Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

A Clinical Treatment Trial Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

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.

Study Overview

• Status: Terminated
• Conditions: Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis
• Intervention / Treatment: Drug: Sildenafil; Drug: Losartan; Drug: Sildenafil and Losartan; Drug: Placebo Oral Tablet

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52246
      • University of Iowa Hospitals and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: DOUBLE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: All study participants; Study participants are patients that have been diagnosed with idiopathic pulmonary fibrosis (IPF).

Drug: Sildenafil; Sildenafil 20mg three times per day for 3 months followed by a one month washout prior to next intervention.; Other Names: Viagra; Revatio; Drug: Losartan; Losartan 25mg two times a day for 3 months followed by a one month washout prior to next intervention.; Other Names: Cozaar: losartan; Drug: Sildenafil and Losartan; Sildenafil 20mg three times per day and Losartan 25mg two times per day followed by a one month washout prior to next intervention.; Other Names: Cozaar: losartan; Viagra, Revatio: sildenafil; Drug: Placebo Oral Tablet; Placebo pill three times per day for 3 months followed by a one month washout prior to next intervention.; Other Names: Placebo pill (sugar)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Alicia Gerke
• Collaborators: Pulmonary Fibrosis Foundation

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2009
• Primary Completion (ACTUAL): December 1, 2016
• Study Completion (ACTUAL): December 1, 2016

Study Registration Dates

• First Submitted: September 19, 2009
• First Submitted That Met QC Criteria: September 19, 2009
• First Posted (ESTIMATE): September 22, 2009

Study Record Updates

• Last Update Posted (ACTUAL): November 13, 2018
• Last Update Submitted That Met QC Criteria: October 10, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Losartan; Sildenafil Citrate
• Other Study ID Numbers: 200906736

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes