A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic Effects of ARO-ENaC in Normal Healthy Volunteers and Safety, Tolerability and Efficacy in Patients With Cystic Fibrosis
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 43
- 试验地点
- 7
- 主要终点
- Number of Participants With Adverse Events (AEs)
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) of single doses of ARO-ENaC in healthy adult volunteers; and to evaluate the safety, tolerability, PK and efficacy of multiple doses of ARO-ENaC in patients with pulmonary cystic fibrosis.
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 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding, and must be willing to use contraception
- •Willing to provide written informed consent and to comply with study requirements
- •Normal electrocardiogram (ECG) at Screening
- •Non-smoking
- •Normal pulmonary function tests at Screening (NHVs only)
- •No abnormal finding of clinical relevance at Screening other than CF for CF patients
- •Confirmed diagnosis of CF based on source verifiable medical record (CF patients only)
- •All other treatments for CF have been stable for at least 2 months and patient is willing to continue this treatment regimen without change for duration of study (CF patients only)
排除标准
- •Acute lower respiratory infection within 30 days of Screening (NHVs only)
- •History of asthma (specifically, those subjects at risk of bronchial hyperactivity), anaphylaxis or airway hyper-reactivity
- •Clinically significant history of hyperkalemia or presence of hyperkalemia at Screening
- •Clinically significant health concerns (other than CF in CF patients)
- •Human Immunodeficiency virus (HIV) infection, seropositive for Hepatitis B Virus (HBV), seropositive for Hepatitis C Virus (HCV)
- •Uncontrolled hypertension
- •Excessive use of alcohol within one month prior to Screening
- •Use of illicit drugs within 1 year prior to Screening
- •Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study
- •CF exacerbation within 30 days of Dosing (CF patients)
- •History of solid organ transplant (CF patients)
- •Diagnosis of hepatic cirrhosis (CF patients)
- •Note: additional inclusion/exclusion criteria may apply per protocol
研究组 & 干预措施
Normal Healthy Volunteer Cohort: ARO-ENaC 20 mg, Days 1-3
Normal healthy volunteers receive double-blind ARO-ENaC 20 mg on Days 1, 2, 3
干预措施: ARO-ENaC (Drug)
Normal Healthy Volunteer Cohort: ARO-ENaC 40 mg, Days 1-3
Normal healthy volunteers receive double-blind ARO-ENaC 40 mg on Days 1, 2, 3
干预措施: ARO-ENaC (Drug)
Normal Healthy Volunteer Cohort: ARO-ENaC 65 mg, Days 1-3
Normal healthy volunteers receive double-blind ARO-ENaC 65 mg on Days 1, 2, 3
干预措施: ARO-ENaC (Drug)
Normal Healthy Volunteer Cohort: ARO-ENaC 180 mg, Days 1-3
Normal healthy volunteers receive double-blind ARO-ENaC 180 mg on Days 1, 2, 3
干预措施: ARO-ENaC (Drug)
Normal Healthy Volunteer Cohort: ARO-ENaC 180 mg, Days 1-3 With Bronchoscopy
Normal healthy volunteers receive double-blind ARO-ENaC 180 mg on Days 1, 2, 3 with the purpose of collecting bronchoscopic samples
干预措施: ARO-ENaC (Drug)
Cystic Fibrosis Cohort: ARO-ENaC 40 mg, Days 1-3, 22-24
Participants with cystic fibrosis receive double-blind ARO-ENaC 40 mg dosed on Days 1, 2, and 3, and 40 mg dosed on Days 22, 23, and 24
干预措施: ARO-ENaC (Drug)
Normal Healthy Volunteer Cohort: Placebo for ARO-ENaC 20 mg, Days 1-3
Normal healthy volunteers receive double-blind placebo for ARO-ENaC 20 mg on Days 1, 2, 3
干预措施: Placebo (Drug)
Normal Healthy Volunteer Cohort: Placebo for ARO-ENaC 40 mg, Days 1-3
Normal healthy volunteers receive double-blind placebo for ARO-ENaC 40 mg on Days 1, 2, 3
干预措施: Placebo (Drug)
Normal Healthy Volunteer Cohort: Placebo for ARO-ENaC 65 mg, Days 1-3
Normal healthy volunteers receive double-blind placebo for ARO-ENaC 65 mg on Days 1, 2, 3
干预措施: Placebo (Drug)
Normal Healthy Volunteer Cohort: Placebo for ARO-ENaC 180 mg, Days 1-3
Normal healthy volunteers receive double-blind placebo for ARO-ENaC 180 mg on Days 1, 2, 3
干预措施: Placebo (Drug)
Normal Healthy Volunteer Cohort: Placebo for ARO-ENaC 180 mg, Days 1-3 With Bronchoscopy
Normal healthy volunteers receive double-blind placebo for ARO-ENaC 180 mg on Days 1, 2, 3 to collect bronchoscopic samples
干预措施: Placebo (Drug)
Cystic Fibrosis Cohort: Placebo
Participants with cystic fibrosis receive double-blind placebo for ARO-ENaC 40 mg dosed on Days 1, 2, and 3, and Days 22, 23, and 24.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With Adverse Events (AEs)
时间窗: Normal Healthy Volunteers: Up to 29 (+/- 2) days post-dose; Participants with cystic fibrosis (CF): Up to 113 (+/- 5) days post-dose
Adverse event (AE)=any untoward medical occurrence that does not necessarily have to have a causal relationship with this treatment. Treatment-emergent AEs (TEAEs)=AEs with onset on or after administration of study drug through end of study. Serious adverse event (SAE)= an AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction.
