Sildenafil Exercise: Role of PDE5 Inhibition

Inclusion Criteria:

• Confirmed diagnosis of cystic fibrosis (CF) based on the following criteria:Positive sweat chloride concentration ≥60 milliequivalents (mEq)/liter (bypilocarpine iontophoresis) and/or genotype with two identifiable disease-causingmutations consistent with CF, and accompanied by one or more clinical featuresconsistent with the CF phenotype

• Male or female patients ≥ 9 years of age

• forced expiratory volume at one second (FEV1) ≥ 30% predicted and ≤ 70% for patients ≥ 18 years of age and ≤ 80% for patients ≥ 18 years of age

• Clinically stable without evidence of acute upper or lower respiratory tractinfection or current pulmonary exacerbation within the 14 days prior to thescreening visit

• Resting oxygen saturation (room air) >85%

• Patients with or without CF related diabetes

• Ability to perform spirometry reproducibly (according to American Thoracic Societycriteria)

• Willingness to maintain chronic CF medication schedule (e.g. alternating monthinhaled antibiotics)

Exclusion Criteria:

• Children 8 yrs. old and younger

• Subjects who weigh < 20 Kgs

• History of hypersensitivity to sildenafil

• Use of an investigational agent within the 4-week period prior to Visit 1 (Day 0)

• Breastfeeding, pregnant, or verbal expression of unwillingness to practice anacceptable birth control method (abstinence, hormonal or barrier methods, partnersterilization or intrauterine device) during participation in the study for women ofchild-bearing potential.

• History of significant hepatic disease (aspartate transaminase or alaninetransaminase > 3 times the upper limit of normal at screening, documented biliarycirrhosis, or portal hypertension),

• History of significant cardiovascular disease (history of aortic stenosis, coronaryartery disease, or life-threatening arrhythmia),

• History of severe neurological disease (e.g. history of stroke),

• History of severe hematologic disease (e.g. history of bleeding diathesis; currentinternational normalized ratio (INR) > 2.0

• History of severe ophthalmologic disease (e.g. history of retinal impairment ornon-arteritic ischemic optic neuritis)

• History of severe renal impairment (creatinine >1.8 mg/dL.)

• Inability to swallow pills

• Previous organ transplantation

• Use of concomitant nitrates, α-blocker, or Ca channel blocker (currently or withinone month of Visit 1)

• Use of concomitant medications known to be potent inhibitors of CYP3A4 [e.g.ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin (currently or within one month of initiation of study drug)] (NOTE: use ofazithromycin is NOT a cause for exclusion)

• History of sputum or throat swab culture yielding Burkholderia cepacia orMycobacteria massiliense within 2 years of screening

• History of migraine headaches.

• Presence of a condition or abnormality that in the opinion of the investigator wouldcompromise the safety of the subject or the quality of the data

• Initiation of a cystic fibrosis transmembrane conductance regulator (CFTR) modulatortherapy less than 1 month prior to first dose of sildenafil or placebo

• Use of anticoagulants

• Frank pulmonary hypertension[right ventricular systolic pressure (RVSP) >40 mm Hg byechocardiography)

• History of Priapism or known penile anatomical deformities