Study of ARO-ENaC in Healthy Volunteers and in Patients With Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Cystic Fibrosis, Pulmonary

Intervention / Treatment
-----------------
* Drug: ARO-ENaC
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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) Exclusion Criteria: 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARO-ENaC<br>ARO-ENaC Inhalation | Drug: ARO-ENaC<br>* single or multiple doses of ARO-ENaC by inhalation of nebulized solution<br>|
| Placebo Comparator: Placebo<br>Sterile normal saline (0.9% NaCl) | Drug: Placebo<br>* calculated volume to match active treatment by inhalation of nebulized solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) Possibly or Probably Related to Treatment |  | single dose phase: Up to 29 (+/- 2) days; multiple dose phase: Up to 113 (+/- 5 days) post-dose for patients with CF | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Serum Electrolytes: Potassium, Sodium, Bicarbonate and Chloride (all in mmol/L) |  | Baseline, single dose phase: Up to 29 (+/- 2) days; multiple dose phase: Up to 113 (+/- 5 days) post-dose for patients with CF | 
| Change from Baseline in Forced Expiratory Volume (FEV1) in Normal Healthy Volunteers |  | Baseline, Up through Day 29 after a single dose | 
| PK of ARO-ENaC: Maximum observed Plasma Concentration (Cmax) |  | single dose phase: Up through Day 5; multiple dose phase: Up through Day 30 (+/- 2 days) | 
| PK of ARO-ENaC: Time to Maximum Plasma Concentration (Tmax) |  | single dose phase: Up through Day 5; multiple dose phase: Up through Day 30 (+/- 2 days) | 
| PK of ARO-ENaC: Terminal Elilmination Half-Life (t1/2) |  | single dose phase: Up through Day 5; multiple dose phase: Up through Day 30 (+/- 2 days) | 
| PK of ARO-ENaC: Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours (AUC0-24) |  | single dose phase: Up through Day 5; multiple dose phase: Up through Day 30 (+/- 2 days) | 
| PK of ARO-ENaC: Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUCinf) |  | single dose phase: Up through Day 5; multiple dose phase: Up through Day 30 (+/- 2 days) | 
| PK of ARO-ENaC: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Quantifiable Plasma Concentration (AUClast) |  | single dose phase: Up through Day 5; multiple dose phase: Up through Day 30 (+/- 2 days) |