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

Primary Purpose

Pulmonary Fibrosis

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
N-acetylcysteine (NAC)
Placebo
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Fibrosis focused on measuring Idiopathic Pulmonary Fibrosis, Prednisone, Azathioprine, NAC, N-acetylcysteine

Eligibility Criteria

35 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama - Birmingham
  • University of California - Los Angeles
  • University of California - San Francisco
  • National Jewish Medical and Research Center
  • Yale University School of Medicine
  • University of Miami Miller School of Medicine
  • University of Chicago
  • University of Louisville
  • Tulane University
  • Brigham and Women's Hospital
  • Beth Israel Deaconess Medical Center
  • University of Michigan
  • Mayo Clinic
  • St. Luke's Hospital
  • Weill Medical College of Cornell University
  • Mount Sinai Hospital
  • Highland Hospital - University of Rochester Medical Center
  • Duke Universtiy
  • Cleveland Clinic
  • University of Pennsylvania Health System
  • Temple University
  • Medical University of South Carolina
  • Vanderbilt University
  • University of Texas Southwestern Medical Center
  • University of Utah Health Research Center
  • University of Washington

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

1

2

Arm Description

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

Participants will receive placebo for 60 weeks.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Disease Progression
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
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
Number of Participants With Maintained Forced Vital Capacity Response
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.

Full Information

First Posted
March 28, 2008
Last Updated
May 27, 2015
Sponsor
Duke University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00650091
Brief Title
Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in Patients With IPF
Acronym
PANTHER-IPF
Official Title
Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in IPF
Study Type
Interventional

2. Study Status

Record Verification Date
February 2015
Overall Recruitment Status
Completed
Study Start Date
October 2009 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Fibrosis
Keywords
Idiopathic Pulmonary Fibrosis, Prednisone, Azathioprine, NAC, N-acetylcysteine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
264 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Participants will receive N-acetylcysteine (NAC) for 60 weeks.
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo for 60 weeks.
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine (NAC)
Intervention Description
Participants will receive 600 mg of NAC three times a day.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Participants will receive placebo each day.
Primary Outcome Measure Information:
Title
Overall Change in Forced Vital Capacity
Description
Change from Baseline in Forced Vital Capacity at 60 weeks (units in liters)
Time Frame
Measured as the estimated change from baseline to Week 60
Secondary Outcome Measure Information:
Title
Disease Progression
Description
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.
Time Frame
Measured at Week 60
Title
Acute Exacerbations
Description
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.
Time Frame
Measured at Week 60
Title
Respiratory Infections
Time Frame
Measured at Week 60
Title
Number of Participants With Maintained Forced Vital Capacity Response
Description
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.
Time Frame
Measured at Week 60

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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: Creatinine greater than twice the upper limit of normal (ULN) Hematology outside of specified limits White blood cells less than 3,500/mm3 Hematocrit less than 25% or greater than 59% Platelets less than 100,000 mm3 at the time of screening Any of the following liver function test criteria above specified limits Total bilirubin greater than twice the ULN Aspartate (AST) or alanine aminotransferases (ALT) greater than 1.5 the ULN Alkaline phosphatase greater than three times the ULN 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marvin I Schwarz, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Kevin Brown, MD
Organizational Affiliation
National Jewish Health
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Rob Kaner, MD
Organizational Affiliation
Weill Medical College at Cornell University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Talmadge King, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joe Lasky, MD
Organizational Affiliation
Tulane University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
James Loyd, MD
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fernando Martinez, MD
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Imre Noth, MD
Organizational Affiliation
University of Chicago
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ganesh Raghu, MD
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jesse Roman, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jay Ryu, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John Belperio, MD
Organizational Affiliation
University of California, Los Angeles
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kevin Anstrom, PhD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gail Weinmann, MD
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Jeffrey Chapman, MD
Organizational Affiliation
The Cleveland Clinic
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lake Morrison, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Michael Kallay, MD
Organizational Affiliation
Highland Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Steven Sahn, MD
Organizational Affiliation
Medical University of South Carolina
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marilyn Glassberg, MD
Organizational Affiliation
University of Miami
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Milton Rossman, MD
Organizational Affiliation
University of Pennsylvania
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John Fitzgerald, MD
Organizational Affiliation
University of Texas
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mary Beth Scholand, MD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Neil Ettinger, MD
Organizational Affiliation
St. Luke's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Danielle Antin-Ozerkis, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joao deAndrade, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ivan Rosas, MD
Organizational Affiliation
Brigham and Women's
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joseph Zibrak, MD
Organizational Affiliation
Beth Isreal-Deaconess
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gerald Criner, MD
Organizational Affiliation
Temple University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Maria Padilla, MD
Organizational Affiliation
MOUNT SINAI HOSPITAL
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama - Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
University of California - Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California - San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
National Jewish Medical and Research Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
Yale University School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
University of Miami Miller School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40425
Country
United States
Facility Name
Tulane University
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70118
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
St. Luke's Hospital
City
Chesterfield
State/Province
Missouri
ZIP/Postal Code
63107
Country
United States
Facility Name
Weill Medical College of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Mount Sinai Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Highland Hospital - University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14620
Country
United States
Facility Name
Duke Universtiy
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania Health System
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Temple University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
University of Utah Health Research Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98165
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
35688625
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.
Results Reference
derived
PubMed Identifier
26111071
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.
Results Reference
derived
PubMed Identifier
25890798
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.
Results Reference
derived
PubMed Identifier
24836309
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.
Results Reference
derived
PubMed Identifier
22607134
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.
Results Reference
derived
Links:
URL
http://www.nlm.nih.gov/databases/alerts/2011_nhlbi_ifp.html
Description
Clinical Alert: Commonly used three-drug regimen for idiopathic pulmonary fibrosis found harmful

Learn more about this trial

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

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