Now Recruiting: A New Gilead Medicine

A Randomized, Double-Blind, Placebo-Controlled Multiple Dose Trial of GS-9411 in Healthy Volunteers

This study is currently recruiting participants.

Verified by Gilead Sciences, October 2009

First Received: October 20, 2009 Last Updated: October 21, 2009 History of Changes

Sponsor:	Gilead Sciences
Information provided by:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00999531

Purpose

The purpose of this study is to evaluate the safety and tolerability of repeated doses of GS-9411 in healthy volunteers. GS-9411 is a sodium channel inhibitor, that may restore airway hydration and mucociliary clearance in the lung.

Condition	Intervention	Phase
Cystic Fibrosis Mucociliary Clearance Airway Hydration	Drug: GS-9411 Drug: Placebo	Phase I

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety Study
Official Title:	A Phase 1, Randomized, Double-Blind, Placebo-Controlled Multiple Dose Trial to Assess the Safety, Tolerability, and Pharmacokinetics of GS-9411 in Healthy Volunteers

Resource links provided by NLM:

Genetics Home Reference related topics: cystic fibrosis

MedlinePlus related topics: Cystic Fibrosis

U.S. FDA Resources

Further study details as provided by Gilead Sciences:

Primary Outcome Measures:

• Safety and tolerability of multiple doses of inhaled GS-9411 in healthy volunteers [ Time Frame: 21 Days ] [ Designated as safety issue: No ]
  

Secondary Outcome Measures:

• Assess the pharmacokinetics of GS-9411 and its metabolites [ Time Frame: 21 Days ] [ Designated as safety issue: No ]
  

Estimated Enrollment:	24
Study Start Date:	October 2009
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental GS-9411 9.6 mg	Drug: GS-9411 Inhaled GS-9411 dissolved in sterile saline
2: Experimental GS-9411 4.8 mg	Drug: GS-9411 Inhaled GS-9411 dissolved in sterile saline
3: Placebo Comparator Placebo, sterile saline	Drug: Placebo Inhaled Placebo, sterile saline

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, administered twice daily for 14 days.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Males and females, 18 to 65 years of age
• No clinically important abnormal physical findings at Screening
• No clinically relevant abnormalities in the results of laboratory evaluation at Screening
• Must test negative for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) at Screening
• Normal electrocardiogram (ECG) at Screening
• Normal blood pressure (BP) and heart rate (HR) in the absence of any medications for
• Body weight between 50 and 100 kg and within ± 15% of ideal body weight or body mass index (BMI) between 18 and 28 kg/m2 at Screening
• 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 of at least 180 days (6 months) duration (<>
• Negative for drugs of abuse (including alcohol) at Screening and Day -5
• Must be willing to abstain from alcohol and strenuous exercise during the 48 hours prior to Day -5 and during the study
• Forced expiratory volume in 1 second (FEV1) ≥ 80% of predicted normal for age, gender, and height at Screening and predose
• Normal intraocular pressure (IOP) between 10 and 21 mm Hg at Screening
• Male subjects who are sexually active must be willing to use effective barrier contraception (e.g., condoms) during heterosexual intercourse from Day -5 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 -5 through completion of the study and continuing for at least 90 days from the date of last dose of study drug
• Non-lactating 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%>

Exclusion Criteria:

• Any prior exposure to GS-9411
• Administration of any investigational drug in the period 84 days (12 weeks) prior to Screening; 112 days (16 weeks) if the previous investigational drug was a new chemical entity
• A need for any medication during the period 0 to 5 days prior to Screening, except those deemed by the principal investigator/clinical investigator not to interfere with the outcome of the study
• 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
• Presence or history of allergy requiring treatment. Hay fever is allowed unless it is active or has required treatment within 56 days (8 weeks) of Screening
• Donation or loss of greater than 400 mL of blood in the period 84 days (12 weeks) prior to Screening
• Serious adverse reaction or hypersensitivity to any drug
• Presence or history of any pulmonary diseases (e.g., asthma, emphysema, chronic bronchitis, CF, bronchiectasis)
• 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) or enzyme-inhibiting agents (e.g., cimetidine) or similar drugs within 28 days (or 5 half-lives of inducing/inhibiting agent, whichever is longer) of Screening
• Major surgery within 180 days (6 months) of the start of this study
• Subjects who have experienced a significant upper or lower respiratory tract infection within the 42 days (6 weeks) prior to Screening
• Subjects with significant history of respiratory, renal, hepatic, cardiovascular (including history of systemic hypertension requiring therapy), metabolic, neurological, hematological, gastrointestinal, cerebrovascular, or other significant medical illness or disorder which, in the judgment of the investigator, may interfere with the study or require treatment which may affect the evaluation of the safety of the study drug
• Subjects with elevated liver enzyme concentrations at Screening and at Day -1
• Hemoglobin level <>
• Serum potassium > 5 mEq/L taken at Screening and at Day -1
• Poor venous access

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00999531

Contacts

Contact: Bianca Scott

613-9076-9825

b.scott@nucleusnetwork.com.au

Locations

Australia, Victoria
Nucleus Network, Ltd.	Recruiting
Melbourne, Victoria, Australia
Principal Investigator: Peter Hodsman, MD

Sponsors and Collaborators

Gilead Sciences

Investigators

Principal Investigator:

