Roflumilast with long-acting &bgr;2-agonists for COPD: influence of exacerbation history Use of a 4-week up-titration regimen of roflumilast in patients with severe COPD Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? the REACT study protocol Roflumilast in Asian patients with COPD: A randomized placebo-controlled trial. Physiological effects of roflumilast at rest and during exercise in COPD Efficacy and Safety of Roflumilast in Korean Patients with COPD Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast Defining the “Frequent Exacerbator” Phenotype in COPD: A Hypothesis‐Free Approach Roflumilast for the treatment of COPD in an Asian population: a randomized, double-blind, parallel-group study. Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Effects of roflumilast in COPD patients receiving inhaled corticosteroid/long-acting β2-agonist fixed-dose combination: RE2SPOND rationale and study design A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials A 1-Year Prospective Cost-Effectiveness Analysis of Roflumilast for the Treatment of Patients with Severe Chronic Obstructive Pulmonary Disease Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease? Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial.
The oral , selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy and safety of roflumilast used concomitantly with long-acting & bgr;2-agonists ( LABAs ) to reduce exacerbations , and the influence of exacerbation history . Pooled data were analysed from two 12-month , placebo-controlled roflumilast ( 500 μg once daily ) studies involving 3,091 patients with severe-to-very severe COPD . Approximately half of patients used concomitant LABAs ; 39 % used concomitant short-acting muscarinic antagonists ( SAMAs ) ; 27 % were frequent exacerbators ( two or more exacerbations per year ) . Roflumilast  reduced the rate of moderate or severe exacerbations , with LABA ( rate ratio ( RR ) 0.79 , 95 % CI 0.69–0.91 ; p=0.001 ) or without LABA ( RR 0.85 , 95 % CI 0.74–0.99 ; p=0.039 ) and prolonged time both to first ( p=0.035 with LABA , p=0.300 without LABA ) and second ( p=0.018 with LABA , p=0.049 without LABA ) exacerbations . Frequent exacerbators experienced a reduction in moderate or severe exacerbations ( RR 0.78 , 95 % CI 0.66–0.91 ; p=0.002 ) . Similarly , roflumilast remained effective with concomitant SAMA . No differences arose in adverse events between these subgroups . Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function , without increasing adverse events in COPD patients receiving concomitant LABAs Background The oral selective phosphodiesterase-4 inhibitor roflumilast ( ROF ) reduces exacerbations in patients with severe COPD . Adverse events ( AEs ) can cause early ROF discontinuation . Alternative dosing strategies may help patients continue their therapy . Methods In this multicenter , double-blind trial , 1,321 patients with severe COPD were r and omized 1:1:1 to 4 weeks ’ treatment with ROF 250 µg once daily ( OD ) , 500 µg every other day ( EOD ) , or 500 µg OD , each followed by ROF 500 µg OD for 8 weeks , plus st and ard therapy . The primary end point was the percentage of patients prematurely discontinuing study treatment . Results Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations ( odds ratio [ OR ] 0.66 [ 95 % CI 0.47–0.93 ] , p=0.017 ) and lower rates of AEs of interest such as diarrhea , nausea , headache , decreased appetite , insomnia and abdominal pain ( OR 0.63 [ 95 % CI 0.47–0.83 ] , p=0.001 ) compared with those in the 500 µg OD group . Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD , the difference was not significant ( OR 0.76 , p=0.114 , and OR 0.78 , p=0.091 , respectively ) compared with ROF 500 µg OD . Conclusion A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD result ed in reduced treatment discontinuation and improved tolerability Cilomilast ( Ariflo ) , a new oral phosphodiesterase-4 selective inhibitor , improves lung function in chronic obstructive pulmonary disease ( COPD ) . We have evaluated its antiinflammatory effects in 59 patients with COPD r and omized to receive cilomilast , 15 mg two times a day , or placebo for 12 weeks . Induced sputum differential cell counts were obtained at baseline and at five further visits . Interleukin-8 and neutrophil elastase were measured in sputum supernatant . Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils , CD8 + and CD4 + T-lymphocyte subsets , and CD68 + macrophages . Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified . Compared with placebo , analysis of variance ( ANOVA ) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1 . However , bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8 + ( p = 0.001 ; ANOVA ) and CD68 + cells ( p < 0.05 ; ANOVA ) . In addition , by Poisson analysis , comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8 + ( 48 % p < 0.01 ) and CD68 + ( 47 % p = 0.001 ) cells . This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD . Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease Background Many patients with chronic obstructive pulmonary disease ( COPD ) continue to suffer exacerbations , even when treated with maximum recommended therapy ( eg , inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids , with or without a long-acting anticholinergic [ long-acting muscarinic antagonist ] ) . Roflumilast is approved to treat severe COPD in patients with chronic bronchitis – and a history of frequent exacerbations – as an add-on to bronchodilators . Purpose The REACT ( Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment ) study ( identification number RO-2455 - 404-RD , clinical trials . gov identifier NCT01329029 ) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations . Patients and methods REACT is a 1-year r and omized , double-blind , multicenter , phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination . A concomitant long-acting muscarinic antagonist will be allowed at stable doses . The primary outcome is the rate of moderate or severe COPD exacerbations . Using a Poisson regression model with a two-sided significance level of 5 % , a sample size of 967 patients per treatment group is needed for 90 % power . COPD patients with severe to very severe airflow limitation , symptoms of chronic bronchitis , and at least two exacerbations in the previous year will be recruited . Conclusion It is hypothesized that because roflumilast ( a phosphodiesterase-4 inhibitor ) has a different mode of action to bronchodilators and inhaled corticosteroids , it may provide additional benefits when added to these treatments in frequent exacerbators . REACT will be important to determine the role of roflumilast in COPD management . Here , the design and rationale for this important study is described BACKGROUND AND OBJECTIVE Roflumilast , an oral , selective phosphodiesterase 4 inhibitor , has been shown to reduce exacerbations and improve pulmonary function in patients with COPD . This study examined the efficacy , safety and tolerability of roflumilast in Asian patients with COPD . METHODS Patients with COPD were r and omized 1:1 to enter a 12-week treatment period and receive either oral roflumilast , 500 µg once daily , or placebo , following a single-blind , 4-week baseline period in which all patients received placebo . The primary end point was mean change in FEV₁ from baseline to each postr and omization visit during the treatment period . Other spirometric lung function measurements were evaluated as secondary end points . COPD exacerbations were monitored . Safety was assessed from clinical laboratory tests , vital signs , physical examination ( including electrocardiogram ) and monitoring of adverse events ( AEs ) . RESULTS Of 551 patients recruited , 410 were r and omized and received at least one dose of study medication ( roflumilast , n = 203 ; placebo , n = 207 ) . Superiority of roflumilast over placebo was demonstrated by a statistically significant difference in postbronchodilator FEV₁ ( 79 mL , P < 0.0001 ) . Other spirometry end points , including prebronchodilator FEV₁ , pre- and postbronchodilator FEV₆ , forced vital capacity and peak expiratory flow significantly favoured roflumilast over placebo . AEs were more common with roflumilast than with placebo , but were comparable with those reported in previous studies . CONCLUSIONS Roflumilast , 500 µg once daily , improves pulmonary function in Asian patients with COPD .  The safety and tolerability of roflumilast in this population was similar to that in a Caucasian population The purpose of this study was to investigate the effects of 500 & mgr;g roflumilast , taken once daily for 12 weeks , on airway physiology during rest and exercise in patients with moderate-to-severe chronic obstructive pulmonary disease . This r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 250 patients with a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of 30–80 % predicted and a functional residual capacity of ≥120 % pred .  Pre- and post-bronchodilator spirometry and body plethysmography , and pre-bronchodilator constant work rate cycle exercise at 75 % of peak work rate were evaluated . Exercise measurements included ventilation , breathing pattern , inspiratory capacity ( IC ) and arterial oxygen saturation measured by pulse oximetry ( Sp , O2 ) . Compared with placebo , 12 weeks of treatment with roflumilast was associated with : small but progressive increases in pre- and post-bronchodilator FEV1 and FEV1/forced vital capacity ; small decreases in specific airway resistance ; and no significant changes in resting vital capacity , IC or measurements of lung hyperinflation . There was no treatment effect on exercise endurance time . At a st and ardised exercise time after roflumilast , compared with  placebo , IC increased by 0.12 L ( p=0.008 ) and Sp , O2 increased by 0.7 % ( p=0.020 ) ; peak ventilation increased by 1.9 L·min−1 ( p=0.014 ) . Roflumilast treatment was associated with progressive improvement of airway function but not lung hyperinflation . Newly described non-bronchodilator effects of roflumilast included small but consistent improvements in air trapping and Sp , O2 during exercise Purpose Roflumilast is the only oral phosphodiesterase 4 inhibitor approved to treat chronic obstructive pulmonary disease ( COPD ) patients [ post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted ] with chronic bronchitis and a history of frequent exacerbations . This study evaluated the efficacy and safety of roflumilast in Korean patients with COPD and compared the efficacy based on the severity of airflow limitation . Material s and Methods A post-hoc subgroup analysis was performed in Korean COPD patients participating in JADE , a 12-week , double-blinded , placebo-controlled , parallel-group , phase III trial in Asia . The primary efficacy endpoint was the mean [ least-squares mean adjusted for covariates ( LSMean ) ] change in post-bronchodilator FEV1 from baseline to each post-r and omization visit . Safety endpoints included adverse events ( AEs ) and changes in laboratory values , vital signs , and electrocardiograms . Results A total of 260 Korean COPD patients were recruited , of which 207 were r and omized to roflumilast ( n=102 ) or placebo ( n=105 ) treatment . After 12 weeks , LSMean post-bronchodilator FEV1 increased by 43 mL for patients receiving roflumilast and decreased by 60 mL for those taking placebo .  