Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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.
Brief Summary: The purpose of this study is to determine whether the safety, tolerability and pharmacodynamics of SB656933 in patients that have cystic fibrosis


Options:
A: Inclusion Criteria:

* Written informed consent
* Confirmed diagnosis of CF based on the following criteria:

Positive sweat chloride greater than 60mEq/liter, and/or a genotype with 2 identifiable mutations consistent with CF, and one or more clinical features consistent with the CF phenotype

* Age \>/= 18 years of age with the potential for age 12 \>/=
* Screening Pa sputum culture
* FEV1% predicted \>/= 40 (based on Wang's equations for Males aged 12-17 and females 12-15 years, and Hankinson's equations for all other patients)

Exclusion Criteria:

* Evidence of an acute respiratory infection or pulmonary exacerbation within 4 weeks prior to day 0
* Use of systemic corticosteroids or antibiotics within 4 weeks prior to day 0, or cyclic inhaled antibiotics within 14 days prior to day 0.
* History of positive B. cepacia complex, organ transplantation, hepatic disease or venal dysfunction
* Current cigarette smoker, history of drug addiction or alcohol abuse
* Use of investigational medication or participation in an investigational study within 4 weeks prior to day 0
* Women who are pregnant or breastfeeding and patients and/or partner unwilling to use an effective form of barrier contraception throughout the study
B: Inclusion Criteria:

* Male or female ≥10 years of age
* Documentation of a Cystic Fibrosis (CF) diagnosis as evidenced by 1 or more clinical features consistent with the CF phenotype and 1 or more of the following criteria:

  * Sweat chloride equal to or greater than 60 milliequivalent (mEq/L) by quantitative pilocarpine iontophoresis test (QPIT)
  * 2 well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
* Pancreatic insufficiency documented by having a spot fecal elastase-1 (FE-1) ≤ 100μg/g in a stool sample done either historically or at the screening visit
* Clinically stable with no significant changes in health status within 2 weeks prior to randomization
* Forced expiratory volume over one second (FEV1) ≥ 40 and ≤ 100% of predicted for age based on the Wang (males \< 18 years,females \< 16 years) or Hankinson (males ≥ 18 years, females ≥ 16 years) standardized equations at the screening visit
* Weight ≥ 30 kg at the screening visit
* Able to perform repeatable, consistent efforts in pulmonary function testing
* Able to tolerate sputum induction with 3% hypertonic saline and to expectorate with induction
* Written informed consent (and assent when applicable) obtained from subject or subject's legal representative
* Ability to swallow softgel capsules

Exclusion Criteria:

* Subjects being treated with ivacaftor (Kalydeco™)
* Liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyl transferase (GGT) \> 3 times the upper limits of normal at the screening visit
* Use of antibiotics (oral, iv, and/or inhaled) for acute respiratory symptoms within 2 weeks prior to randomization
* Active treatment for allergic bronchopulmonary aspergillosis (ABPA)
* Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone/day or 20 mg prednisone every other day
* Active treatment for nontuberculous mycobacterial (NTM) infection
* Initiation of any new chronic therapy (e.g., ibuprofen, Pulmozyme®, hypertonic saline,azithromycin,Tobramycin Inhalation solution (TOBI®), Cayston® within 8 weeks prior to randomization
* Unwilling to discontinue current oral vitamin and antioxidant supplementation (e.g.,AquADEKs®, another source of β-carotene, vitamin A, vitamin E or tocopherols,vitamins D or K, n-acetylcysteine, glutathione, CoQ10, other over-the-counter antioxidant) for the duration of the study
* Use of vitamins (other than control vitamin) or antioxidants within 4 weeks prior to randomization
* Daily use of \> 2 cans of Boost or Pulmocare dietary supplement formulas
* Known hypersensitivity to oral AquADEKs®
* For women of child bearing potential:

  1. positive pregnancy test at Visit 1 or at Visit 2, or
  2. lactating or
  3. unwilling to practice a medically acceptable form of contraception (acceptable forms of contraception: abstinence, hormonal birth control, intrauterine device, or barrier method plus a spermicidal agent)
* Subject unlikely to complete the study as determined by the Investigator
* Any condition that the Investigator believes would interfere with the intent of this study or would make participation not in the best interest of the subject
* Use of investigational therapies within 4 weeks prior to randomization
* Current tobacco smoker
* Current use of anticoagulant medications
* Severe malnutrition based either on having a BMI less than the 5th percentile for subjects \< 18 years of age or a body mass index (BMI) less than 18 kg/m2 for subjects \> 18 years of age.
* Subjects with poorly controlled CF-related diabetes on active insulin therapy, defined as having a Glycosylated Hemoglobin (HgbA1c) ≥ 7.5% at the most recent historic evaluation of HgbA1c
C: Inclusion Criteria:

* CF as diagnosed by:

  1. Documented sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test; or
  2. Two well-characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or
  3. Abnormal nasal potential difference with accompanying symptoms characteristic of CF.
* PA present in expectorated sputum or throat swab culture at Screening.
* Participants must have received three or more courses of TIS within the previous 12 months.
* Participants on chronic azithromycin must have had no change in regimen in the previous 3 months and must have had a need for TIS and/or additional antipseudomonal therapy since initiation of azithromycin.
* Forced expiratory volume in 1 second (FEV1) between (and including) 25% and 75% predicted at Screening.
* Ability to perform reproducible pulmonary function tests.
* Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening.

Exclusion Criteria:

* Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day.
* History of sputum or throat culture swab yielding Burkholderia cepacia in the past 2 years.
* History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night.
* Administration of any investigational drug or device within 28 days of Screening (Visit 1) or within 6 half-lives of the investigational drug (whichever was longer).
* Known local or systemic hypersensitivity to monobactam antibiotics.
* Inability to tolerate inhalation of a short acting Beta-2 agonist.
* Changes in antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days before Screening or between Screening and the next visit.
* Changes in physiotherapy technique or schedule within 7 days before Screening or between Screening and the next visit.
* History of lung transplantation.
* A chest X-ray indicating abnormal findings at Screening or within the previous 90 days.
* Abnormal renal or hepatic function or serum chemistry at Screening (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\] greater than 5 times the upper limit of normal range; Creatinine greater than 2 times the upper limit of normal range).
* Positive pregnancy test at Screening.
* Female of childbearing potential who was lactating or in the opinion of the investigator was not practicing acceptable birth control.
* Any serious or active medical or psychiatric illness, which in the opinion of the investigator would have interfered with participant treatment, assessment, or compliance with the protocol.
D: 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.

Answer: D