Peter Hodsman, MD

Nucleus Network Ltd

More Information
No publications provided

Responsible Party:	Gilead Sciences, Inc. ( Thomas O'Riordan, MD )
Study ID Numbers:	GS-US-221-0107
Study First Received:	October 20, 2009
Last Updated:	October 21, 2009
ClinicalTrials.gov Identifier:	NCT00999531 History of Changes
Health Authority:	Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Gilead Sciences:

Cystic Fibrosis CF Mucociliary Clearance Epithelial Sodium Channel Inhibitor

ENaC Inhibitor Airway Hydration Amiloride

Additional relevant MeSH terms:

Pathologic Processes Digestive System Diseases Genetic Diseases, Inborn Respiratory Tract Diseases Lung Diseases

Infant, Newborn, Diseases Pancreatic Diseases Cystic Fibrosis Fibrosis

ClinicalTrials.gov processed this record on October 27, 2009

http://www.clinicaltrials.gov/ct2/show/NCT00999531?term=cystic+fibrosis&recr=Open&rcv_d=14

New Spray Could Benefit Cystic Fibrosis Patients

MONDAY, May 18 -- A new aerosol spray may help keep the airways of cystic fibrosis patients moist and clear, researchers say.

Using a special agent called GS-9411, the spray prevents sodium from being absorbed too quickly, which is a common problem for people with cystic fibrosis. The quick absorption of sodium from the surface of the airway causes their airways to dry, and allows mucous and bacteria to accumulate..

In tests on airway surface cells grown in a laboratory, GS-9411 helped the cells retain moisture for more than eight hours while tests on animals found the spray helped clear excessive mucus for at least four hours.

The findings were presented Sunday at the American Thoracic Society's annual international conference in San Diego.

"GS-9411 administered by aerosol can effectively increase airway surface liquid and enhance mucous clearance in an animal model," study author Andrew Hirsh, senior director of drug discovery and preclinical development for Parion Sciences, a pharmaceutical company, said in a news release. "The results demonstrate that GS-9411 warrants further investigation as a new drug therapy to decrease respiratory infection and improve pulmonary function."

In cystic fibrosis, a genetic defect causes the airway to absorb sodium, and therefore moisture, too quickly. When the airway is too dry, the body can't clear mucus, a key defense mechanism of the respiratory system, Hirsh said. This deficiency can cause cystic fibrosis patients to have chronic respiratory infection and impaired lung function, he explained.

"The potency and the length of time that the drug was effective in cells and in animal studies was an outstanding feature that distinguishes this compound from other agents," he said.

Sodium channel blocker shows promise as a potential treatment for cystic fibrosis

ATS 2009, SAN DIEGO—Cystic fibrosis patients may benefit from a new therapy that increases airway hydration, preventing the buildup of mucous, which is a key factor in the disease, according to researchers at Parion Sciences in Durham, N.C.

The research will be presented on Sunday, May 17, during the American Thoracic Society's 105th International Conference in San Diego.

"Our results suggest that we have identified a new agent that acts directly on a specific pathway, which is involved in the development of cystic fibrosis," said lead author Andrew Hirsh, Ph.D., senior director of drug discovery and preclinical development for Parion Sciences.

In normal respiration, the moist surface of the airway allows individuals to effectively clear mucous, keeping airways open and viable. But in individuals with cystic fibrosis, the hydration level of the airway is altered and the airway mucous builds up, interfering with normal respiration. One of the mechanisms causing airways to not clear mucous correctly in these patients involves the body's natural homeostasis of sodium which, when absorbed too quickly from the surface of the airway, causes moisture to become absorbed too quickly.

"Cystic fibrosis patients have a genetic ion transport defect, which decreases the hydration level on the airway surface and therefore reduces the body's ability to effectively clear mucous, which is a primary defense mechanism of the respiratory system," Dr. Hirsh said. "Diminished mucous clearance leads to chronic respiratory infection and impaired pulmonary function. Currently there are no therapies available to specifically target this channel in patients with cystic fibrosis."

The aerosol-based therapy uses a specific epithelial sodium channel-blocking agent called GS-9411, which prevents sodium from being absorbed across the airway, allowing the surface to remain moist. The increase in moisture allows individuals to more effectively clear the airway of mucous and infectious agents.

This study was performed during the pre-clinical stage of development to compare GS-9411 to an established epithelial sodium channel blocker, called amiloride. Currently, GS-9411 is in Phase I clinical trials being conducted by Parion's development partner, Gilead Sciences, Inc., in Foster City, CA.

During the study, researchers applied GS-9411 to airway surface cells grown in the laboratory, and assessed the potency and reversibility of the drug on these cells. Results of the study indicated GS-9411 allowed the cells to retain liquid for more than eight hours. Concurrent animal studies revealed that the agent enhanced mucous clearance for more than four hours.

The results offer new hope for cystic fibrosis sufferers, according to Dr. Hirsh. "The potency and the length of time that the drug was effective in cells and in animal studies was an outstanding feature that distinguishes this compound from other agents," he said.

The clinical phase of the drug development cycle will enable researchers to continue to refine the treatment for eventual distribution to cystic fibrosis patients.

"GS-9411 administered by aerosol can effectively increase airway surface liquid and enhance mucous clearance in an animal model," he said. "The results demonstrate that GS-9411 warrants further investigation as a new drug therapy to decrease respiratory infection and improve pulmonary function."