Adverse events were more common in the roflumilast group than in the placebo group ; however , the types and frequency of AEs were comparable to those reported in previous studies . Conclusion Roflumilast significantly improved lung function with a tolerable safety profile in Korean COPD patients irrespective of the severity of airflow limitation Background Chronic obstructive pulmonary disease ( COPD ) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators , but above all , CD8 + T-lymphocytes , macrophages and neutrophils are important players in disease pathogenesis . Roflumilast , a first-in-class , potent and selective phosphodiesterase 4 ( PDE4 ) inhibitor , reduces the rate of exacerbations in patients with a high risk of future exacerbations and has been shown to reduce inflammatory cells and mediators in induced sputum , a surrogate of airway inflammation . However , these anti-inflammatory effects are yet to be confirmed in another robust study directly assessing inflammatory markers in bronchial sub-mucosa . Methods / Design An international , 16-week , r and omized , double-blind , placebo-controlled , parallel-group study investigating the effects of roflumilast 500 μg once-daily versus placebo on inflammatory parameters in bronchial biopsy tissue specimens , sputum and blood serum . One hundred and fifty patients with COPD and chronic bronchitis for at least 12 months will be recruited into the study and r and omized in a 1:1 ratio to receive either roflumilast or placebo . The primary endpoint will be the number of CD8 + cells ( cell counts per mm2 ) in bronchial biopsy tissue specimens ( sub-mucosa ) and the key secondary endpoint will be the number of CD68 + cells ( cell counts per mm2 ) , assessed by indirect immunohistochemistry . Discussion It is hypothesized that treatment with roflumilast reduces the characteristic inflammation found in the airways of patients with moderate-to-severe COPD , compared with placebo . The design of the present study has built on the work of previous bronchial biopsy studies available in the literature . It is hoped that it will reveal the cellular mechanisms underlying the anti-inflammatory effects of roflumilast and identify potentially important biomarkers and other surrogate endpoints in patients with COPD . The design and rationale for this trial are described herein . Trial registration Clinical trial identifier : NCT01509677 ( clinical trials.gov Background The COPD “ frequent exacerbator ” phenotype is usually defined by at least two treated exacerbations per year and is associated with a huge impact on patient health . However , existence of this phenotype and corresponding thresholds still need to be formally confirmed by statistical methods analyzing exacerbation profiles with no specific a priori hypothesis . The aim of this study was to confirm the existence of the frequent exacerbator phenotype with an innovative unbiased statistical analysis of prospect ively recorded exacerbations . Methods Data from patients with COPD from the French cohort in Exacerbations of COPD Patients ( EXACO ) were analyzed using the KmL method design ed to cluster longitudinal data and receiver operating characteristic ( ROC ) curve analysis to determine the best threshold to allocate patients to identified clusters . Univariate and multivariate analyses were performed to study characteristics associated with different clusters . Results Two clusters of patients were identified based on exacerbation frequency over time , with 2.89 exacerbations per year on average in the first cluster ( n = 348 ) and 0.71 on average in the second cluster ( n = 116 ) . The best threshold to distinguish these clusters was two moderate to severe exacerbations per year . Frequent exacerbators had more airflow limitation , symptoms , and health‐related quality of life impairment . A simple clinical score was derived to help identify patients at risk of exacerbations . Conclusions These analyses confirmed the existence and clinical relevance of a frequent exacerbator subgroup of patients with COPD and the currently used threshold to define this phenotype BACKGROUND Roflumilast is the only oral phosphodiesterase 4 inhibitor indicated for use in the treatment of COPD . Previous studies of roflumilast have predominantly involved European and North American population s. A large study was necessary to determine the efficacy and safety of roflumilast in a predominantly ethnic Chinese population . METHODS In a placebo-controlled , double-blind , parallel-group , multicenter , phase 3 study , patients of Chinese , Malay , and Indian ethnicity ( N = 626 ) with severe to very severe COPD were r and omized 1:1 to receive either roflumilast 500 μg once daily or placebo for 24 weeks . The primary end point was change in prebronchodilator FEV1 from baseline to study end . RESULTS Three hundred thirteen patients were assigned to each treatment . Roflumilast provided a sustained increase over placebo in mean prebronchodilator FEV1 ( 0.071 L ; 95 % CI , 0.046 , 0.095 L ; P < .0001 ) . Similar improvements were observed in the secondary end points of postbronchodilator FEV1 ( 0.068 L ; 95 % CI 0.044 , 0.092 L ; P < .0001 ) and prebronchodilator and postbronchodilator FVC ( 0.109 L ; 95 % CI , 0.061 , 0.157 L ; P < .0001 and 0.101 L ; 95 % CI , 0.055 , 0.146 L ; P < .0001 , respectively ) . The adverse event profile was consistent with previous roflumilast studies . The most frequently reported treatment-related adverse event was diarrhea ( 6.0 % and 1.0 % of patients in the roflumilast and placebo groups , respectively ) . CONCLUSIONS Roflumilast plays an important role in lung function improvement and is well tolerated in an Asian population . It provides an optimal treatment choice for patients with severe to very severe COPD BACKGROUND Inhibition of phosphodiesterase 4 ( PDE4 ) represents an approach to anti-inflammatory therapy in chronic obstructive pulmonary disease ( COPD ) .  