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Meta-Analysis
. 2017 Sep 19;9(9):CD002309.
doi: 10.1002/14651858.CD002309.pub5.

Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Jimmy Chong  1 , Bonnie Leung, Phillippa Poole
Affiliations
Meta-Analysis

Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Jimmy Chong et al. Cochrane Database Syst Rev. .

Update in

Abstract

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 update of a Cochrane review first published in 2011 and updated in 2013.

Objectives: To evaluate the efficacy and safety of oral PDE4 inhibitors in the management of stable COPD.

Search methods: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search October 2016). We found other trials from web-based clinical trials registers.

Selection criteria: We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy.

Data collection and analysis: One review author extracted data and a second review author checked the data. We reported pooled data in Review Manager as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR). We converted the odds ratios into absolute treatment effects in a 'Summary of findings' table.

Main results: Thirty-four separate RCTs studying roflumilast (20 trials with 17,627 participants) or cilomilast (14 trials with 6457 participants) met the inclusion criteria, with a duration of between six weeks and one year. These included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II-IV), with a mean age of 64 years.We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall. Treatment with a PDE4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV1) over the trial period compared with placebo (MD 51.53 mL, 95% confidence interval (CI) 43.17 to 59.90, 27 trials with 20,585 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias). There were small improvements in quality of life (St George's Respiratory Questionnaire (SGRQ), MD -1.06 units, 95% CI -1.68 to -0.43, 11 trials with 7645 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias) and COPD-related symptoms, but no significant change in exercise tolerance. Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.78, 95% CI 0.73 to 0.83; 23 trials with 19,948 participants, high-quality evidence). For every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 26). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting or dyspepsia. For every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). Roflumilast in particular was associated with weight loss during the trial period and an increase in insomnia and depressive mood symptoms. There was no significant effect of treatment on non-fatal serious adverse events (OR 0.99, 95% CI 0.91 to 1.07) or mortality (OR 0.97, 95% CI 0.76 to 1.23), although mortality was a rare event during the trials. Participants treated with PDE4 inhibitors were more likely to withdraw from the trials because of adverse effects; on average 14% in the treatment groups withdrew compared with 8% in the control groups.

Authors' conclusions: In people with COPD, PDE4 inhibitors offered benefit over placebo in improving lung function and reducing the likelihood of exacerbations; however, they had little impact on quality of life or symptoms. Gastrointestinal adverse effects and weight loss were common, and safety data submitted to the US Food and Drug Administration (FDA) have raised concerns over psychiatric adverse events with roflumilast. The findings of this review give cautious support to the use of PDE4 inhibitors in COPD. They may be best used as add-on therapy in a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management. This is in accordance with the GOLD 2017 guidelines. Longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation or mortality in COPD.

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Conflict of interest statement

Jimmy Chong: none known Phillippa Poole: none known Bonnie Leung: none known

Figures

1
1
In the control group 33 people out of 100 had an exacerbation of COPD over 6‐52 weeks, compared to 28 (95% CI 27 to 29) out of 100 for the active treatment group.
2
2
In the control group 4 people out of 100 had diarrhoea over 6‐52 weeks, compared to 11 (95% CI 10 to 12) out of 100 for the active treatment group.
3
3
Study flow diagram
4
4
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
5
5
Funnel plot of comparison: 1 PDE4 inhibitor versus placebo, outcome: 1.6 FEV1 (published versus unpublished).
1.1
1.1. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 1 FEV1 (by drug).
1.2
1.2. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 2 FEV1 (by mean COPD severity).
1.3
1.3. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 3 FEV1 (Roflumilast 500 μg by mean COPD severity).
1.4
1.4. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 4 FEV1 (by study duration).
1.5
1.5. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 5 FEV1 (additional medication).
1.6
1.6. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 6 FEV1 (published versus unpublished).
1.7
1.7. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 7 FEV1 (random‐effects model).
1.8
1.8. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 8 FEV1 (roflumilast 500 μg versus 250 μg).
1.9
1.9. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 9 FVC.
1.10
1.10. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 10 PEF.
1.11
1.11. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 11 SGRQ total score.
1.12
1.12. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 12 SGRQ total score (by published versus unpublished).
1.13
1.13. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 13 SGRQ total score (by duration).
1.14
1.14. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 14 SGRQ total score (by mean COPD severity).
1.15
1.15. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 15 SGRQ symptom score.
1.16
1.16. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 16 Number of participants with one or more exacerbations (by drug).
1.17
1.17. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 17 Number of participants on roflumilast with one or more exacerbations (additional medication).
1.18
1.18. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 18 Exacerbation rate (inverse variance).
1.19
1.19. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 19 Borg Scale.
1.20
1.20. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 20 Summary symptom score.
1.21
1.21. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 21 Shortness of breath questionnaire.
1.22
1.22. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 22 6‐minute walk test.
1.23
1.23. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 23 Number of participants experiencing an adverse effect.
1.24
1.24. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg).
1.25
1.25. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 25 Diarrhoea.
1.26
1.26. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 26 Nausea.
1.27
1.27. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 27 Headache.
1.28
1.28. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 28 Vomiting.
1.29
1.29. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 29 Dyspepsia.
1.30
1.30. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 30 Abdominal pain.
1.31
1.31. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 31 Weight loss.
1.32
1.32. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 32 Influenza‐like symptoms.
1.33
1.33. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 33 Upper respiratory tract infection.
1.34
1.34. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 34 Withdrawals due to adverse events.
1.35
1.35. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 35 Non‐fatal serious adverse events.
1.36
1.36. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 36 Mortality.
1.37
1.37. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 37 All psychiatric disorders (roflumilast).
1.38
1.38. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 38 Insomnia and sleep disorders (roflumilast).
1.39
1.39. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 39 Anxiety or anxiety disorder (roflumilast).
1.40
1.40. Analysis
Comparison 1 PDE4 inhibitor versus placebo, Outcome 40 Depression (roflumilast).
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References

