Clinical trial NCT00650091: Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in Patients With IPF
Official title: Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in IPF
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Fibrosis
Keywords: Idiopathic Pulmonary Fibrosis
Prednisone
Azathioprine
NAC
N-acetylcysteine
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2008-04-01
Enrollment: 264
Sex: ALL
Minimum age (years): 35
Maximum age (years): 85
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 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.

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

Primary outcomes:
measure: Overall Change in Forced Vital Capacity
timeFrame: Measured as the estimated change from baseline to Week 60
Secondary outcomes:
measure: Disease Progression
timeFrame: Measured at Week 60
measure: Acute Exacerbations
timeFrame: Measured at Week 60
measure: Respiratory Infections
timeFrame: Measured at Week 60
measure: Number of Participants With Maintained Forced Vital Capacity Response
timeFrame: Measured at Week 60
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: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chesterfield
country: United States
facility: St. Luke's Hospital
state: Missouri
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Rochester
country: United States
facility: Highland Hospital - University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke Universtiy
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Research Center
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Colorado, Denver
name: Marvin I Schwarz, 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: John Belperio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Kevin Anstrom, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Gail Weinmann, MD
role: STUDY_DIRECTOR
affiliation: The Cleveland Clinic
name: Jeffrey Chapman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Lake Morrison, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Highland Hospital
name: Michael Kallay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: Steven Sahn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Marilyn Glassberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Milton Rossman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas
name: John Fitzgerald, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Mary Beth Scholand, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Luke's Hospital
name: Neil Ettinger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Danielle Antin-Ozerkis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Joao deAndrade, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brigham and Women's
name: Ivan Rosas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beth Isreal-Deaconess
name: Joseph Zibrak, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Temple University
name: Gerald Criner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MOUNT SINAI HOSPITAL
name: Maria Padilla, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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; 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.
citation: 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.