GSK256066 is a potent and selective inhaled PDE4 inhibitor . The aim of this study was to investigate the safety and tolerability of 28 days repeat inhaled dosing with GSK256066 in moderate COPD . METHODS This was a Phase IIa , multicenter , parallel-group , double-blind , three-arm , placebo-controlled , four-week , r and omized study with two doses of GSK256066 ( 25 μg , 87.5 μg ) . The primary endpoint was safety and tolerability . Secondary endpoints included changes in inflammatory markers in induced sputum and blood , lung function ( spirometry , body plethysmography , impulse oscillometry ) , and pharmacokinetics . RESULTS 104 patients were r and omized and 94 patients completed the study . The incidence and intensity of treatment-related adverse events were similar between treatment groups . The most frequent adverse event was nasopharyngitis and there were no serious adverse events in patients receiving GSK256066 . The overall incidence of gastrointestinal adverse events was low in all treatment groups . There were no statistically significant changes in inflammatory markers in induced sputum and blood following treatment with GSK256066 . Analysis of sputum mRNA suggested engagement of pharmacology , based on increased expression of cAMP-dependent genes including amphiregulin and CREM in subjects receiving GSK256066 . There was a trend for an increase in post-bronchodilator FEV1 for both doses of GSK256066 ; in addition , for the 87.5 μg group , there was a mean reduction in residual volume of 0.367 L ( 95 % confidence interval : 0.112 , 0.622 L ) relative to placebo . CONCLUSIONS Administration of inhaled GSK256066 was well-tolerated in patients with moderate COPD . Further studies would be required to confirm the favorable safety profile and to demonstrate clinical efficacy of this compound . ( Clinical Trials.gov identifier : NCT00549679 ) BACKGROUND Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease . Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown . We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations , even in combination with inhaled corticosteroid and longacting β2 agonist treatment . METHODS For this 1-year double-blind , placebo-controlled , parallel group , multicentre , phase 3 - 4 trial , the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy ( REACT ) study , we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres ( outpatient clinics , hospitals , specialised pulmonologists , and family doctors ) in 21 countries . Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation , symptoms of chronic bronchitis , and at least two exacerbations in the previous year . We used a computerised central r and omisation system to r and omly assign patients in a 1:1 ratio to the two treatment groups : roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination . Background tiotropium treatment was allowed . All patients and investigators were masked to group assignment . The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year , analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT01329029 . FINDINGS Between April 3 , 2011 , and May 27 , 2014 , we enrolled 1945 eligible participants and r and omly assigned 973 to the roflumilast group and 972 to the placebo group . The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2 % lower in the roflumilast group than in the placebo group according to a Poisson regression analysis ( roflumilast 0·805 vs placebo 0·927 ; rate ratio [ RR ] 0·868 [ 95 % CI 0·753 - 1·002 ] , p=0·0529 ) , and 14·2 % lower according to a predefined sensitivity analysis using negative binomial regression ( 0·823 vs 0·959 ; 0·858 [ 0·740 - 0·995 ] , p=0·0424 ) . Adverse events were reported by 648 ( 67 % ) of 968 patients receiving roflumilast and by 572 ( 59 % ) of 967 patients in the placebo group ; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group ( 104/968 [ 11 % ] ) than in the placebo group ( 52/967 [ 5 % ] ) . The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia , and 17 ( 1·8 % ) deaths occurred in the roflumilast group compared with 18 ( 1·9 % ) in the placebo group . INTERPRETATION Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy , even in combination with tiotropium . FUNDING Takeda RATIONALE The oral phosphodiesterase-4 ( PDE4 ) inhibitor , roflumilast , can improve lung function in moderate chronic obstructive pulmonary disease ( COPD ) . Whether treatment is effective in more severe COPD ( GOLD [ Global Initiative for Chronic Obstructive Lung Disease ] stages III and IV ) over a longer period is unknown . OBJECTIVES To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD . METHODS We conducted a r and omized , placebo-controlled , double-blind , parallel-group trial for 1 year . We recruited 1,513 patients ( mean post-bronchodilator FEV1 41 % predicted ) , 760 receiving oral 500 microg roflumilast and 753 receiving placebo once daily . MEASUREMENTS AND MAIN RESULTS We recorded post-bronchodilator FEV1 , exacerbation rate , St. George 's Respiratory Question naire total score at the study end point , and number and type of reported adverse events during treatment . Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks ( p=0.001 ) . The mean exacerbation rate was low and comparable in both treatment groups ( 0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo , respectively ) . In a retrospective analysis , the exacerbation rate in patients in GOLD stage IV disease was 36 % lower in patients treated with roflumilast than in those treated with placebo ( 1.01 vs. 1.59 exacerbations/patient/year , respectively ; p=0.024 ) . The St. George 's Respiratory Question naire total score did not differ between treatments . The commonest adverse events related to roflumilast treatment were diarrhea , nausea , and headache , which usually subsided during continued treatment . However , roflumilast result ed in more withdrawals within the first 3 to 4 weeks of administration . CONCLUSIONS In severe , stable COPD , PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status . However , patients with very severe disease experienced fewer exacerbations with roflumilast Background Roflumilast , a once-daily , selective phosphodiesterase-4 inhibitor , reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations . The RE2SPOND study is examining whether roflumilast , when added to an inhaled corticosteroid/long-acting β2-agonist ( ICS/LABA ) fixed-dose combination ( FDC ) , further reduces exacerbations . The methodology is described herein . Methods In this Phase IV , multicenter , double-blind , placebo-controlled , parallel-group trial , participants were r and omized 1:1 ( stratified by long-acting muscarinic antagonist use ) to receive roflumilast or placebo , plus ICS/LABA FDC , for 52 weeks . Eligible participants had severe COPD associated with chronic bronchitis , had two or more moderate – severe exacerbations within 12 months , and were receiving ICS/LABA FDC for ≥3 months . The primary efficacy measure is the rate of moderate or severe COPD exacerbations per participant per year . The secondary efficacy outcomes include mean change in prebronchodilator forced expiratory volume in 1 second ( FEV1 ) over 52 weeks , rate of severe exacerbations , and rate of moderate , severe , or antibiotic-treated exacerbations . Additional assessment s include spirometry , rescue medication use , the COPD assessment test , daily symptoms using the EXACT-Respiratory symptoms ( E-RS ) question naire , all-cause and COPD -related hospitalizations , and safety and pharmacokinetic measures . Results Across 17 countries , 2,354 participants were r and omized from September 2011 to October 2014 . Enrollment goal was met in October 2014 , and study completion occurred in June 2016 . Conclusion This study will further characterize the effects of roflumilast added to ICS/LABA on exacerbation rates , lung function , and health of severe – very severe COPD participants at risk of further exacerbations . The results will determine the clinical benefits of roflumilast combined with st and ard-of-care inhaled COPD treatment RATIONALE Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease ( COPD ) . It has antiinflammatory effects ; however , it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression . The self-propagating acetyl-proline-glycine-proline ( AcPGP ) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD . AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation , respectively . OBJECTIVES We hypothesized that roflumilast would decrease AcPGP , halting the feed-forward cycle of inflammation . METHODS We conducted a single-center , placebo-controlled , r and omized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis . Subjects underwent sputum and blood analyses , pulmonary function testing , exercise tolerance , and quality -of-life assessment at 0 , 4 , and 12 weeks . MEASUREMENTS AND MAIN RESULTS Twenty-seven patients were enrolled in the intention-to-treat analysis .  Roflumilast treatment decreased sputum AcPGP by more than 50 % ( P < 0.01 ) and prolyl endopeptidase by 46 % ( P = 0.02 ) , without significant improvement in leukotriene A4 hydrolase activity compared with placebo . Roflumilast also reduces other inflammatory markers . There were no significant changes in lung function , quality of life , or exercise tolerance between roflumilast- and placebo-treated groups . CONCLUSIONS Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP . As expected for lower AcPGP levels , markers of neutrophilic inflammation are blunted . Inhibiting this self-propagating pathway lessens the overall inflammatory burden , which may alter the natural history of COPD , including the risk of exacerbation . Clinical trial registered with www . clinical trials.gov ( NCT 01572948 ) BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) have few options for treatment . The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD , but not in those concomitantly treated with longacting inhaled bronchodilators . The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium  was investigated . METHODS In two double-blind , multicentre studies done in an outpatient setting , after a 4-week run-in , patients older than 40 years with moderate-to-severe COPD were r and omly assigned to oral roflumilast 500 microg or placebo once a day for 24 weeks , in addition to salmeterol ( M2 - 127 study ) or tiotropium ( M2 - 128 study ) . The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) . Analysis was by intention to treat . The studies are registered with Clinical Trials.gov , number NCT00313209 for M2 - 127 , and NCT00424268 for M2 - 128 . FINDINGS In the salmeterol plus roflumilast trial , 466 patients were assigned to and treated with roflumilast and 467 with placebo ;  in the tiotropium plus roflumilast  trial , 371 patients were assigned to and treated with roflumilast  and 372 with  placebo .  