? ? The idiopathic interstitial pneumonias (IIP) represent a group of acute and chronic diffuse parenchymal lung diseases of unknown etiology. Idiopathic pulmonary fibrosis (IPF) is the most deadly and common type of IIP. As our understanding IPF evolves, it is evident that IPF is a heterogeneous disease. We previously demonstrated that multiple histopathologic patterns of IIP often exist within the same patient. Similarly, the same patient may exhibit areas of both inflammation and fibrosis, depending on the area of lung examined. ? ? There is no cure for IPF. The current recommended treatment regimen is anti-inflammatory and combines a cytotoxic agent (such as azathioprine or cyclophosphamide) with prednisone (American Thoracic Society, 2000). Although some patients seem to respond or stabilize, there are few rigorous data clearly elucidating the efficacy and safety of this regimen for patients diagnosed with IPF using current diagnostic guidelines. It is plausible that the failure of current therapeutic approaches reflects the lack of a simultaneous, multi-faceted assault against multiple biologically plausible targets involved in the pathogenesis of IPF. We hypothesize that novel therapies engineered to exploit specific pathophysiologic features of IPF will prove to have the greatest therapeutic success. With these concepts in mind, we propose two novel therapeutic trials for previously untreated patients with IPF. ? ? IPF is characterized by the overproduction of pro-fibrotic leukotrienes and underproduction of anti-inflammatory PGE2. Our first protocol compares the combination of two agents selected to correct this imbalance: zileuton plus N-acetyl cysteine versus standard therapy with azathioprine plus prednisone. IPF is also characterized by increased expression of the profibrotic cytokine IL-13 receptor compared to other types of IIP. Our second protocol advantages this observation by utilizing an aerosolized fusion protein comprised of human IL-13 and a mutated form of Pseudomonas exotoxin. Internalization of this fusion protein results in cellular apoptosis. Both trials are randomized, double-blind, placebo-controlled trials. The primary endpoint in each trial is a combination of death or decline in FVC of >10%. Secondary endpoints include safety, changes in pulmonary function, quality of life, dyspnea, six-minute walk distance, change in saturation during a six-minute walk test, and respiratory hospitalizations. These protocols will define the role of standard therapy, test the efficacy of targeted combination therapy, and explore the promise of a novel approach to the design and delivery of therapeutic agents for IPF. (End of Abstract) ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
5U10HL080371-02
Application #
7060026
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F1))
Program Officer
Reynolds, Herbert Y
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$289,978
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Salisbury, Margaret L; Lynch, David A; van Beek, Edwin J R et al. (2017) Idiopathic Pulmonary Fibrosis: The Association between the Adaptive Multiple Features Method and Fibrosis Outcomes. Am J Respir Crit Care Med 195:921-929
Andrade, Joao de; Schwarz, Marvin; Collard, Harold R et al. (2015) The Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet): diagnostic and adjudication processes. Chest 148:1034-1042
Durheim, Michael T; Collard, Harold R; Roberts, Rhonda S et al. (2015) 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 3:388-96
Idiopathic Pulmonary Fibrosis Clinical Research Network; Martinez, Fernando J; de Andrade, Joao A et al. (2014) Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 370:2093-101
Swigris, Jeffrey J; Streiner, David L; Brown, Kevin K et al. (2014) Assessing exertional dyspnea in patients with idiopathic pulmonary fibrosis. Respir Med 108:181-8
Collard, Harold R; Brown, Kevin K; Martinez, Fernando J et al. (2014) Study design implications of death and hospitalization as end points in idiopathic pulmonary fibrosis. Chest 146:1256-1262
Han, MeiLan K; Bach, David S; Hagan, Peter G et al. (2013) Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 143:1699-1708
Idiopathic Pulmonary Fibrosis Clinical Research Network; Raghu, Ganesh; Anstrom, Kevin J et al. (2012) Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 366:1968-77
Noth, Imre; Anstrom, Kevin J; Calvert, Sara Bristol et al. (2012) A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 186:88-95
Swigris, Jeffrey J; Han, Meilan; Vij, Rekha et al. (2012) The UCSD shortness of breath questionnaire has longitudinal construct validity in idiopathic pulmonary fibrosis. Respir Med 106:1447-55

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