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

NCT ID: NCT00650091

Last Updated: 2015-06-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 264 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-10-31
• Study Completion Date: 2014-01-31

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.

Conditions

Pulmonary Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

Group Type: ACTIVE_COMPARATOR

N-acetylcysteine (NAC)

Intervention Type: DRUG

Participants will receive 600 mg of NAC three times a day.

2

Participants will receive placebo for 60 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Participants will receive placebo each day.

Interventions

N-acetylcysteine (NAC)

Participants will receive 600 mg of NAC three times a day.

Intervention Type: DRUG

Placebo

Participants will receive placebo each day.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marvin I Schwarz, MD

Role: STUDY_CHAIR

University of Colorado, Denver

Kevin Brown, MD

Role: PRINCIPAL_INVESTIGATOR

National Jewish Health

Rob Kaner, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Medical College at Cornell University

Talmadge King, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Joe Lasky, MD

Role: PRINCIPAL_INVESTIGATOR

Tulane University

James Loyd, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Fernando Martinez, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Imre Noth, MD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

Ganesh Raghu, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Jesse Roman, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Jay Ryu, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

John Belperio, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Kevin Anstrom, PhD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Gail Weinmann, MD

Role: STUDY_DIRECTOR

National Heart, Lung, and Blood Institute (NHLBI)

Jeffrey Chapman, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Lake Morrison, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Michael Kallay, MD

Role: PRINCIPAL_INVESTIGATOR

Highland Hospital

Steven Sahn, MD

Role: PRINCIPAL_INVESTIGATOR

Medical University of South Carolina

Marilyn Glassberg, MD

Role: PRINCIPAL_INVESTIGATOR

University of Miami

Milton Rossman, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

John Fitzgerald, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Mary Beth Scholand, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Neil Ettinger, MD

Role: PRINCIPAL_INVESTIGATOR

St. Luke's Hospital

Danielle Antin-Ozerkis, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Joao deAndrade, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Ivan Rosas, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's

Joseph Zibrak, MD

Role: PRINCIPAL_INVESTIGATOR

Beth Isreal-Deaconess

Gerald Criner, MD

Role: PRINCIPAL_INVESTIGATOR

Temple University

Maria Padilla, MD

Role: PRINCIPAL_INVESTIGATOR

MOUNT SINAI HOSPITAL

Locations

University of Alabama - Birmingham

Birmingham, Alabama, United States

University of California - Los Angeles

Los Angeles, California, United States

University of California - San Francisco

San Francisco, California, United States

National Jewish Medical and Research Center

Denver, Colorado, United States

Yale University School of Medicine

New Haven, Connecticut, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

University of Chicago

Chicago, Illinois, United States

University of Louisville

Louisville, Kentucky, United States

Tulane University

New Orleans, Louisiana, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

St. Luke's Hospital

Chesterfield, Missouri, United States

Weill Medical College of Cornell University

New York, New York, United States

Mount Sinai Hospital

New York, New York, United States

Highland Hospital - University of Rochester Medical Center

Rochester, New York, United States

Duke Universtiy

Durham, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States

Temple University

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Vanderbilt University

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

University of Utah Health Research Center

Salt Lake City, Utah, United States

University of Washington

Seattle, Washington, United States

Countries

United States

References

Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, Flores C, Noth I, Yaspan BL, Jenkins RG, Wain LV; International IPF Genetics Consortium. Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis. Thorax. 2022 Aug;77(8):829-833. doi: 10.1136/thoraxjnl-2021-218577. Epub 2022 Jun 10.

Reference Type: DERIVED

PMID: 35688625 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26111071 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25890798 (View on PubMed)

Idiopathic Pulmonary Fibrosis Clinical Research Network; Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2093-101. doi: 10.1056/NEJMoa1401739. Epub 2014 May 18.

Reference Type: DERIVED

PMID: 24836309 (View on PubMed)

Idiopathic Pulmonary Fibrosis Clinical Research Network; Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012 May 24;366(21):1968-77. doi: 10.1056/NEJMoa1113354. Epub 2012 May 20.

Reference Type: DERIVED

PMID: 22607134 (View on PubMed)

Related Links

http://www.ipfnet.org

Click here for the Idiopathic Pulmonary Fibrosis Clinical Research Network web site.

http://www.nlm.nih.gov/databases/alerts/2011_nhlbi_ifp.html

Clinical Alert: Commonly used three-drug regimen for idiopathic pulmonary fibrosis found harmful

Other Identifiers

U10HL080413-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro00020066

Identifier Type: -

Identifier Source: org_study_id