Idiopathic pulmonary fibrosis (IPF), the most common idiopathic interstitial pneumonia, is characterized by progressive fibrosis leading to increased disability and death. There is no cure for IPF. Mortality is the most important and easily definable endpoint for clinical trials of novel therapeutic agents. Unfortunately the size, duration, and cost of mortality-powered trials are prohibitive. This fact has led investigators to actively pursue identification of easily-measurable surrogate endpoints that predict future mortality. We demonstrated that six and 12 month decline in forced vital capacity (FVC) is associated with an increased risk of subsequent mortality. Unfortunately decline in physiology is unable to correctly predict mortality in all patients as many patients die acutely prior to demonstrating a decline in FVC while others can survive for extended periods of time despite large losses of lung function. These data highlight the need for novel surrogate endpoints that can be used to efficiently evaluate therapeutic agents for patients with IPF. High resolution computed tomography (HRCT) plays a pivotal role in the diagnosis of IPF. Baseline qualitative and semi- quantitative scoring of HRCT features consistently predicts long-term prognosis;longitudinal change has been studied less consistently. Difficulties in utilizing semi-quantitative HRCT scoring systems include physician time, inter-rater disagreement, and the rather large changes required to impact semi-quantitative scores. The Adaptive Multiple Feature Method (AMFM) is a computerized texture-based method for characterizing lung HRCT features. The overall hypothesis of this application is that the computer aided AMFM can be trained to recognize 3D features of IPF (honeycomb pattern, ground glass opacity). Furthermore, quantitative scoring by the AMFM will have better correlation with longitudinal change in forced vital capacity (FVC) &mortality compared to semi-quantitative methodology. This study will utilize cases from the Lung Tissue Research Consortium and the IPF network (IPFnet) to obtain a diverse group of patients with IPF for training the AMFM. Longitudinal aims will utilize the IPFnet's multi-center, randomized, double-blind placebo controlled trial of prednisone + azathioprine + N-acetylcysteine or N-acetylcysteine alone versus placebo in IPF patients (PANTHER study). PANTHER will enroll 130 patients, followed for 60 weeks, into each treatment arm beginning March, 2008. This application will provide a mechanism for obtaining longitudinal HRCT scans which are not part of the PANTHER protocol. This application will take advantage of the IPFnet to develop a HRCT database with baseline and longitudinal data. Through this award we will 1) test if computer aided analysis can recognize and quantify HRCT features of IPF 2) compare the agreement of semi- quantitative (radiologist) and quantitative (AMFM) measures of baseline and longitudinal changes in HRCT features 3) evaluate if longitudinal changes in HRCT can function as surrogate endpoints in clinical trials through correlations with changes in pulmonary function, quality of life, and mortality. Statement of Relevance: Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology characterized by progressive fibrosis of the lung parenchyma leading to increased disability and eventual death. The study of novel agents to impact this disease is critical to access for potential impact on quantity and quality of life. Unfortunately the size, duration, and cost of mortality-powered trials are prohibitive. This study will evaluate if computer aided analysis of longitudinal changes in high resolution computed tomography scans correlates with changes in physiology, quality of life, and survival in patients with IPF. If true, changes in high resolution computed tomography could serve as a non-invasive surrogate endpoint in the study of novel agents to treat this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091743-04
Application #
8117529
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Eu, Jerry Pc
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$384,431
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
Sheth, Jamie S; Belperio, John A; Fishbein, Michael C et al. (2017) Utility of Transbronchial vs Surgical Lung Biopsy in the Diagnosis of Suspected Fibrotic Interstitial Lung Disease. Chest 151:389-399
Callahan, Sean J; Xia, Meng; Murray, Susan et al. (2016) Clinical characteristics in patients with asymmetric idiopathic pulmonary fibrosis. Respir Med 119:96-101
Suissa, Samy; Ernst, Pierre (2015) The INPULSIS enigma: exacerbations in idiopathic pulmonary fibrosis. Thorax 70:508-10
Flaherty, Kevin R; Khanna, Dinesh (2014) Idiopathic or connective tissue disease-associated interstitial lung disease: a case of HRCT mimicry. Thorax 69:205-6
Schmidt, S L; Nambiar, A M; Tayob, N et al. (2011) Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema. Eur Respir J 38:176-83
Fell, Charlene D; Martinez, Fernando J; Liu, Lyrica X et al. (2010) Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 181:832-7