Drugs 2008; 68 Suppl. 2: 3-57 REVIEW ARTICLE 0012-6667/08/0002-0003/$53.45/0 © 2008 Adis Data Information BV. All rights reserved. The Efficacy and Safety of Cilomilast in COPD Stephen Rennard,1 Katharine Knobil,2 Klaus F. Rabe,3 Andrea Morris,2 Neil Schachter,4 Nicholas Locantore,2 Walter G. Canonica,5 Yuanjue Zhu6 and Frank Barnhart2 1 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA 2 GlaxoSmithKline, Research Triangle Park, North Carolina, USA 3 Leiden University Medical Centre, Leiden, the Netherlands 4 Mount Sinai School of Medicine, New York City, New York, USA 5 Medical University of Genoa, Genoa, Italy 6 Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China Contents Abstract ..................................................................................... 5 1. Introduction .............................................................................. 6 1.1 Chronic Obstructive Pulmonary Disease (COPD) ......................................... 6 1.2 Potential Shortcomings of Pharmacotherapy in COPD .................................... 6 1.3 Phosphodiesterase Inhibitors ........................................................... 7 1.4 Clinical Studies with Cilomilast .......................................................... 8 2. Evidence of Anti-Inflammatory Activity of Cilomilast in Induced Sputum and Bronchial Biopsies from COPD Patients ....................................................................... 8 2.1 Study Objectives ...................................................................... 8 2.2 Methods ............................................................................. 9 2.2.1 Patients ........................................................................ 9 2.2.2 Study Design ................................................................... 9 2.2.3 Statistical Methods ..............................................................11 2.3 Results ...............................................................................11 2.3.1 Study Population ................................................................11 2.3.2 Primary Efficacy Measures .......................................................11 2.3.3 Secondary Efficacy Endpoints ....................................................12 2.4 Safety Results .........................................................................13 2.4.1 Adverse Events .................................................................13 2.4.2 Adverse Events Leading to Withdrawal ............................................14 2.4.3 Other Safety Assessments ........................................................14 2.5 Summary .............................................................................15 3. Efficacy and Safety of Cilomilast in the Pivotal Phase III Studies ................................17 3.1 Study Objectives ......................................................................17 3.2 Materials and Methods ................................................................17 3.2.1 Study Design ...................................................................17 3.2.2 Patients ........................................................................17 3.2.3 Study Procedures ...............................................................18 3.2.4 Statistical Analysis ...............................................................19 3.2.5 Sample Sizes ....................................................................20 3.3 Results ...............................................................................20 3.3.1 Patient Disposition ...............................................................20 3.3.2 Baseline Characteristics ..........................................................21 4 Rennard et al. 3.3.3 Primary Efficacy Endpoints .......................................................22 3.3.4 Secondary Endpoints ............................................................22 3.4 Safety and Tolerability .................................................................24 3.5 Summary .............................................................................25 4. Long-Term Tolerability and Safety of Cilomilast in Patients with COPD ...........................26 4.1 Study Objectives ......................................................................26 4.2 Materials and Methods ................................................................26 4.2.1 Study Design ...................................................................26 4.2.2 Assessments ....................................................................27 4.2.3 Statistical Analysis ...............................................................28 4.3 Results ...............................................................................28 4.3.1 Baseline Characteristics; Studies 040 and 041 ......................................28 4.3.2 Baseline Characteristics; Study 157 ................................................29 4.4 Safety and Tolerability Measurements ...................................................29 4.4.1 Adverse Events .................................................................29 4.4.2 Deaths .........................................................................30 4.4.3 Withdrawals ....................................................................30 4.4.4 Laboratory Safety and Vital Signs .................................................31 4.5 Efficacy Evaluations ...................................................................31 4.5.1 COPD Exacerbations ............................................................31 4.5.2 Lung Function ..................................................................32 4.6 Summary .............................................................................32 5. Cardiovascular Safety and Tolerability of Cilomilast ...........................................33 5.1 Study Objective ......................................................................33 5.2 Methods .............................................................................33 5.2.1 Patients ........................................................................33 5.2.2 Study Design ...................................................................34 5.2.3 Statistical Methods ..............................................................34 5.3 Results ...............................................................................35 5.3.1 Study Population ................................................................35 5.3.2 Holter Monitoring ................................................................36 5.3.3 Electrocardiograms .............................................................36 5.4 Other Safety Results ...................................................................37 5.5 Efficacy Results .......................................................................38 5.6 Summary .............................................................................38 6. Effect of Cilomilast on Hyperinflation ........................................................40 6.1 Study Objectives ......................................................................40 6.2 Methods .............................................................................41 6.2.1 Patients ........................................................................41 6.2.2 Study Design ...................................................................41 6.2.3 Statistical Methods ..............................................................42 6.3 Results ...............................................................................42 6.3.1 Study Population ................................................................42 6.3.2 Primary Efficacy Measures of Hyperinflation ........................................43 6.3.3 Secondary Efficacy Endpoints ....................................................43 6.4 Safety Results .........................................................................44 6.4.1 Adverse Events .................................................................44 6.4.2 Other Safety Assessments ........................................................45 6.5 Summary .............................................................................45 7. Efficacy and Safety of Cilomilast in Chinese Patients with COPD ...............................46 7.1 Study Objective ......................................................................46 7.2 Materials and Methods ................................................................46 7.2.1 Study Design ...................................................................46 7.2.2 Patients ........................................................................46 7.2.3 Study Procedures ...............................................................47 © 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 Suppl. 2 Efficacy and Safety of Cilomilast in COPD 5 7.2.4 Statistical Analysis ...............................................................47 7.3 Results ...............................................................................47 7.3.1 Patient Disposition ...............................................................47 7.3.2 Baseline Characteristics ..........................................................47 7.3.3 Primary Efficacy Endpoint; Trough FEV1 ............................................48 7.3.4 Secondary Endpoints ............................................................48 7.4 Safety and