Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

It is currently suspected that the fibrosis in IPF is based upon an abnormal reparative
process in the lung. Normally, an insult to the endothelium or epithelium of the lung would
trigger an inflammatory process to help repair the site of injury; epithelial and endothelial
cells then replicate and repair the tissue damage. In pulmonary fibrosis, alterations in this
cascade change the balance of the inflammatory products and reduce the regulatory response
which can produce continued inflammation. Fibrosis results from continued deposition of
collagen by proliferating fibroblasts and lack of collagen breakdown.

In addition to fibrosis and microvascular destruction, pulmonary hypertension in IPF patients
is a significant contributor to morbidity and mortality. The prevalence ranges from 32-85%,
suggesting that pulmonary vascular disease is one of several processes that contribute to
severity of disease.

We propose use of two therapeutic agents that affect the balance of vasoconstriction and
vasodilation to improve basal tone of the vasculature. First, we propose the use of a
phosphodiesterase inhibitor. Sildenafil (Viagra, Revatio) is an orally administered
vasodilator that prolongs the effect of nitric oxide by inhibiting phosphodiesterase type 5
(PDE-5) which is responsible for degradation of cGMP. Increased cGMP concentration results in
pulmonary vasculature relaxation and consequent vasodilation. Second, the use of an
angiotensin receptor blocker (ARB) acts to diminish the direct vasoconstrictor effect of
angiotensin and endothelin-1 in the vessels. In treatment of systemic hypertension, ARBs have
been shown to be associated with a decrease in the amount of circulating endothelin-1 and
increase in basal nitric oxide release. They have also been shown to rapidly inhibit the
generation of reactive oxygen species by inflammatory cells. We test these interventions in a
randomized cross-over trial in IPF patients.

Inclusion Criteria:

- Age 18-99

- Have not taken any of the study medications in the past 6 weeks

- Diagnosed with idiopathic pulmonary fibrosis

Exclusion Criteria:

- FVC<50%, DLco <30% or FEV1/FVC ratio <65%

- Greater amount of emphysema than fibrotic change on chest CT scan

- Acute myocardial infarction within the past 6 months

- Nitrate use

- Contraindications, hypersensitivity, or allergic reaction to any study medication

- Presence of aortic stenosis

- Life-threatening arrhythmia within 1 month of evaluation

- Diabetes requiring insulin therapy

- Second-degree or third-degree atrioventricular block on electrocardiogram

- Echocardiographic evidence of severe pulmonary hypertension (>50mmHg) • Severe
terminal illness (survival predicted to be less than 1 year)

- Severe congestive heart failure

- Renal impairment (creatinine >2.0 mg/dl)

- Moderate to severe hepatic impairment

- Concurrent treatment with immunosuppressive, cytotoxic, or investigational agents.

- Pregnant or Breastfeeding (Women of childbearing age must use effective form of birth
control or abstinence during study participation)

- History of acute exacerbation of IPF

- Current enrollment in another investigational protocol

- Acute or chronic impairment other than dyspnea that limits the patient's ability to
perform the six minute walk test

- Current drug or alcohol dependence

- Initiation of pulmonary rehabilitation within 30 days of enrollment. Subjects
currently undergoing maintenance pulmonary rehabilitation at study entry will be asked
to maintain their levels of rehabilitation for the duration of the trial

- Treatment of pulmonary hypertension with prostaglandins, endothelin-1 antagonists, or
any other phosphodiesterase inhibitor within 30 days of enrollment

- Addition or discontinuation of calcium channel blockers, digitalis, diuretics or
vasodilators within 30 days of enrollment. Dosage must be stable for 7 days prior to
enrollment (except for diuretics)

- Listed for lung transplantation

- Due to drug interactions, all of the following agents will be prohibited:
alpha-blockers, endothelin-1 antagonists, and CYP3A4 inhibitors

- Resting oxygen saturation of <92% with greater than 6 liters of supplemental oxygen