Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Inclusion criteria

• Confirmed diagnosis of CF based on the following criteria: Positive sweat chloride ≥60mEq/liter (by pilocarpine iontophoresis) and genotype with two F508del CFTR mutations, and accompanied by one or more clinical features consistent with the CF phenotype
• Male or female subjects ≥ 18 years of age
• FEV1 ≥ 50% predicted (Hankinson)
• Clinically stable without evidence of acute upper or lower respiratory tract infection or current pulmonary exacerbation within the 14 days prior to the screening visit
• Ability to reproducibly perform spirometry (according to ATS criteria)
• Ability to understand and sign a written informed consent or assent and comply with the requirements of the study
• Willing and able to perform nasal potential difference testing
• No changes in use of nasal medications within 2 weeks of screening visit
• If on Orkambi, has been on stable Orkambi dose for at least 4 weeks at day 1.

Exclusion criteria

• 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 an acceptable birth control method (abstinence, hormonal or barrier methods, partner sterilization or intrauterine device) during participation in the study
• History of significant hepatic (SGOT or SGPT > 3 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension), cardiovascular (history of aortic stenosis, coronary artery disease, pulmonary hypertension with right ventricular systolic pressure >55 mmHg or life-threatening arrhythmia), neurological (history of stroke), hematologic (history of bleeding diathesis), ophthalmologic (history of retinal impairment or non-arteritic ischemic optic neuritis) or renal impairment (creatinine >1.8 mg/dL.)
• Inability to swallow pills
• Previous lung transplantation
• Use of concomitant nitrates, α-blocker, or Ca channel blocker
• Use of concomitant medications known to be potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin, verapamil)
• Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the subject or the quality of the data
• Weight less than 40 kg
• History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years of screening
• History of nasal disease or nasal surgery that would, in the opinion of the investigator, impede accurate measurements of NPD
• Use of anticoagulant medication (e.g. heparin, coumadin)
• Resting room air oxygen saturation <93%
• Use of nighttime oxygen

• History of migraine headaches 16) Baseline BP of < 90/50 mm Hg