Evaluation and Treatment of Pulmonary Vascular Disease in Moderate to Severe CF

Over time, patients with Cystic Fibrosis (CF) develop disabling lung disease that progresses
to chronic respiratory failure, exercise intolerance with marked limitation of physical
activity, and premature death. Despite substantial improvements in care, patients with CF
often develop pulmonary vascular disease (PVD) that leads to pulmonary hypertension. Previous
studies have clearly linked severe pulmonary hypertension and right heart failure with high
mortality in CF. Early clinical manifestations of PVD prior to the development of cor
pulmonale include shortness of breath and dyspnea with exertion, but the extent to which PVD
contributes to the decline in exercise tolerance and quality of life in patients with CF is
not known. Early evidence of PVD could be recognized in CF patients through standardized
exercise testing and echocardiographic evaluation. Identifying those CF patients with PVD
prior to the onset of right ventricular dysfunction may allow pharmacologic intervention to
attenuate the progression of cardiovascular disease and improve quality of life. Clinical
trials have demonstrated that treatment with the phosphodiesterase type 5 inhibitor,
sildenafil, can decrease pulmonary vascular resistance and improve exercise tolerance in
non-CF patients with pulmonary hypertension. Because experimental and clinical studies have
implicated impaired NO-cGMP signaling in the pathophysiology of lung disease in CF,
sildenafil may provide a novel pharmacological approach for treating PVD in patients with CF
lung disease.

Inclusion Criteria:

1. Confirmed diagnosis of CF based on the following criteria: Positive sweat chloride
≥60mEq/liter (by pilocarpine iontophoresis) and/or Genotype with two identifiable
mutations consistent with CF, and accompanied by one or more clinical features
consistent with the CF phenotype

2. Male or female patients ≥ 18 years of age

3. FEV1 ≥ 20% predicted and ≤ 70% 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. Willingness to maintain chronic CF medication schedule (e.g. alternating month inhaled
antibiotics)

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 for women of
child-bearing potential.

4. History of significant hepatic disease (AST or ALT > 5 times the upper limit of normal
at screening, documented biliary cirrhosis, or portal hypertension),

5. History of significant cardiovascular disease (history of aortic stenosis, coronary
artery disease, or life-threatening arrhythmia),

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

7. History of severe hematologic disease (e.g. history of bleeding diathesis; current INR
> 2.0

8. History of severe ophthalmologic disease (e.g. history of retinal impairment or
non-arteritic ischemic optic neuritis)

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

10. Inability to swallow pills

11. Previous organ transplantation

12. Use of concomitant nitrates, α-blocker, or Ca channel blocker (currently or within one
month of Visit 1)

13. 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

14. History of sputum or throat swab culture yielding Burkholderia cepacia or
Mycobacterium massiliense within 2 years of screening

15. Weight less than 40 kg at Screening

16. History of migraine headaches.

17. Resting room air oxygen saturation <80% without supplemental oxygen

18. 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

19. Start of CFTR modulator therapy less than 1 month prior to first dose of sildenafil or
placebo

20. Use of anticoagulants

21. Frank pulmonary hypertension (RVSP >40 mmHg by ECHO)