28 Day Repeat Dose in Cystic Fibrosis Patients

Inclusion Criteria

• Diagnosis of CF based on the following: sweat chloride > 60 mEq/L and/or genotype with 2 identifiable mutations consistent with CF; (ΔF508 homozygote, or ΔF508 heterozygote with a second allele known to cause the disease, or two alleles known to cause a class I, II, or III mutation) and one or more clinical features consistent with CF.
• Male and female subjects aged ≥18 years of age
• A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol 40% and 15% over the past 12 months
• Clinically colonized by a bacterial organism commonly seen in cystic fibrosis other than Burkholderia cepacia (i.e. Pseudomonas spp., Staphylococcus aureus, Stenotrophomonas, B. Gladioli) as evidenced by identification in sputum culture within the past year. To be eligible a CF patient must have colonization of at least one typical CF organism.
• To be eligible, female patients must have a negative pregnancy test (urine or serum) and not be nursing at screening or prior to dosing.
• Subjects must have a QTcB or QTcF 2.0 xULN (isolated bilirubin >2.0xULN is acceptable if bilirubin is fractionated and direct bilirubin 155/95 mmHg at screening.
• Positive HIV, Hepatitis B surface antigen or Hepatitis C antibody at screening.
• History of regular alcohol consumption averaging >7 drinks/week for women or >14 drinks/week for men. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits) within 6 months of screening.
• Urinary cotinine levels indicative of smoking.
• Use of oral or parenteral corticosteroids within 4 weeks of screening; regular use (>3 x/wk) of high dose NSAIDS (e.g. >1.6g ibuprofen/day on a regular basis), within 4 weeks of screening.
• Colonization with Burkholderia cepacia
• Subjects currently being treated for mycobacterial infection
• Subjects with presumed active Allergic Bronchopulmonary Aspergillosis (ABPA)
• Subjects who have newly started therapy with azithromycin within the past 3 months.
• In the judgment of the investigator, clinically significant hemoptysis (> 30 cc per episode) within the last 6 months
• Donation of blood in excess of 500 mL within a 56-day period prior to dosing
• Participation in a trial with any drug within 30 days or 5 half-lives (whichever is longer), or participation in a trial with a new chemical entity within 2 months prior to first dose of current study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.
• The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, and cannabinoids. Subjects who use benzodiazepines or other anxiolytic on a regular basis can be included at the discretion of the investigator and in consultation with the GSK medical monitor
• Patients may not be on an inhaled antibiotic during the study (i.e. must be an "off-TOBI" month; cessation of TOBI or other inhaled antibiotics commences from one week prior to dosing until final PK draw). Patients on maintenance therapy with hypertonic saline solution or inhaled DNase may continue these therapies.
• Unwillingness or inability to follow the procedures outlined in the protocol.