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

• ClinicalTrials.gov Identifier: NCT00650091
• Recruitment Status: Completed
• First Posted: April 1, 2008
• Results First Posted: June 2, 2015
• Last Update Posted: June 2, 2015
• Sponsor: Duke University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: March 28, 2008
• First Posted Date: April 1, 2008
• Results First Submitted Date: July 31, 2014
• Results First Posted Date: June 2, 2015
• Last Update Posted Date: June 2, 2015
• Study Start Date: October 2009
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 27, 2015)

Overall Change in Forced Vital Capacity [ Time Frame: Measured as the estimated change from baseline to Week 60 ]

Change from Baseline in Forced Vital Capacity at 60 weeks (units in liters)

• Original Primary Outcome Measures (submitted: March 28, 2008): Change in serial forced vital capacity [ Time Frame: Measured at Week 60 ]

Current Secondary Outcome Measures (submitted: May 27, 2015)

• Disease Progression [ Time Frame: 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.
• Acute Exacerbations [ Time Frame: 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.
• Respiratory Infections [ Time Frame: Measured at Week 60 ]
• Number of Participants With Maintained Forced Vital Capacity Response [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: March 28, 2008)

• Time to disease progression [ Time Frame: Measured at Week 60 ]
• Acute exacerbations [ Time Frame: Measured at Week 60 ]
• Respiratory infections [ Time Frame: Measured at Week 60 ]
• Maintained forced vital capacity response [ Time Frame: Measured at Week 60 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Fibrosis

Intervention

• Drug: N-acetylcysteine (NAC)
  Participants will receive 600 mg of NAC three times a day.
• Drug: Placebo
  Participants will receive placebo each day.

Study Arms

• Active Comparator: 1
  Participants will receive N-acetylcysteine (NAC) for 60 weeks.
  Intervention: Drug: N-acetylcysteine (NAC)
• Placebo Comparator: 2
  Participants will receive placebo for 60 weeks.
  Intervention: Drug: Placebo

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 19, 2014): 264
• Original Estimated Enrollment (submitted: March 28, 2008): 390
• Actual Study Completion Date: January 2014
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 35 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00650091
• Other Study ID Numbers: Pro00020066; U10HL080413-03 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Duke University
• Original Responsible Party: Kevin J. Anstrom, Principal Investigator, DCC, Duke Clinical Research Institute
• Current Study Sponsor: Duke University
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: Marvin I Schwarz, MD; University of Colorado, Denver
• Principal Investigator: Kevin Brown, MD; National Jewish Health
• Principal Investigator: Rob Kaner, MD; Weill Medical College at Cornell University
• Principal Investigator: Talmadge King, MD; University of California, San Francisco
• Principal Investigator: Joe Lasky, MD; Tulane University
• Principal Investigator: James Loyd, MD; Vanderbilt University
• Principal Investigator: Fernando Martinez, MD; University of Michigan
• Principal Investigator: Imre Noth, MD; University of Chicago
• Principal Investigator: Ganesh Raghu, MD; University of Washington
• Principal Investigator: Jesse Roman, MD; Emory University
• Principal Investigator: Jay Ryu, MD; Mayo Clinic
• Principal Investigator: John Belperio, MD; University of California, Los Angeles
• Principal Investigator: Kevin Anstrom, PhD; Duke University
• Study Director: Gail Weinmann, MD; National Heart, Lung, and Blood Institute (NHLBI)
• Principal Investigator: Jeffrey Chapman, MD; The Cleveland Clinic
• Principal Investigator: Lake Morrison, MD; Duke University
• Principal Investigator: Michael Kallay, MD; Highland Hospital
• Principal Investigator: Steven Sahn, MD; Medical University of South Carolina
• Principal Investigator: Marilyn Glassberg, MD; University of Miami
• Principal Investigator: Milton Rossman, MD; University of Pennsylvania
• Principal Investigator: John Fitzgerald, MD; University of Texas
• Principal Investigator: Mary Beth Scholand, MD; University of Utah
• Principal Investigator: Neil Ettinger, MD; St. Luke's Hospital
• Principal Investigator: Danielle Antin-Ozerkis, MD; Yale University
• Principal Investigator: Joao deAndrade, MD; University of Alabama at Birmingham
• Principal Investigator: Ivan Rosas, MD; Brigham and Women's
• Principal Investigator: Joseph Zibrak, MD; Beth Isreal-Deaconess
• Principal Investigator: Gerald Criner, MD; Temple University
• Principal Investigator: Maria Padilla, MD; MOUNT SINAI HOSPITAL

• PRS Account: Duke University
• Verification Date: February 2015