Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis

Hypertension, Pulmonary Clinical Trial

— STEP-IPF  

Official title:

Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00517933
• Other study ID #: Pro00018538
• Secondary ID: U10HL080413507
• Status: Completed
• Phase: Phase 3
• First received: August 15, 2007
• Last updated: June 22, 2015
• Start date: August 2007
• Est. completion date: October 2009

Study information

• Verified date: June 2015
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects an individual's ability to breathe. This study will evaluate the effectiveness of sildenafil, a medication that increases blood flow to the lungs, at improving breathing function, exercise capacity, and quality of life in people with advanced IPF.

Description:

IPF is a disease in which fibrous tissue clogs the lungs. This eventually damages air sacs in the lungs and leads to widespread and permanent scarring of lung tissue. Individuals with IPF may experience breathing difficulties, cough, chest pain, and a decreased exercise capacity. Pulmonary hypertension, which is high blood pressure in the arteries of the lungs, affects half of all people with IPF. The fibrous tissue that clogs the lungs also blocks blood from flowing through the lungs effectively, reducing the amount of oxygen in the lungs. The fibrous tissue also reduces the lungs' ability to use what oxygen is available. These factors can cause breathing difficulties and may eventually lead to heart disease. Sildenafil is a medication that can increase blood supply to the lungs and reduce the heart's workload. The purpose of this study is to evaluate the effectiveness of sildenafil at improving breathing function, exercise capacity, and quality of life in people with advanced IPF.

This study will enroll people with advanced IPF. Participants will be randomly assigned to receive sildenafil or placebo three times a day for 12 weeks. Study visits will occur at baseline and Weeks 1, 6, and 12. At Week 12, participants will have the option to continue in the study for an additional 12 weeks. All participants who agree to continue in the study will receive sildenafil three times a day for the second 12 weeks. Study visits will occur at Weeks 13, 18, and 24. At all study visits, a physical exam and blood collection will occur. At selected visits, the following study procedures will occur: lung function testing; urine collection; a 6-minute walk test, which will measure the distance walked in a 6-minute period; and questionnaires to assess health status, breathing, and quality of life. Participants will record medication usage and symptoms in a daily diary. Study researchers will review medical records and the Social Security death index 5 years following the end of the study to determine the incidence of death among study participants.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: October 2009
• Est. primary completion date: May 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Clinical diagnosis of IPF

• Diffusing capacity of the lung (DLCO) level less than 35% (adjusted for hemoglobin)

Exclusion Criteria:

• Current enrollment in another investigational study

• Six-minute walk distance of less than 50 meters at screening or study entry

• Difference of greater than 15% between the screening and study entry 6-minute walk distance

• Acute or long-term impairment other than dyspnea (e.g., angina pectoris, intermittent claudication) that limits the ability to comply with the 6-minute walk test or other study requirements

• Forced Expiratory Volume 1-second (FEV1)/forced vital capacity (FVC) ratio of less than 0.65 after bronchodilator use

• Extent of emphysema greater than the extent of fibrotic change (e.g., honeycombing, reticular changes) on high-resolution computed tomography (HRCT) scan

• Acute heart attack within the 6 months prior to study entry

• Nitrate use

• Hypersensitivity to sildenafil or any component of the formulation

• Presence of aortic stenosis (AS)

• Life-threatening arrhythmia within 1 month of study entry

• Diabetes mellitus requiring insulin therapy

• Second-degree or third-degree atrioventricular (AV) block on electrocardiogram

• Severe chronic heart failure, defined by left ventricular ejection fraction (LVEF) of less than 25%

• Presence of idiopathic hypertrophic subaortic stenosis (IHSS)

• Hypotension (i.e., systolic blood pressure [SBP] less than 100 mm Hg or diastolic blood pressure [DBP] less than 50 mm Hg)

• Uncontrolled systemic hypertension (i.e., SBP greater than 180 mm Hg or DBP greater than 100 mm Hg)

• Known penile deformities or conditions (e.g., sickle cell anemia, multiple myeloma, leukemia) that may predispose participant to priapism

• Aspartate aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT), alanine aminotransferase (ALT), or serum glutamic oxaloacetic transaminase (SGOT) greater than three times the upper limit of normal range

• Kidney impairment (i.e., creatinine clearance less than 30 mL/minute)

• Current drug or alcohol dependence

• Retinitis pigmentosa

• History of vision loss

• History of nonarteritic ischemic optic neuropathy

• Recently initiated pulmonary rehabilitation within 30 days of study entry. Participants will be prohibited from starting pulmonary rehabilitation during the study. Participants who are currently undergoing maintenance pulmonary rehabilitation at study entry will be asked to maintain their levels of rehabilitation for the duration of the study.

• Use of any investigational therapy as part of a clinical trial for any medical condition within 30 days of study entry

• Start or change in dose of treatment for IPF investigational agent (e.g., interferon gamma-1b, pirfenidone, etanercept, N-acetylcysteine, any other investigational agent intended to treat IPF), corticosteroids, or cytotoxic agents within 30 days of study entry

• Use of certain medications. More information about this criterion can be found in the study protocol.

• Treatment for pulmonary hypertension with prostaglandins (e.g., epoprostenol, treprostinil), endothelin-1 antagonists (e.g., bosentan, sitaxsentan, ambrisentan), or any other phosphodiesterase inhibitor (e.g., tadalafil, vardenafil) within 30 days of study entry

• Addition or discontinuation of calcium channel blockers, digitalis, diuretics, or vasodilators within 30 days of study entry (dosage must be stable for 7 days prior to study entry [except for diuretics])

• Currently on the waiting list for a lung transplant

• Use of L-arginine supplements

• Use of grapefruit juice or St. John's wort

• Pregnant or breastfeeding

• Resting saturation of peripheral oxygen (SpO2) (i.e., oxygen saturation measured using pulse oximetry) less than 92% with 6 liters of supplemental oxygen

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fibrosis
• Hypertension, Pulmonary
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• Sildenafil Citrate
Sildenafil citrate (20mg 3 times a day [TID] orally for 12 weeks followed by 20mg TID open-label sildenafil for an additional 12 weeks)

Other:
• Placebo
Placebo (20mg TID orally for 12 weeks followed by 20mg open-label sildenafil for 12 weeks)

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	University of Chicago	Chicago	Illinois
United States	National Jewish Medical and Research Center	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	University of California - Los Angeles	Los Angeles	California
United States	Vanderbilt University	Nashville	Tennessee
United States	Tulane University	New Orleans	Louisiana
United States	Weill Medical College of Cornell University	New York	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California - San Francisco	San Francisco	California
United States	University of Washington	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Duke University	National Heart, Lung, and Blood Institute (NHLBI), Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in 6-minute Walk Distance From Enrollment to Week 12 (= 20% Improvement)	This is a binary score (1 or 0) with 1 being better than 0. All models adjust for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Measured at Week 12	No
Secondary	6-minute Walk Distance (6MWT)	The 6MWT measures the distance that a participant can walk in a period of 6 minutes.	Baseline, 6 week, 12 week	No
Secondary	Estimated Change From Baseline to 12 Weeks in 6-minute Walk Distance	The 6MWT measures the distance that a participant can walk in a period of 6 minutes. All models adjust for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, week 12	No
Secondary	Desaturation During 6-minute Walk Test (6MWT)	The 6MWT was stopped when the pulse oximetry (SpO2) dropped to below 80% for six consecutive seconds. The estimates are based on the Kaplan-Meier event curves with minutes walked as the x-axis.	Week 12	No
Secondary	Change in Dyspnea	The University of California at San Diego Shortness of Breath Questionnaire (SOBQ) uses a 6-point scale (0 = "not at all" to 5 = "maximal or unable to do because of breathlessness") to rate 24 items. The final score ranges from 0 to 120 -- lower scores are better.	Measured from enrollment to 12 weeks (phase I)	No
Secondary	University of California at San Diego (UCSD) Shortness of Breath Questionnaire Total	The University of California at San Diego Shortness of Breath Questionnaire (SOBQ) uses a 6-point scale (0 = "not at all" to 5 = "maximal or unable to do because of breathlessness") to rate 24 items. The final score ranges from 0 to 120 -- lower scores are better. (Raw scores); Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in Forced Vital Capacity (FVC) Adjusted Values	Change in FVC (liters) from baseline (time 0) to week 12 comparing the sildenafil and placebo groups. Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, Week 12	No
Secondary	Forced Vital Capacity (FVC)	Raw scores of FVC (liters) from baseline (time 0) to week 6 and 12 comparing the sildenafil and placebo groups	Baseline, Week 6, Week 12	No
Secondary	Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Adjusted Values	Change in DLCO (% predicted) measured at baseline (time 0), and week 12 comparing the sildenafil and placebo groups. All models adjust for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, Week 12	No
Secondary	Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)	Raw scores of DLCO (% predicted) measured at baseline (time 0), week 6, and week 12 comparing the sildenafil and placebo groups	Baseline, Week 6, Week 12	No
Secondary	Change in Borg Dyspnea Index (BDI) After 6 Minute Walk Test (Adjusted Values)	The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum) and indicates the degree of breathlessness after completion of the 6-minute walk test. Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 week	No
Secondary	Borg Dyspnea Index (BDI) After 6 Minute Walk Test (Raw Scores)	The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum) and indicates the degree of breathlessness after completion of the 6-minute walk test.	Baseline, 6 week, 12 week	No
Secondary	Change in St. George's Respiratory Questionnaire (Total Score) (Adjusted Values)	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment.) Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 week	No
Secondary	St. George's Respiratory Questionnaire (Total Score)	Mean raw scores of the St. George's Respiratory Questionnaire. The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment.)	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in St. George's Respiratory Questionnaire (Symptoms Score) Adjusted Value	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment). Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	St. George's Respiratory Questionnaire (Symptoms Score)	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment). Mean raw scores of the St. George's Respiratory Questionnaire. Mean raw scores of the St. George's Respiratory Questionnaire.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in St. George's Respiratory Questionnaire (Activity Score) Adjusted Value	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment). Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	St. George's Respiratory Questionnaire (Activity Score)	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment). Mean raw scores of the St. George's Respiratory Questionnaire.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in St. George's Respiratory Questionnaire (Impacts Score) Adjusted Value	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment). Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	St. George's Respiratory Questionnaire (Impacts Score)	The St. George's Respiratory Questionnaire asks patients how breathing problems impair their life and is scored from 0 (no impairment) to 100 (maximum impairment). Mean raw scores of the St. George's Respiratory Questionnaire.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in ICECAP-O Adjusted Value	The ICEpop CAPability measure for Older people (ICECAP-O) is a measure of capability in older people for use in economic evaluation. The values of ICECAP-O range from 0 (worst) to 1 (best).; Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	ICECAP-O	The ICEpop CAPability measure for Older people (ICECAP-O) is a measure of capability in older people for use in economic evaluation. The values of ICECAP-O range from 0 (worst) to 1 (best). Mean raw scores of ICECAP-O.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in EuroQOL Thermometer (Adjusted Value)	The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher scores indicate a better health state.; Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	EuroQOL Thermometer	The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher scores indicate a better health state.; Mean raw scores of EuroQOL Thermometer.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in EuroQOL (EQ-5D) Utility - Adjusted Value	EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (eg, "confined to bed"). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in total score range -0.594 to 1.000; higher score indicates better health state.; Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	EuroQOL (EQ-5D) Utility	EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (eg, "confined to bed"). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in total score range -0.594 to 1.000; higher score indicates better health state.; Mean raw scores of EuroQOL Utility.	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in Short Form Health Survey (SF36) General Health - Adjusted Value	The SF36 measures functional health and well-being scores on eight scales that correlate with two aggregate scores.; Each score ranges from 0 to 100, with a higher score indicating better function.; Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	Short Form Health Survey (SF36) General Health	The SF36 measures functional health and well-being scores on eight scales that correlate with two aggregate scores.; Each score ranges from 0 to 100, with a higher score indicating better function.; Mean raw scores of SF36 General Health	Baseline, 6 weeks, 12 weeks	No
Secondary	Change in SF36 Aggregate Physical (Adjusted Value)	The SF36 measures functional health and well-being scores on eight scales that correlate with two aggregate scores.; Each score ranges from 0 to 100, with a higher score indicating better function.; Values adjusted for baseline values of age, height, sex, white race, and DLCO. Values from models are estimated changes from baseline to 12 weeks (with 95% confidence intervals). The difference estimate is based on sildenafil - placebo.	Baseline, 12 weeks	No
Secondary	Short Form Health Survey (SF36) Aggregate Physical	The SF36 measures functional health and well-being scores on eight scales that correlate with two aggregate scores.; Each score ranges from 0 to 100, with a higher score indicating better function.; Mean raw scores of SF36 Aggregate Physical.	Baseline, 6 weeks, 12 weeks	No