次要结局
- PK of ARO-ENaC: AUClast in Participants With CF(Cycle 1 Day 1: Pre-dose (PrD), 30, 60, 120 minutes (m), 4 hours (h) post-dose (PoD); Day 2: PrD, 60, 120 m, 4 h PoD; Day 3: PrD, 30, 60, 120 m, 4 h PoD. Cycle 2 Days 22 and 23: PrD, 30 m, 4 h PoD; Day 24: PrD, 30, 60, 120 m, 4 h PoD)
- PK of ARO-ENaC: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Plasma Concentration (AUClast) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- Change From Baseline in Serum Electrolytes: Potassium, Sodium, Bicarbonate and Chloride(Normal Healthy Volunteers: Baseline, Days 2, 3, 4, 8, 15, 18, 29 ; Participants with CF: Baseline, Days 2, 3, 4, 15, 22, 23. 24, 29, 37, 57, 71, 85, 91, 113)
- Change From Baseline in Forced Expiratory Volume (FEV1) in Normal Healthy Volunteers(Baseline, Up through Day 29 after a single dose)
- Pharmacokinetics (PK) of ARO-ENaC: Maximum Observed Plasma Concentration (Cmax) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: Cmax in Participants With CF(Cycle 1 Day 1: Pre-dose (PrD), 30, 60, 120 minutes (m), 4 hours (h) post-dose (PoD); Day 2: PrD, 60, 120 m, 4 h PoD; Day 3: PrD, 30, 60, 120 m, 4 h PoD. Cycle 2 Days 22 and 23: PrD, 30 m, 4 h PoD; Day 24: PrD, 30, 60, 120 m, 4 h PoD)
- PK of ARO-ENaC: Time to Maximum Plasma Concentration (Tmax) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: Tmax in Participants With CF(Cycle 1 Day 1: Pre-dose (PrD), 30, 60, 120 minutes (m), 4 hours (h) post-dose (PoD); Day 2: PrD, 60, 120 m, 4 h PoD; Day 3: PrD, 30, 60, 120 m, 4 h PoD. Cycle 2 Days 22 and 23: PrD, 30 m, 4 h PoD; Day 24: PrD, 30, 60, 120 m, 4 h PoD)
- PK of ARO-ENaC: Elimination Half-Life (t1/2) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUCinf) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: CL/F in Participants With CF(Cycle 1 Day 1: Pre-dose (PrD), 30, 60, 120 minutes (m), 4 hours (h) post-dose (PoD); Day 2: PrD, 60, 120 m, 4 h PoD; Day 3: PrD, 30, 60, 120 m, 4 h PoD. Cycle 2 Days 22 and 23: PrD, 30 m, 4 h PoD; Day 24: PrD, 30, 60, 120 m, 4 h PoD)
- PK of ARO-ENaC: Amount Recovered in Urine Over 0 to 24 Hours Postdose (Ae0-24h) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: Plasma Clearance (CL/F) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: Fraction Excreted in Urine as Unchanged Drug Over 0 to 24 Hours Postdose (fe0-24h) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))
- PK of ARO-ENaC: Renal Clearance (CLR) in Normal Healthy Volunteers(Day 1: Pre-dose, 30, 60, 120 mins and 4, 6, 8, 16 hours post-inhalation; Day 2: Pre-dose (Day 1, 24-hour timepoint), then 1, 2, 4 hours post-inhalation; Day 3: (Day 2, 24 hour timepoint), 30, 60, 120 mins, 4, 6, 8, 16, 24 (On Day 4), 48 (on Day 5))