Compared with placebo , roflumilast consistently improved mean prebronchodilator FEV(1 ) by 49 mL ( p<0.0001 ) in patients treated with salmeterol , and 80 mL ( p<0.0001 ) in those treated with tiotropium . Similar improvement in postbronchodilator FEV(1 ) was noted in both groups . Furthermore , roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups . Nausea , diarrhoea , weight loss , and , to a lesser extent , headache were more frequent in patients in the roflumilast groups . These adverse events were associated with increased patient withdrawal . INTERPRETATION Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium , and could become an important treatment for these patients . FUNDING Nycomed BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is characterised by progressive airflow limitation associated with chronic inflammation . There are few treatment options for the disease . This study assessed the efficacy and safety of roflumilast , a phosphodiesterase-4 inhibitor , in patients with moderate to severe COPD . METHODS This phase III , multicentre , double-blind , r and omised , placebo-controlled study was undertaken in an outpatient setting . 1411 patients with COPD were r and omly assigned roflumilast 250 microg ( n=576 ) , roflumilast 500 microg ( n=555 ) , or placebo ( n=280 ) given orally once daily for 24 weeks . Primary outcomes were postbronchodilator FEV1 and health-related quality of life . Secondary outcomes included other lung function parameters and COPD exacerbations . Analyses were by intention to treat . FINDINGS 1157 ( 82 % ) patients completed the study ; 32 ( 11 % ) withdrew from the placebo group , 100 ( 17 % ) from the roflumilast 250 microg group , and 124 ( 22 % ) from the roflumilast 500 microg group . Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 microg ( by 74 mL [ SD 18 ] ) and roflumilast 500 microg ( by 97 mL [ 18 ] ) compared with placebo ( p<0.0001 ) . Improvement in health-related quality of life was greater with roflumilast 250 microg ( -3.4 units [ 0.6 ] ) and roflumilast 500 microg ( -3.5 units [ 0.6 ] ) than with placebo ( -1.8 units [ 0.8 ] ) , although the differences between treatment groups were not significant . The mean numbers of exacerbations per patient were 1.13 ( 2.37 ) , 1.03 ( 2.33 ) , and 0.75 ( 1.89 ) with placebo , roflumilast 250 microg , and roflumilast 500 microg , respectively . Most adverse events were mild to moderate in intensity and resolved during the study . INTERPRETATION Roflumilast is a promising c and i date for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo . Long-term studies are needed to fully assess the effect on health-related quality of life BACKGROUND The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease ( COPD ) . We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD . METHODS In two placebo-controlled , double-blind , multicentre trials ( M2 - 124 and M2 - 125 ) with identical design that were done in two different population s in an outpatient setting , patients with COPD older than 40 years , with severe airflow limitation , bronchitic symptoms , and a history of exacerbations were r and omly assigned to oral roflumilast ( 500 microg once per day ) or placebo for 52 weeks . Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) and the rate of exacerbations that were moderate ( glucocorticosteroid-treated ) or severe . Analysis was by intention to treat . The trials are registered with Clinical Trials.gov , number NCT00297102 for M2 - 124 , and NCT00297115 for M2 - 125 . FINDINGS Patients were assigned to treatment , stratified according to smoking status and treatment with longacting beta(2 ) agonists , and given roflumilast  ( n=1537 ) or placebo ( n=1554 ) . In both studies , the prespecified primary endpoints were achieved and were similar in magnitude . In a pooled analysis , prebronchodilator FEV(1 ) increased by 48 mL with roflumilast compared with placebo ( p<0.0001 ) . The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo ( reduction 17 % [ 95 % CI 8 - 25 ] , p<0.0003 ) . Adverse events were more common with roflumilast ( 1040 [ 67 % ] ) than with placebo ( 963 [ 62 % ] ) ; 219 ( 14 % ) patients in the roflumilast group and 177 ( 12 % ) in the placebo group discontinued because of adverse events . In the pooled analysis , the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg . INTERPRETATION Since different subsets of patients exist within the broad spectrum of COPD , targeted specific therapies could improve disease management . This possibility should be explored further in prospect i ve studies . FUNDING Nycomed Abstract Rationale : Roflumilast is an oral , once-daily phosphodiesterase IV ( PDE4 ) inhibitor under investigation for chronic obstructive pulmonary disease ( COPD ) . This study investigated the cost effectiveness of roflumilast in patients with severe to very severe COPD from the perspective of the UK society and UK NHS . Methods : The analysis was conducted alongside a 1-year , r and omised , double-blind , placebo-controlled , multinational trial . The trial included 1514 COPD patients aged ≥40 years with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) % predicted = 50 % who were r and omised to receive either roflumilast 500μg once daily ( n = 761 ) or placebo ( n = 753 ) . Patients in both treatment groups were allowed to receive active treatment with a short-acting bronchodilator ( salbutamol or anticholinergic ) as needed . About 62 % of patients in both groups were using an inhaled corticosteroid at trial entry . They were allowed to continue this on a stable dosage . Direct healthcare and productivity costs were calculated . Re source utilisation was recorded at every scheduled visit in health economics case report forms ( HECRFs ) . Trial-wide re source use was combined with UK unit cost ( 2004 values ) . Roflumilast was assumed to cost € 1 per day . Incremental costs were related to the differences in the number of moderate to severe exacerbations and the net proportion of patients with an improvement of at least 4 units on the total score of the St George ’s Respiratory