a phase 1 trial to assess the safety, tolerability, and pharmacokinetics of gs 9411 in subjects with cystic fibrosis (cf)

Conditions: Cystic Fibrosis; Mucociliary Clearance

Summary: 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.

Eligibility criteria:
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

Keywords: cystic fibrosis cf mucociliary clearance epithelial sodium channel inhibitor enac inhibitor airway hydration amiloride