28 Day Repeat Dose in Cystic Fibrosis Patients
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Intervention: SB656933; SB656933; Placebo
Intervention description: 20 mg; 50mg; placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 146.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cystic fibrosis

Summary:

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

Eligibility criteria:

        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.