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

• Status: Withdrawn
• Trial end date: 2010-04-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Gilead Sciences

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