Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in Patients With IPF

Phase 3

Completed

Conditions: Pulmonary Fibrosis

Interventions: Drug: N-acetylcysteine (NAC)
Drug: Placebo

Registration Number: NCT00650091

Lead Sponsor: Duke University

Brief Summary: Idiopathic pulmonary fibrosis (IPF) is a long-term lung disease that affects an individual's ability to breathe. In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups - receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo - in a 1:1:1 ratio.

Detailed Description: IPF is a disease with widespread and permanent scarring of lung tissue which eventually results in death. Individuals with IPF may experience breathing difficulties, cough, chest pain, and a decreased exercise capacity. Although the cause of IPF is unknown, it may be a result of an inflammatory response to an unknown substance. NAC, an antioxidant that is effective at loosening up mucus that forms in the lungs, may improve lung function. The purpose of this study is to evaluate the effectiveness of NAC at preventing the loss of lung function in people with IPF.

In the initial double-blind, placebo-controlled trial, subjects who have idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function are randomly assigned to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo.

After safety concerns were identified by the data and safety monitoring board, the three-drug regimen was stopped by the National Heart, Lung, and Blood Institute (NHLBI) on October 14, 2011, and a clinical alert was issued. After a brief period of interruption for modification of the protocol and approval by the institutional review boards, patients continued to be recruited for the acetylcysteine group and the placebo group and were followed for the pre-specified duration of 60 weeks.

Study visits will occur at baseline and Weeks 4, 15, 30, 45, and 60. 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, and questionnaires to assess health status, breathing, and quality of life. Participants will record medication usage and symptoms in a daily diary.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 264

Inclusion Criteria

Forced vital capacity (FVC) greater than or equal to 50% of predicted value
Diffusion capacity (DLCO) greater than or equal to 30% of predicted value
Diagnosis of IPF by modified American Thoracic Society (ATS) criteria in the 48 months before study entry

Exclusion Criteria

History of clinically significant environmental exposure known to cause pulmonary fibrosis
Diagnosis of connective tissue disease as the likely cause of the interstitial disease
Extent of emphysema greater than the extent of fibrotic change (i.e., honeycombing, reticular changes) on high resolution computed tomography (HRCT) scan
Forced expiratory volume in 1 second (FEV1)/FVC ratio less than 0.65 at the time of screening (post-bronchodilator)
Partial pressure of arterial oxygen (PaO2) less than 55 mm Hg (less than 50 mm Hg at Denver study site)
Residual volume greater than 120% predicted at the time of screening (post-bronchodilator)
Evidence of active infection
Significant bronchodilator response on screening spirometry, defined as change in FEV1 greater than or equal to 12% and absolute change greater than 200 mL OR change in FVC greater than or equal to 12% and absolute change greater than 200 mL
Screening and baseline FVC measurements (in liters, post-bronchodilator) differing by 11%
Listed for lung transplantation
History of unstable or deteriorating cardiac disease
Heart attack, coronary artery bypass, or angioplasty in the 6 months before study entry
Unstable angina pectoris or congestive heart failure requiring hospitalization in the 6 months before study entry
Uncontrolled arrhythmia
Severe uncontrolled high blood pressure
Known HIV or hepatitis C
Known cirrhosis and chronic active hepatitis
Active substance and/or alcohol abuse
Pregnant or breastfeeding
Women of childbearing potential who are not using a medically approved means of contraception
Any clinically relevant lab abnormalities, including the following:
1. Creatinine greater than twice the upper limit of normal (ULN)
2. Hematology outside of specified limits
  1. White blood cells less than 3,500/mm3
  2. Hematocrit less than 25% or greater than 59%
  3. Platelets less than 100,000 mm3 at the time of screening
3. Any of the following liver function test criteria above specified limits
  1. Total bilirubin greater than twice the ULN
  2. Aspartate (AST) or alanine aminotransferases (ALT) greater than 1.5 the ULN
  3. Alkaline phosphatase greater than three times the ULN
  4. Albumin less than 3.0 mg/dL at the time of screening
Known hypersensitivity to study medication
Any condition other than IPF that, in the opinion of the site PI, is likely to result in death in the 1 year after study entry
Any condition that, in the judgment of the PI, might cause participation in this study to be detrimental or makes the person a poor candidate for the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	N-acetylcysteine (NAC)	Participants will receive N-acetylcysteine (NAC) for 60 weeks.
2	Placebo	Participants will receive placebo for 60 weeks.

Primary Outcome Measures

Name	Time	Method
Overall Change in Forced Vital Capacity	Measured as the estimated change from baseline to Week 60	Change from Baseline in Forced Vital Capacity at 60 weeks (units in liters)

Secondary Outcome Measures

Name	Time	Method
Acute Exacerbations	Measured at Week 60	The following 3 criteria will define acute exacerbations in subjects with acute worsening of their respiratory conditions: 1. Clinical (all of the following required): A) Unexplained worsening of dyspnea or cough within 30 days, triggering unscheduled medical care (e.g., emergency room, clinic, study visit, hospitalization). B) No clinical suspicion or overt evidence of cardiac event, pulmonary embolism, or deep venous thrombosis to explain acute worsening of dyspnea. C) No pneumothorax.
Disease Progression	Measured at Week 60	The time-to-death or a 10% decline in FVC will be defined as the time-to-disease progression. The 10% decline in FVC from enrollment must be confirmed on 2 consecutive visits no less than 6 weeks apart. For subjects with 2 consecutive visits with a 10% decline in FVC, the time-to-disease progression will be defined as the time interval between enrollment and the initial visit with a 10% FVC decline.
Respiratory Infections	Measured at Week 60
Number of Participants With Maintained Forced Vital Capacity Response	Measured at Week 60	Maintained forced vital capacity response was a binary variable taking on a value of 1 for participants with higher FVC % predicted at week 60 compared to baseline.

Trial Locations

Locations (26): University of Chicago
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Chicago, Illinois, United States
University of California - San Francisco
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San Francisco, California, United States
Vanderbilt University
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Nashville, Tennessee, United States
University of Utah Health Research Center
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Salt Lake City, Utah, United States
University of Washington
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Seattle, Washington, United States
National Jewish Medical and Research Center
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Denver, Colorado, United States
Mayo Clinic
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Rochester, Minnesota, United States
University of Michigan
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Ann Arbor, Michigan, United States
Brigham and Women's Hospital
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Boston, Massachusetts, United States
University of Miami Miller School of Medicine
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Miami, Florida, United States
University of Louisville
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Louisville, Kentucky, United States
Tulane University
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New Orleans, Louisiana, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
Yale University School of Medicine
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New Haven, Connecticut, United States
University of Alabama - Birmingham
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Birmingham, Alabama, United States
University of California - Los Angeles
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Los Angeles, California, United States
St. Luke's Hospital
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Chesterfield, Missouri, United States
Weill Medical College of Cornell University
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New York, New York, United States
Mount Sinai Hospital
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New York, New York, United States
Highland Hospital - University of Rochester Medical Center
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Rochester, New York, United States
Duke Universtiy
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Durham, North Carolina, United States
Cleveland Clinic
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Cleveland, Ohio, United States
University of Pennsylvania Health System
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Philadelphia, Pennsylvania, United States
Temple University
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Philadelphia, Pennsylvania, United States
Medical University of South Carolina
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Charleston, South Carolina, United States
University of Texas Southwestern Medical Center
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Dallas, Texas, United States