References to studies included in this review

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    1. Mclvor RA, Calverley PM, Sanchez‐Toril F, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of roflumilast on quality of life: a 1‐year study in patients with severe to very severe COPD. American Thoracic Society Conference; 2006 May 19‐24; San Diego. 2006; Vol. 3:A850.
Roflumilast M2‐118 {published data only}
    1. O'Donnell DE, Bredenbroker D, Brose M, Webb KA. Physiological effects of roflumilast at rest and during exercise in COPD. European Respiratory Journal 2012;39(5):1104‐12. [ES:1399‐3003: IL:0903‐1936] - PubMed
Roflumilast M2‐119 {published data only}
    1. Hui D, Mahayiddin A, Roa C, Kwa KH, Bredenbröker D, Goehring UM, et al. Roflumilast in Asian patients with COPD: a randomised placebo‐controlled trial. European Respiratory Society Annual Congress; 2011 Sep 24‐28; Amsterdam. 2011; Vol. 38, issue 55:600s [P3364]. - PubMed
    1. Lee JS, Hong YK, Park TS, Lee SW, Oh Y‐M, Lee S‐D. Efficacy and safety of roflumilast in Korean patients with COPD. Yonsei Medical Journal 2016;57(4):928‐35. [CENTRAL: 1158901; CRS: 4900132000022927; EMBASE: 20160381439; PUBMED: 27189287] - PMC - PubMed
    1. Lee SD, Hui DS, Mahayiddin AA, Roa CC, Kwa KH, Goehring UM, et al. Roflumilast in Asian patients with COPD: a randomized placebo‐controlled trial. Respirology 2011;16(8):1249‐57. - PubMed
Roflumilast M2‐121 {unpublished data only}
    1. NCT00108823. The HERO‐study: effects of roflumilast in patients with COPD (Chronic Obstructive Pulmonary Disease) (BY217/M2‐121) [A 24‐week, double blind, randomized study to investigate the effect of 500 µg roflumilast tablets once daily versus placebo on parameters indicative of hyperinflation in patients with chronic obstructive pulmonary disease]. clinicaltrials.gov/ct2/show/NCT00108823 (first received 19 April 2005).
Roflumilast M2‐124 {published and unpublished data}
    1. Calverley PM, Rabe KF, Goehring U‐M, Kristiansen S, Fabbri LM, Martinez FJ, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374(9691):685‐94. - PubMed
    1. Martinez F, Hanania N, AURA Study Team. Efficacy and safety of the phosphodiesterase‐4 inhibitor roflumilast in patients with symptomatic chronic obstructive pulmonary disease in the M2‐124 study. Chest 2009;136(4):3S‐e.
    1. Nowak D, Ehlken B, Kotchie R, Wecht S, Magnussen H. Roflumilast in combination with long‐acting bronchodilators. Deutsche Medizinische Wochenschrift 2013;138(4):119‐25. - PubMed
Roflumilast M2‐124+M2‐125 {published data only}
    1. Bateman ED, Rabe KF, Calverley PMA, Goehring UM, Brosee M, Bredenbroker D, et al. Roflumilast with long‐acting beta2‐agonists for COPD: influence of exacerbation history. European Respiratory Journal 2011;38(3):553‐60. - PubMed
    1. Calverley P, Fabbri L, Rabe K, Goehring UM, Martinez F. Efficacy of the PDE4 inhibitor roflumilast in COPD patients with chronic bronchitis. European Respiratory Society Annual Congress; 2009 Sep 12‐16; Vienna. 2009:1629.
    1. Calverley P, Martinez F, Goehring UM, Bredenbröker D, Brose M, Vogelmeier C. Impact of roflumilast treatment on the rate and duration of exacerbations and overall steroid load in patients with COPD. European Respiratory Society Annual Congress; 2011 Sep 24‐28; Amsterdam. 2011; Vol. 38, issue 55:19s [P248].
    1. Calverley PM, Rabe KF, Goehring U‐M, Kristiansen S, Fabbri LM, Martinez FJ, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374(9691):685‐94. - PubMed
