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Feasibility of Retinoids for the Treatment of Emphysema Study^*

Michael D. Roth, MD, FCCP; John E. Connett, PhD; Jeanine M. D’Armiento, MD, PhD; Robert F. Foronjy, MD; Paul J. Friedman, MD; Jonathan G. Goldin, MbChb, PhD; Thomas A. Louis, PhD; Jenny T. Mao, MD, FCCP; Josephia R. Muindi, MD, PhD; George T. O’Connor, MD, FCCP; Joe W. Ramsdell, MD, FCCP; Andrew L. Ries, MD, FCCP; Steven M. Scharf, MD, PhD; Neil W. Schluger, MD; Frank C. Sciurba, MD, FCCP; Melissa A. Skeans, MS; Robert E. Walter, MD; Christine H. Wendt, MD; Robert A. Wise, MD; for the FORTE Study Investigators

^* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Roth and Mao) and Radiology (Dr. Goldin), University of California, Los Angeles, CA; Boston University (Drs. O’Connor and Walter), Boston, MA; Columbia University (Drs. D’Armiento, Foronjy, and Schluger), New York, NY; Johns Hopkins University (Drs. Louis and Wise), Baltimore, MD; Roswell Park Cancer Institute (Dr. Muindi), Buffalo, NY; University of California, San Diego (Drs. Friedman, Ramsdell, and Ries), San Diego, CA; University of Maryland (Dr. Scharf), Baltimore, MD; University of Pittsburgh (Dr. Sciurba), Pittsburgh, PA; and the Divisions of Pulmonary and Critical Care Medicine (Dr. Wendt) and Biostatistics/CCBR (Ms. Skeans and Dr. Connett), University of Minnesota, Twin Cities, MN. For a list of FORTE investigators see ^Appendix.

Correspondence to: Michael D. Roth, MD, FCCP; Division of Pulmonary and Critical Care; Department of Medicine, CHS 37–131; David Geffen School of Medicine at UCLA; Los Angeles, CA 90095-1690; e-mail: mroth{at}mednet.ucle.edu

Abstract

Background: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema.

Methods: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (DLCO) [37.1 ± 12.0% of predicted] and CT density mask (38.5 ± 12.8% of voxels <– 910 Hounsfield units) [mean ± SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period.

Results: No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in DLCO (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild.

Conclusions: No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in DLCO, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.

Key Words: clinical trial • CT scan • emphysema • health-related quality of life • pulmonary function test • radiograph • retinoic acid