A Phase 1 Trial to Assess the Safety, Tolerability, and Pharmacokinetics of GS 9411 in Subjects With Cystic Fibrosis (CF)

A Phase 1, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of GS 9411 in Subjects With Cystic Fibrosis (CF)

The purpose of this study is to evaluate the safety and tolerability of GS-9411 in patients with Cystic Fibrosis. GS-9411 is a sodium channel inhibitor, that may restore airway hydration and mucociliary clearance in the lung.

GS-9411 is being evaluated as a potential therapy to improve airway hydration and mucociliary clearance in patients with cystic fibrosis. This study is evaluating the safety and tolerability of 2 dose levels of GS-9411 as an inhaled product, compared to a matched placebo.

Inclusion Criteria:

• Males and females aged 18 to 65 years
• Patients with diagnosis of CF as confirmed by at least one of the following:
• Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test OR
• Documented sweat sodium test ≥ 60 mmol/L OR
• Abnormal nasal potential difference test OR
• At least one well-characterized disease-causing genetic mutation in the CF transmembrane conductance regulatory (CFTR) gene AND
• Accompanying symptoms characteristic of CF
• Normal (or abnormal but not clinically significant) electrocardiogram (ECG)
• Normal intraocular pressure (IOP) between 10 and 21 mm Hg at Screening.
• Normal (or abnormal but not clinically significant) blood pressure (BP) and heart rate (HR) in the absence of any medications for hypertension; these will be measured after the subject has rested supine for 3 minutes; normal BP is taken to be 90 to 140 mm Hg systolic and 50 to 89 mm Hg diastolic; normal HR is taken to be 40 to 100 beats per minute (bpm)
• Able to communicate well with the investigator and to comply with the requirements of the entire study
• Provision of written informed consent to participate as shown by a signature on the volunteer consent form
• Nonsmokers for at least 180 days (6 months) prior to Screening
• Must be willing to abstain from alcohol and strenuous exercise during the 48 hours prior to Screening, 72 hours prior to initial dosing, and during the study
• Forced expiratory volume in 1 second (FEV1) ≥ 50% predicted normal for age, gender, and height at Screening as per Knudson et al
• Stable regimen of oral CF medications, dornase alfa, and physiotherapies for the period 28 days prior to Screening; those subjects taking continuous (non-cycling) inhaled antibiotics for prophylaxis must be on a stable regimen of these drugs for at least 90 days prior to Screening
• Subjects must be in the off-phase of any cyclical inhaled antibiotic treatment regimen
• Must test negative for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) at Screening
• Male subjects who are sexually active must be willing to use effective barrier contraception (e.g., condom) during heterosexual intercourse from Day -1 through completion of the study and continuing for at least 90 days from date of last dose of study drug
• Male subjects must refrain from sperm donation from Day -1 through completion of the study and continuing for at least 90 days from the date of last dose of study drug
• Nonlactating females. Females on hormone replacement therapy (estrogen/progesterone) or contraceptive therapy must be stabilized on a product and dose for at least 90 days prior to Screening
• Females must have a negative serum gonadotropin pregnancy test at Screening and Day -1
• Nonpregnant females of childbearing potential must agree to use highly effective (<1% failure rate) contraception during heterosexual intercourse from Screening, throughout the study, and for at least 30 days following the last dose of study drug
• Glomerular filtration rate (GFR) of < 60 mL/min/1.73m2 at Screening (GFR to be calculated using the Cockcroft-Gault equation), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3× upper limits of normal (ULN)
• Chest radiograph at Screening without significant acute findings (e.g., infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax); or chest radiograph, CT, or MRI obtained within the 90 days prior to Screening without acute findings or significant intercurrent illness; chronic, stable findings (e.g., chronic scarring or atelectasis) are allowed. A chest radiograph obtained and interpreted between Screening and Day 1 is also acceptable for determining eligibility.

Exclusion Criteria:

• Administration of any investigational drug or device in the 28 days prior to Screening
• A need for any new medication during the period 28 days before first dosing with study drug, except those deemed by the principal investigator/clinical investigator not to interfere with the outcome of the study
• Subjects who routinely use inhaled hypertonic saline must discontinue use for at least 14 days prior to clinic admission and for the duration of the study
• Use of trimethoprim or high dose ibuprofen (> 800 mg/day) during the 28 days prior to first dosing
• Serious adverse reaction or hypersensitivity to any drug
• Existence of any surgical or medical condition which, in the judgment of the clinical investigator, might interfere with the absorption, distribution, metabolism, or excretion of the drug
• Lactating females
• History of airway intolerance to hypertonic saline
• History of lung transplantation
• History of a positive test for Burkholderia cepacia
• History of cirrhosis or ascites
• History of clinically significant adrenal disease
• History of congestive heart failure diagnosed clinically or with documented left ventricular ejection fraction (LVEF) ≤ 40%
• History of glaucoma
• Consumption of drugs and/or herbal preparations capable of inducing hepatic enzyme metabolism (e.g., barbiturates, rifampicin, carbamazepine, phenytoin, primidone, or St. John's Wort) within 28 days (or 5 half-lives of inducing agent, whichever is longer) of Screening
• Subjects requiring any of the following drugs in the 28 days prior to Screening: diuretics (e.g., spironolactone, amiloride, thiazide), ACE inhibitors, angiotensin receptor blockers, oral corticosteroids, or medicines for hypertension
• Donation or loss of greater than 400 mL of blood in the period 90 days (3 months) prior to Screening
• Major surgery within 180 days (6 months) of Screening
• Hemoglobin levels < 120 g/L in females or < 130 g/L in males taken at Screening and at Day -1
• Serum potassium > 5 mEq/L taken at Screening and at Day -1
• Poor venous access