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Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

Primary Purpose

Idiopathic Pulmonary Fibrosis, Pulmonary Fibrosis

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Sildenafil

Losartan

Sildenafil and Losartan

Placebo Oral Tablet

About this trial

This is an interventional treatment trial for Idiopathic Pulmonary Fibrosis

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

University of Iowa Hospitals and Clinics

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

All study participants

Arm Description

Study participants are patients that have been diagnosed with idiopathic pulmonary fibrosis (IPF).

Outcomes

Primary Outcome Measures

Change in Six Minute Walk Distance in Meters

Change in 6MWD before and after treatment compared to placebo

Secondary Outcome Measures

Change in Forced Vital Capacity (FVC)

Change in FVC before and after treatment compared to placebo. FVC is a measure of lung size.

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.

Full Information

NCT ID

NCT00981747

First Posted

September 19, 2009

Last Updated

October 10, 2018

Sponsor

Alicia Gerke

Collaborators

Pulmonary Fibrosis Foundation

1. Study Identification

Unique Protocol Identification Number

NCT00981747

Brief Title

Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

Official Title

A Clinical Treatment Trial Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Terminated

Why Stopped

Funding was withdrawn.

Study Start Date

September 2009 (Actual)

Primary Completion Date

December 2016 (Actual)

Study Completion Date

December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Alicia Gerke

Collaborators

Pulmonary Fibrosis Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Idiopathic Pulmonary Fibrosis, Pulmonary Fibrosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Single Group Assignment

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

ParticipantInvestigator

Allocation

N/A

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

All study participants

Arm Type

Experimental

Arm Description

Study participants are patients that have been diagnosed with idiopathic pulmonary fibrosis (IPF).

Intervention Type

Drug

Intervention Name(s)

Sildenafil

Other Intervention Name(s)

Viagra, Revatio

Intervention Description

Sildenafil 20mg three times per day for 3 months followed by a one month washout prior to next intervention.

Intervention Type

Drug

Intervention Name(s)

Losartan

Other Intervention Name(s)

Cozaar: losartan

Intervention Description

Losartan 25mg two times a day for 3 months followed by a one month washout prior to next intervention.

Intervention Type

Drug

Intervention Name(s)

Sildenafil and Losartan

Other Intervention Name(s)

Viagra, Revatio: sildenafil, Cozaar: losartan

Intervention Description

Sildenafil 20mg three times per day and Losartan 25mg two times per day followed by a one month washout prior to next intervention.

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Tablet

Other Intervention Name(s)

Placebo pill (sugar)

Intervention Description

Placebo pill three times per day for 3 months followed by a one month washout prior to next intervention.

Primary Outcome Measure Information:

Title

Change in Six Minute Walk Distance in Meters

Description

Change in 6MWD before and after treatment compared to placebo

Time Frame

At baseline and three months post each intervention.

Secondary Outcome Measure Information:

Title

Change in Forced Vital Capacity (FVC)

Description

Change in FVC before and after treatment compared to placebo. FVC is a measure of lung size.

Time Frame

At baseline and three months post each intervention.

Title

Change in Shortness of Breath (SOB) Score

Description

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.

Time Frame

At baseline and three months post each intervention.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alicia K Gerke, MD

Organizational Affiliation

University of Iowa

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Iowa Hospitals and Clinics

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52246

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis

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