Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Inclusion Criteria:

1. 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

2. Male or female subjects ≥ 18 years of age

3. FEV1 ≥ 50% predicted (Hankinson)

4. 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

5. Ability to reproducibly perform spirometry (according to ATS criteria)

6. Ability to understand and sign a written informed consent or assent and comply with the requirements of the study

7. Willing and able to perform nasal potential difference testing

8. No changes in use of nasal medications within 2 weeks of screening visit

9. If on Orkambi, has been on stable Orkambi dose for at least 4 weeks at day 1.

Exclusion Criteria:

1. History of hypersensitivity to sildenafil

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

3. 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

4. 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.)

5. Inability to swallow pills

6. Previous lung transplantation

7. Use of concomitant nitrates, α-blocker, or Ca channel blocker

8. Use of concomitant medications known to be potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin, verapamil)

9. 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

10. Weight less than 40 kg

11. History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years of screening

12. History of nasal disease or nasal surgery that would, in the opinion of the investigator, impede accurate measurements of NPD

13. Use of anticoagulant medication (e.g. heparin, coumadin)

14. Resting room air oxygen saturation <93%

15. Use of nighttime oxygen

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