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

• ClinicalTrials.gov Identifier: NCT01025713
• Recruitment Status: Withdrawn
• First Posted: December 3, 2009
• Last Update Posted: July 9, 2015
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis; Mucociliary Clearance	Drug: GS-9411; Drug: Placebo	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: December 2009
• Actual Primary Completion Date: March 2010
• Estimated Study Completion Date: April 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; GS-9411 2.4 mg	Drug: GS-9411; Inhaled GS-9411
Experimental: 2; GS-9411 4.8 mg	Drug: GS-9411; Inhaled GS-9411
Placebo Comparator: Placebo; Placebo	Drug: Placebo; Inhaled Placebo

Outcome Measures

Primary Outcome Measures :

1. To evaluate the safety and tolerability of escalating doses of inhaled GS-9411 in subjects with CF. [ Time Frame: 5 Days ]

Secondary Outcome Measures :

1. To assess the pharmacokinetics (PK) of GS-9411 and its metabolites, in plasma, urine, and sputum after single inhaled doses. [ Time Frame: 5 Days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Australia, Victoria

Nucleus Network, Ltd.

Melbourne, Victoria, Australia

Sponsors and Collaborators

Gilead Sciences

Investigators

• Principal Investigator: John Wilson, MD; The Alfred

More Information

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01025713
• Other Study ID Numbers: GS-US-221-0106
• First Posted: December 3, 2009
• Last Update Posted: July 9, 2015
• Last Verified: July 2015

Keywords provided by Gilead Sciences:

Cystic Fibrosis; CF; Mucociliary Clearance; Epithelial Sodium Channel Inhibitor; ENaC Inhibitor; Airway Hydration; Amiloride

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases