Clinical trial NCT00517933: Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis
Official title: Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Fibrosis
Hypertension, Pulmonary
Keywords: Idiopathic Pulmonary Fibrosis
Pulmonary Hypertension
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Pfizer
First posted: 2007-08-17
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in 6-minute Walk Distance From Enrollment to Week 12 (≥ 20% Improvement)
timeFrame: Measured at Week 12
Secondary outcomes:
measure: 6-minute Walk Distance (6MWT)
timeFrame: Baseline, 6 week, 12 week
measure: Estimated Change From Baseline to 12 Weeks in 6-minute Walk Distance
timeFrame: Baseline, week 12
measure: Desaturation During 6-minute Walk Test (6MWT)
timeFrame: Week 12
measure: Change in Dyspnea
timeFrame: Measured from enrollment to 12 weeks (phase I)
measure: University of California at San Diego (UCSD) Shortness of Breath Questionnaire Total
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in Forced Vital Capacity (FVC) Adjusted Values
timeFrame: Baseline, Week 12
measure: Forced Vital Capacity (FVC)
timeFrame: Baseline, Week 6, Week 12
measure: Change in Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Adjusted Values
timeFrame: Baseline, Week 12
measure: Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)
timeFrame: Baseline, Week 6, Week 12
measure: Change in Borg Dyspnea Index (BDI) After 6 Minute Walk Test (Adjusted Values)
timeFrame: Baseline, 12 week
measure: Borg Dyspnea Index (BDI) After 6 Minute Walk Test (Raw Scores)
timeFrame: Baseline, 6 week, 12 week
measure: Change in St. George's Respiratory Questionnaire (Total Score) (Adjusted Values)
timeFrame: Baseline, 12 week
measure: St. George's Respiratory Questionnaire (Total Score)
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in St. George's Respiratory Questionnaire (Symptoms Score) Adjusted Value
timeFrame: Baseline, 12 weeks
measure: St. George's Respiratory Questionnaire (Symptoms Score)
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in St. George's Respiratory Questionnaire (Activity Score) Adjusted Value
timeFrame: Baseline, 12 weeks
measure: St. George's Respiratory Questionnaire (Activity Score)
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in St. George's Respiratory Questionnaire (Impacts Score) Adjusted Value
timeFrame: Baseline, 12 weeks
measure: St. George's Respiratory Questionnaire (Impacts Score)
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in ICECAP-O Adjusted Value
timeFrame: Baseline, 12 weeks
measure: ICECAP-O
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in EuroQOL Thermometer (Adjusted Value)
timeFrame: Baseline, 12 weeks
measure: EuroQOL Thermometer
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in EuroQOL (EQ-5D) Utility - Adjusted Value
timeFrame: Baseline, 12 weeks
measure: EuroQOL (EQ-5D) Utility
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in Short Form Health Survey (SF36) General Health - Adjusted Value
timeFrame: Baseline, 12 weeks
measure: Short Form Health Survey (SF36) General Health
timeFrame: Baseline, 6 weeks, 12 weeks
measure: Change in SF36 Aggregate Physical (Adjusted Value)
timeFrame: Baseline, 12 weeks
measure: Short Form Health Survey (SF36) Aggregate Physical
timeFrame: Baseline, 6 weeks, 12 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Denver
country: United States
facility: National Jewish Medical and Research Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Iowa
name: Gary Hunninghake, MD
role: STUDY_CHAIR
affiliation: National Jewish Health
name: Kevin Brown, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College at Cornell University
name: Rob Kaner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Talmadge King, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tulane University
name: Joe Lasky, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University
name: James Loyd, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Fernando Martinez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Imre Noth, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Ganesh Raghu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Jesse Roman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Jay Ryu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: David Zisman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Kevin Anstrom, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Herbert Reynolds, MD
role: STUDY_DIRECTOR
affiliation: Duke University
name: Lake D Morrison, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Andrade J, Schwarz M, Collard HR, Gentry-Bumpass T, Colby T, Lynch D, Kaner RJ; IPFnet Investigators. The Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet): diagnostic and adjudication processes. Chest. 2015 Oct;148(4):1034-1042. doi: 10.1378/chest.14-2889.
citation: Durheim MT, Collard HR, Roberts RS, Brown KK, Flaherty KR, King TE Jr, Palmer SM, Raghu G, Snyder LD, Anstrom KJ, Martinez FJ; IPFnet investigators. Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med. 2015 May;3(5):388-96. doi: 10.1016/S2213-2600(15)00093-4. Epub 2015 Apr 15.
citation: Idiopathic Pulmonary Fibrosis Clinical Research Network; Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010 Aug 12;363(7):620-8. doi: 10.1056/NEJMoa1002110. Epub 2010 May 18.