Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether combination therapy with sildenafil and losartan can improve function and exercise tolerance in patients with idiopathic pulmonary fibrosis.

Detailed Description
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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.

Official Title
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A Clinical Treatment Trial Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

Conditions
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Idiopathic Pulmonary Fibrosis, Pulmonary Fibrosis

Intervention / Treatment
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* Drug: Sildenafil
* Drug: Losartan
* Drug: Sildenafil and Losartan
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Participants will receive sildenafil for three months then losartan for three months, then sildenafil and losartan for three months and then placebo for three months in a random order.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All study participants<br>Study participants are patients that have been diagnosed with idiopathic pulmonary fibrosis (IPF). | Drug: Sildenafil<br>* Sildenafil 20mg three times per day for 3 months followed by a one month washout prior to next intervention.<br>* Other names: Revatio;Drug: Losartan<br>* Losartan 25mg two times a day for 3 months followed by a one month washout prior to next intervention.<br>* Other names: Cozaar: losartan;Drug: Sildenafil and Losartan<br>* Sildenafil 20mg three times per day and Losartan 25mg two times per day followed by a one month washout prior to next intervention.<br>* Other names: Cozaar: losartan;Drug: Placebo Oral Tablet<br>* Placebo pill three times per day for 3 months followed by a one month washout prior to next intervention.<br>* Other names: Placebo pill (sugar);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Six Minute Walk Distance in Meters | Change in 6MWD before and after treatment compared to placebo | At baseline and three months post each intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Forced Vital Capacity (FVC) | Change in FVC before and after treatment compared to placebo. FVC is a measure of lung size. | At baseline and three months post each intervention. | 
| Change in Shortness of Breath (SOB) Score | Change in symptoms of SOB as determined by St. Georges Respiratory Questionnaire score. This score ranges from 0 to 100 with a higher score indicating more problems breathing. | At baseline and three months post each intervention. |