior 12 months) or drug/chemical abuse
- •Exclusion Criteria (NCFB Patients with P. aeruginosa):
- •Primary asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis (CF)
- •More than 2 pulmonary exacerbations requiring IV antibiotics within 12 months prior to screening
- •Receipt of antibiotics (excluding macrolides) within 30 days prior to screening
- •Clinically significant hemoptysis requiring intervention within 30 days prior to screening
- •Receiving anti-infective treatment for concurrent nontuberculosis mycobacteria (NTM) or fungal infection
研究组 & 干预措施
Cohort 1a
3.5 mg Rev-56 or placebo single dose
干预措施: Rev-56 for Inhalation (Combination Product)
Cohort 2a
7 mg Rev-56 or placebo single dose
干预措施: Placebo: Normal saline (Drug)
Cohort 3a
14 mg Rev-56 or placebo single dose
干预措施: Placebo: Normal saline (Drug)
Cohort 4a
28 mg Rev-56 or placebo single dose
干预措施: Rev-56 for Inhalation (Combination Product)
Cohort 4a
28 mg Rev-56 or placebo single dose
干预措施: Placebo: Normal saline (Drug)
Optional Cohort 5a
≤56 mg Rev-56 or placebo single dose
干预措施: Rev-56 for Inhalation (Combination Product)
Optional Cohort 5a
≤56 mg Rev-56 or placebo single dose
干预措施: Placebo: Normal saline (Drug)
Cohort 1b
≤28 mg Rev-56 or placebo once daily for 7 days
干预措施: Rev-56 for Inhalation (Combination Product)
Cohort 1b
≤28 mg Rev-56 or placebo once daily for 7 days
干预措施: Placebo: Normal saline (Drug)
Cohort 2b
≤28 mg Rev-56 or placebo twice daily for 7 days
干预措施: Rev-56 for Inhalation (Combination Product)
Cohort 2b
≤28 mg Rev-56 or placebo twice daily for 7 days
干预措施: Placebo: Normal saline (Drug)
Cohort 1a
3.5 mg Rev-56 or placebo single dose
干预措施: Placebo: Normal saline (Drug)
Cohort 2a
7 mg Rev-56 or placebo single dose
干预措施: Rev-56 for Inhalation (Combination Product)
Cohort 3a
14 mg Rev-56 or placebo single dose
干预措施: Rev-56 for Inhalation (Combination Product)
结局指标
主要结局
Incidence and severity of treatment-emergent adverse events (AEs)
时间窗: 21 days (healthy participants) or 28 days (NCFB patients with P. aeruginosa)
Number of participants with clinically significant abnormalities in lab parameters, vital signs, respiratory function, and ECG parameters graded by FDA Toxicity Grading Scale (for healthy participants) and DAIDS Toxicity Tables (for NCFB patients)
时间窗: 21 days (healthy participants) or 28 days (NCFB patients with P. aeruginosa)
次要结局
- Half-life of Rev-56 (t½)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Area under the curve from time 0 to infinity (AUC0-inf)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Clearance of Rev-56 (CL/F)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Mean P. aeruginosa burden (CFU/mL) in sputum culture compared to baseline(28 days (NCFB patients with P. aeruginosa))
- Volume of distribution of Rev-56 (Vz/F)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Minimum observed concentration of Rev-56 (Cmin)(NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Maximum observed concentration (Cmax) of Rev-56(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Time to Cmax of Rev-56 (Tmax)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Area under the curve from time 0 to last measurable concentration (AUC0-last)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)
- Area under the curve from time 0 to 24 hours after completion of dosing (AUC0-24)(Healthy Participants: predose, and 5 min, 15 min, 45 min, 90 min, 3h, 6h, 12h, 24h and 48h post inhalation; NCFB Patients: pre-dose, and 5 min, 15 min, 45 min, 90 min, 3h, 8h, 12h (Cohort 2b only) and 24h (Cohort 1b only) after completion of inhalation)