Question naire ( SGRQ ) . An intention-to-treat analysis was conducted . Costs and health outcomes that were missing after withdrawal of patients from the trial were imputed using multiple imputation with the propensity score method . Various sensitivity analyses were conducted to test the robustness of the data . Results : In the total group , annual COPD -related costs from a societal perspective were € 1637 in the roflumilast group and € 1401 in the placebo group . From an NHS perspective , this was € 1418 and € 1242 , respectively . The rate of moderate to severe COPD exacerbations per patient was low , and no statistically significant difference existed between roflumilast ( 0.96 ) and placebo ( 1.06 ) . The net proportion of patients with a relevant improvement on SGRQ total score was higher in the roflumilast group ( 0.19 ) than in the placebo group ( 0.14 ) , but the difference was not statistically significant . From a societal perspective , COPD -related costs were € 2356 per exacerbation avoided and € 4712 per net additional patient with a relevant improvement on the SGRQ . The probability that roflumilast was cost effective exceeded 70 % at a willingness to pay of € 5000 to avoid an exacerbation . In a subgroup of patients with very severe COPD ( n = 223 ) , the placebo group had a high exacerbation rate ( 1.7 per patient per year ) whereas roflumilast recipients showed 35 % fewer exacerbations ( 1.1 per patient per year ) . This result ed in roflumilast dominating placebo . In a subgroup of patients with high healthcare utilisation prior to the study ( n = 549 ) roflumilast recipients showed 19 % fewer exacerbations than those receiving placebo , which translated into an ICER of € 804 per exacerbation avoided . Conclusion : Roflumilast  increased the overall treatment costs of COPD , although the increase was partly offset by reductions in other forms of healthcare use . Roflumilast has the potential to be cost saving in patients with very severe COPD , due to a statistically significant reduction of exacerbations BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is a common , progressive respiratory disease that causes great morbidity and mortality despite treatment . There is evidence for airway inflammation in COPD . Cilomilast is an orally active , potent , selective phosphodiesterase type 4 inhibitor , which in vitro can affect cells thought to be of clinical importance in COPD . Our aim was to assess the safety , efficacy , and dose response of cilomilast in the treatment of patients with this disease . METHODS We did a 6-week , r and omised , dose-ranging study in 424 patients with COPD ( forced expiratory volume in 1 s [ FEV(1 ) ] 46.8 % of predicted , FEV(1)/forced vital capacity [ FVC ] 54.6 % , and postsalbutamol reversibility 5.4 % ) . We r and omly assigned individuals at 60 European centres to receive cilomilast 5 ( n=109 ) , 10 ( n=102 ) , or 15 ( n=107 ) mg twice daily , or placebo ( n=106 ) . The main outcome measure was trough FEV(1 ) before and after use of a bronchodilator . Analyses were by intention to treat . FINDINGS Cilomilast 15 mg twice daily significantly improved FEV(1 ) compared with placebo ( mean 130 mL vs -30 mL [ 95 % CI 90 - 240 ] at week 6 , p<0.0001 ) . FVC and peak expiratory flow were also improved ( p=0.001 and p<0.0001 , respectively ) . Quality of life measures did not differ significantly between the groups . There were no significant differences in serious adverse events between the groups . INTERPRETATION Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD . Further clinical studies are underway Maintenance treatment with PDE(4 ) inhibitor cilomilast improves FEV(1 ) in chronic obstructive pulmonary disease ( COPD ) patients . We investigated the acute bronchodilating effects of a single dose of cilomilast with or without concomitant administration of inhaled salbutamol and /or ipratropium bromide in 21 patients with COPD ( mean ( SD ) age 64 ( 8.1 ) y , post-salbutamol FEV(1 ) 47.7 ( 13.2 ) % predicted ) .  FEV(1 ) was measured before and up to 8 hourly intervals after intake of placebo , cilomilast , or cilomilast in combination with inhaled salbutamol 400 microg and /or ipratropium bromide 80 microg . Maximum increase in FEV(1 ) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA . The mean ( SEM ) maximum increase in FEV(1 ) was 139.6 ( 18.5 ) ml following cilomilast and 151.5 ( 18.5 ) ml following placebo ( 95 % C.I. for mean difference between cilomilast and placebo : -67.3 , 43.6 ml ) . Furthermore , combined treatment of cilomilast with salbutamol or ipratropium result ed in a maximum increase in FEV(1 ) of 280.7 ( 25.6 ) and 297.0 ( 25.9 ) ml , respectively , while this was 379.0 ( 24.6 ) ml following cilomilast with both salbutamol and ipratropium ( p < 0.01 ) . We conclude that a single dose of cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators . Our results implicate that the change in lung function seen after long-term treatment with cilomilast is not the result of acute bronchodilation in patients with COPD BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) BACKGROUND The clinical effects of roflumilast , a selective phosphodiesterase-4 inhibitor , are well established , but little is known about the anti-inflammatory mechanisms underlying the drug 's efficacy . The aim of the ROflumilast Biopsy European Research Trial ( ROBERT ) was to assess the anti-inflammatory effects of roflumilast on bronchial mucosal inflammation in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) and chronic bronchitis . METHODS ROBERT was a r and omised , double-blind , placebo-controlled trial done at 18 sites in five countries . Eligible patients were aged 40 - 80 years , had COPD , and had