? ? Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which current therapies have failed. Preventing alveolar epithelial cell (AEC) injury and myofibroblast (MF) activation/survival in distal airways may slow progression of fibrosis and enhance survival. Recent evidence from in vitro studies, in vivo models of pulmonary fibrosis, and previous clinical trials indicate that agents that block either growth factor production or fibroblast survival may attenuate fibrosis. Pirfenidone and interferon-gamma (IFN-?) may down-regulate both AEC apoptosis and fibroblast survival, HMGCoA reductase inhibitors (lovastatin) down-regulate fibroblast survival and 5-lipoxygenase activating protein (FLAP) inhibitors (MK-0591) down-regulate fibroblast-generated extracellular matrix production. We hypothesize that these agents have the potential to improve survival and slow disease progression in patients with IPF. To address this, we propose the following specific aims: ? ? Specific Aim 1: Determine if down-regulating growth factor production in distal airways via treatment with the combination of pirfenidone and IFN-?-lb improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than pirfenidone agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of pirfenidone and IFN?-1b compared with pirfenidone alone or placebo in a large cohort of patients with IPF. ? ? Specific Aim 2: Determine if down-regulating fibroblast survival and matrix protein production with the combination of lovastatin and MK-0591 improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than either agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of lovastatin and MK-0591 compared with either agent alone or placebo in a large cohort of patients with IPF. These clinical trials will establish whether agents that modulate interactions between AECs and fibroblasts, and thus reduce fibrosis and sequential damage in distal airways, can reduce mortality and slow disease progression in 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 #
5U10HL080513-02
Application #
7060342
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
$191,699
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Huang, Yong; Ma, Shwu-Fan; Vij, Rekha et al. (2015) A functional genomic model for predicting prognosis in idiopathic pulmonary fibrosis. BMC Pulm Med 15:147
Oldham, Justin M; Ma, Shwu-Fan; Martinez, Fernando J et al. (2015) TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 192:1475-82
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
Noth, Imre; Zhang, Yingze; Ma, Shwu-Fan et al. (2013) Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med 1:309-317
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
Herazo-Maya, Jose D; Noth, Imre; Duncan, Steven R et al. (2013) Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 5:205ra136

Showing the most recent 10 out of 18 publications