28 Day Repeat Dose in Cystic Fibrosis Patients

A Randomized, Double Blind, Parallel Group, Placebo Controlled 28 Day Study to Investigate the Safety, Tolerability and Pharmacodynamics of SB-656933 in Patients With Cystic Fibrosis.

The purpose of this study is to determine whether the safety, tolerability and pharmacodynamics of SB656933 in patients that have cystic fibrosis

This proof of mechanism study aims to evaluate the safety, tolerability and pharmacodynamics of SB-656933 following 28 days of daily administration of 20 and 50 mg SB-656933 in patients with CF compared to placebo. The primary endpoints of the study will be the effect of SB-656933 on safety and tolerability (adverse events, vital signs, clinical laboratory assessments, 12-lead electrocardiograms, and urinalysis) following 28 days of dosing. Secondary endpoints will include levels of neutrophil elastase in induced sputum and other sputum markers of inflammation (e.g. myeloperoxidase, total protein), induced sputum cells (i.e. total sputum neutrophil counts, percent sputum neutrophils) and sputum microbiology. Other assessments will include lung function measurements (spirometry); serum and plasma markers of inflammation (e.g. fibrinogen, CC-16, CRP, MMP8, MMP9, SP-D, and CXCL-8), quality of life questionnaire, and population pharmacokinetics parameters of SB-656933

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 pg/ml (<140 pmol/L) is confirmatory].
• Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until one week after the last dose.
• Patients are non-smokers or former smokers by history. Former smokers will be defined as those who have not smoked for ≥6 months. Subjects who only use chewing tobacco products may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor.
• In the judgement of the investigator the patient is clinically stable with no change in symptoms or medication, no admissions to hospital, and no intravenous antibiotic therapy for at least 1 month prior to dosing.
• Able to perform lung function tests reliably.
• FEV1 >40% and <110% predicted.
• Excluding periods of exacerbation, FEV1 has not decreased by >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 < 450 msec at screening as determined by the investigators review.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within twice (2x) the upper limit of normal at screening and bilirubin within 1.25x ULN at screening. AST, ALT, alkaline phosphatase and bilirubin >2.0 xULN (isolated bilirubin >2.0xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Male subjects must agree to use one of the contraception methods listed in Section 8.1.2. This criterion must be followed from the time of the first dose of study medication until one week after the last dose.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

Exclusion Criteria:

• Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or ECG, that is not associated with cystic fibrosis.
• Neutrophil count <1.5x109 /L
• In the judgment of the PI, the patient:
• suffers from clinically unstable pancreatic function
• has clinically significant weight loss( ≥5% after a previously stable period).
• has recent change in pancreatic enzyme requirements in the past 2 months.
• Recent viral infection (within 4 weeks of dosing), with or without steroid or antibiotic treatment. Presumed viral infection will be determined according to the judgment of the Investigator and no specific testing for virus will be required.
• Subjects unable to produce a technically acceptable sputum sample.
• Clinically significant hepatic impairment
• Evidence of cirrhosis
• Patients with elevated INR that is due to suspected vitamin K deficiency may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor
• Blood pressure persistently >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.