had a chronic productive cough for 3 months in each of the two previous years . Patients also had to have a post-bronchodilator predicted FEV1 30 - 80 % and a post-bronchodilator FEV1/forced vital capacity ratio of 70 % or less . Patients entered a 6-week run-in period before being r and omly assigned ( 1:1 ) via a computerised central r and omisation system to roflumilast 500 μg once daily or placebo for 16 weeks , in addition to bronchodilator therapy ( inhaled corticosteroids were not permitted ) . R and omisation was stratified by concomitant use of long-acting β agonist . Both participants and investigators were masked to group assignment . Roflumilast and placebo were supplied as identical yellow , triangular tablets . Airway inflammation was assessed by quantification of inflammatory cells in bronchial biopsy sample s and induced sputum sample s. The primary endpoint was the change in the number of CD8 inflammatory cells in bronchial biopsy submucosa from r and omisation to week 16 in the intention-to-treat population . Changes in cell counts of additional inflammatory markers , including eosinophils , were assessed as secondary endpoints . This trial is registered with Clinical Trials.gov , number NCT01509677 , and is closed to new participants , with follow-up completed . FINDINGS Between Jan 4 , 2012 , and Feb 11 , 2016 , 158 patients were r and omly assigned : 79 to the roflumilast group , and 79 to the placebo group . At week 16 , the change in the number of CD8 cells in the bronchial submucosa did not differ significantly between the roflumilast and placebo groups ( treatment ratio 1·03 [ 95 % CI 0·82 - 1·30 ] ; p=0·79 ) . However , compared with placebo , roflumilast was associated with a significant reduction in eosinophils in bronchial biopsy sample s at week 16 ( treatment ratio 0·53 [ 95 % CI 0·34 - 0·82 ] ; p=0·0046 ) . Significant reductions in both absolute ( p=0·0042 ) and differential ( p=0·0086 ) eosinophil cell counts in induced sputum were also noted with roflumilast compared with placebo , but peripheral blood eosinophil counts were not significantly affected . We noted no other significant effects of roflumilast on bronchial mucosal inflammatory cells . The most common ( ie , occurring in > 5 % patients ) moderate adverse events were worsening of COPD ( three [ 4 % ] patients in the roflumilast group vs seven [ 9 % ] in the placebo group ) , cough ( six [ 8 % ] vs four [ 5 % ] ) , diarrhoea ( four [ 5 % ] vs three [ 4 % ] ) , and nasopharyngitis ( three [ 4 % ] vs five [ 6 % ] ) . Severe adverse events included worsening of COPD , which occurred in four ( 5 % ) patients in the roflumilast group and two ( 3 % ) in the placebo group . No deaths occurred during the study . Serious adverse events occurred in eight ( 10 % ) patients in the roflumilast group and five ( 6 % ) in the placebo group . INTERPRETATION 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo . However , we noted significant reductions in eosinophil cell counts in bronchial biopsy sample s and induced sputum , generating the hypothesis that the effect of roflumilast in COPD could be mediated by an effect on lung eosinophils . FUNDING Takeda and AstraZeneca RATIONALE Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease . OBJECTIVES To determine whether roflumilast reduces moderate and /or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting β2-agonist with or without a long-acting muscarinic antagonist ( LAMA ) .  METHODS In this 52-week , phase 4 , double-blind , placebo-controlled RE(2)SPOND ( Roflumilast Effect on Exacerbations in Patients on Dual [ LABA/ICS ] Therapy ) trial ( NCT01443845 ) , participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease , chronic bronchitis , two or more exacerbations and /or hospitalizations in the previous year , and receiving inhaled corticosteroid/long-acting β2-agonist with or without LAMA daily for 3 or more months were equally r and omized to once-daily roflumilast , 500 μg ( n = 1,178 ) , or placebo ( n = 1,176 ) . Stratification was based on LAMA use . MEASUREMENTS AND MAIN RESULTS Although rate of moderate or severe exacerbations per patient per year ( primary endpoint ) was reduced by 8.5 % with roflumilast versus placebo , the between-group difference was not statistically significant ( rate ratio , 0.92 ; 95 % confidence interval , 0.81 - 1.04 ; P = 0.163 ) . However , roflumilast improved lung function , and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and /or one or more hospitalizations in the prior year . Adverse event-related discontinuations occurred in 11.7 % roflumilast-treated and 5.4 % placebo-treated participants . Deaths occurred in 2.5 % roflumilast and 2.1 % placebo participants . CONCLUSIONS Roflumilast failed to statistically significantly reduce moderate and /or severe exacerbations in the overall  population . Roflumilast  improved lung function and reduced exacerbations in participants with frequent exacerbations and /or hospitalization history . The safety profile of roflumilast was consistent with that of previous studies . Clinical trial registered with www . clinical trials.gov ( NCT01443845 )
BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is associated with cough , sputum production or dyspnoea and a reduction in lung function , quality of life and life expectancy .
Apart from smoking cessation , there are no other treatments that slow lung function decline .
Roflumilast and cilomilast are oral phosphodiesterase 4 ( PDE4 ) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD .
This is an up date of a Cochrane review first published in 2011 and up date d in 2013 .
OBJECTIVES To evaluate the efficacy and safety of oral PDE4 inhibitors in the management of stable COPD .