Effects of Roflumilast in Hospitalized COPD on Mortality and Re-hospitalization

Background :Chronic obstructive pulmonary disease (COPD) afflicts 24 million US residents and is the 3th leading cause of death in the United States. Each year, 150,000 patients die from COPD in the U.S. or about one patient every 4 minutes. Health care costs for COPD patients in the US is approximately $6.5 billion/ year, but its indirect costs probably double the costs of care when taking into account lost productivity and caretaker expenses. COPD exacerbations add considerably to that burden because they: (1) cause frequent hospital admissions and relapses or readmissions, (2) contribute directly to the death of many patients, either during hospitalization or shortly thereafter, (3) cause patients significant stress, prolonged physical discomfort, disability and dramatically reduced quality of life, (4) consume the majority of the resources available to manage this chronic condition, (5) frequently progress to a severe stage warranting hospitalization before any abortive treatment is instituted, and (6) may hasten the progressive loss of lung function, a steady decline that is a cardinal feature of COPD itself.

Hospitalized exacerbations result in a profound impact on patient survival, function, symptoms and health status as well as costs. Re-hospitalization in COPD is frequent and associated with a particularly negative impact. Patients discharged from the hospital after a COPD exacerbation have a high mortality and are frequently readmitted with recurrent exacerbations. Although a number of pharmacologic and behavioral interventions have been used to decrease exacerbations in COPD, it is not clear that these same interventions are successful in reducing hospital admission rates or re-admission rates. Except for the use of noninvasive ventilation in patients that present in acute respiratory failure during COPD hospitalization, no new therapies have been discovered in the last 3 decades.

A. Specific Aims: In this pilot proposal, we will test the feasibility of roflumilast to decrease all cause readmission and mortality 180 days after hospitalization for acute COPD exacerbation. We propose to conduct this study in 100 patients at three centers to assess the tolerance and treatment effect of roflumilast in order to power an appropriate definitive phase III multicenter trial.

B. Study Design and Synopsis: Parallel-group, prospective, randomized, double blind, placebo-controlled trial of roflumilast 500 ug daily vs. placebo in approximately 100 hospitalized AECOPD patients. Both groups will receive GOLD guideline-recommended care.

Patients hospitalized with AECOPD will be eligible for enrollment ≤ 12 hours after admission. Demographics, blood tests, health related quality of life, comorbidity (Deyo-Charlson index), post bronchodilator spirometry, vital signs, dyspnea measured by MMRC, SaO2 and amount of inspired O2 to maintain SaO2> 90% at rest, serum fibrinogen levels, HBA1c, Biomarkers and Genetics will be obtained after enrollment and then patients will be randomized to standard AECOPD care plus roflumilast 500 ug daily vs. placebo. Patients will begin roflumilast or placebo < 12 hours of hospitalization for a total period of 180 days post enrollment. On discharge day (approximately day 3-4 after admission based on the recent COPD CRN zileuton study of hospitalized AECOPD), the measurements will be repeated as indicated (baseline measurements), with follow-up phone assessments at days 7, 30, 60, 90, 120 and 194 days post enrollment. An in-person clinical visit will be conducted at days 14 and 180 post randomization.