Sildenafil Exercise: Role of PDE5 Inhibition

Exercise intolerance is an understudied phenomenon in people with CF. The investigators hypothesized that vascular dysfunction plays a significant role, and can be partially reversed by administration of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil.

While cystic fibrosis (CF) is most common in people of European ancestry, it can occur in individuals of any ethnicity. The predicted median life expectancy age for patients with CF is 47.7 years compared to 78.8 years in the general U.S. population. Exercise intolerance, evaluated as a reduction in exercise capacity (VO2 peak), has been shown to predict mortality in patients with CF independent of lung function. A critical barrier to improving exercise tolerance in CF is the lack of knowledge regarding the different physiological mechanisms which contribute to decreased exercise capacity. The present investigation will not only evaluate the impact that sildenafil has on clinically relevant and patient oriented outcomes, it will also provide mechanistic insight.

Phosphodiesterase type 5 (PDE5) inhibitors reduce inflammation, improve vascular health, increase microvascular O2 delivery and improve skeletal muscle function. Accordingly, the central hypothesis of the study is that treatment with the PDE5 inhibitor, sildenafil, can improve exercise capacity, vascular and cardiac function, and overall quality of life, all of which may contribute to improvement in exercise tolerance in people with CF

Eligibility Criteria:
Inclusion Criteria:

* Confirmed diagnosis of cystic fibrosis (CF) based on the following criteria: Positive sweat chloride concentration ≥60 milliequivalents (mEq)/liter (by pilocarpine iontophoresis) and/or genotype with two identifiable disease-causing mutations consistent with CF, and accompanied by one or more clinical features consistent 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 tract infection or current pulmonary exacerbation within the 14 days prior to the screening visit
* Resting oxygen saturation (room air) \>85%
* Patients with or without CF related diabetes
* Ability to perform spirometry reproducibly (according to American Thoracic Society criteria)
* Willingness to maintain chronic CF medication schedule (e.g. alternating month inhaled 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 an acceptable birth control method (abstinence, hormonal or barrier methods, partner sterilization or intrauterine device) during participation in the study for women of child-bearing potential.
* History of significant hepatic disease (aspartate transaminase or alanine transaminase \> 3 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension),
* History of significant cardiovascular disease (history of aortic stenosis, coronary artery 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; current international normalized ratio (INR) \> 2.0
* History of severe ophthalmologic disease (e.g. history of retinal impairment or non-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 within one 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 of azithromycin is NOT a cause for exclusion)
* History of sputum or throat swab culture yielding Burkholderia cepacia or Mycobacteria massiliense within 2 years of screening
* History of migraine headaches.
* 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
* Initiation of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy 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 by echocardiography)
* History of Priapism or known penile anatomical deformities