Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

Alicia Gerke

Status and phase

Terminated

Phase 3

Phase 2

Conditions

Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis

Treatments

Drug: Sildenafil and Losartan

Drug: Losartan

Drug: Sildenafil

Drug: Placebo Oral Tablet

Study type

Interventional

Funder types

Other

Identifiers

NCT00981747

200906736

Details and patient eligibility

About

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.

Full description

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.

Enrollment

12 patients

Sex

All

Ages

18 to 99 years old

Volunteers

No Healthy Volunteers

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