    1. Calverley PMA, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Erratum: Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials (The Lancet (2009) 374 (685‐694)). Lancet 2010;376(9747):1146. - PubMed
Roflumilast M2‐125 {published data only}
    1. Andrew M, Fernando J, HERMES Study Team. Efficacy and safety of the phosphodiesterase 4 inhibitor roflumilast in patients with symptomatic chronic obstructive pulmonary disease in the M2‐125 study. Chest 2009;136(4):93S‐b,94.
    1. Calverley PM, Rabe KF, Goehring U‐M, Kristiansen S, Fabbri LM, Martinez FJ, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374(9691):685‐94. - PubMed
    1. Nowak D, Ehlken B, Kotchie R, Wecht S, Magnussen H. Roflumilast in combination with long‐acting bronchodilators. Deutsche Medizinische Wochenschrift 2013;138(4):119‐25. - PubMed
Roflumilast M2‐127 {published data only}
    1. Chapman KR, McIvor A, Maltais F, EOS Study Team. Additional clinical benefit in patients with chronic obstructive pulmonary disease treated with roflumilast and salmeterol. Chest 2009;136(4):3S‐f.
    1. Chapman KR, Rabe KF. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease (COPD) concomitantly treated with tiotropium or salmeterol. Primary Care Respiratory Journal 2010;19(2):A12 [44].
    1. Fabbri LM, Calverley PM, Izquierdo‐Alonso JL, Bundschuh DS, Brose M, Martinez FJ, et al. Roflumilast in moderate‐to‐severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet 2009;374(9691):695‐703. - PubMed
    1. Izquierdo JL, MacNee W, Biermann E, Goehring U‐M, McIvor A. The PDE4 inhibitor roflumilast provides additional clinical benefit in COPD patients receiving salmeterol. European Respiratory Society Annual Congress; 2009 Sep 12‐16; Vienna. 2009:1627.
    1. Martinez F, McIvor A, Brose M, Larsson T, Goehring UM. Benefit of roflumilast therapy added to salmeterol in patients with varying chronic obstructive pulmonary disease severity. Chest 2010;138(4):467A.
Roflumilast M2‐128 {published data only}
    1. Chapman KR, Rabe KF. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease (COPD) concomitantly treated with tiotropium or salmeterol. Primary Care Respiratory Journal 2010;19(2):A12 [44].
    1. Fabbri LM, Calverley PM, Izquierdo‐Alonso JL, Bundschuh DS, Brose M, Martinez FJ, et al. Roflumilast in moderate‐to‐severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet 2009;374(9691):695‐703. - PubMed
    1. Fabbri LM, Martinez FJ, Goehring U‐M, Brose M, Lakkis H, Rowe P. Roflumilast treatment with concomitant tiotropium: effect on lung function in severe COPD patients. Journal of General Internal Medicine 2012;27:S303. [CENTRAL: 980891; CRS: 4900126000006483; EMBASE: 71296919]
    1. Paggiaro P, Foden A. Improvements in breathlessness in patients with chronic obstructive pulmonary disease treated with roflumilast and tiotropium. Chest 2009;136(4):3S‐g, 4.
    1. Rabe K, Paggiaro P, Bernabeu L, Brose M, Geohring U‐M, Fabbri L. Roflumilast, a PDE4 inhibitor, improves lung function in patients with COPD treated with tiotropium. European Respiratory Society Annual Congress; 2009 Sep 12‐16; Vienna. 2009:1628.
Roflumilast ROF‐MD‐07(RE2SPOND) {published data only}
    1. Ferguson GT, Rennard SI, Hanania NA, Zhu H, Siddiqui S, Sacks H. Roflumilast treatment in COPD patients taking a fixed‐dose combination of long‐acting β2 agonist (LABA) and inhaled corticosteroid (ICS): rationale and design of a prospective randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2012;185(Meeting Abstracts):A2946.
    1. Martinez FJ, Rabe KF, Sethi S, Pizzichini E, McIvor A, Anzueto A, et al. Effect of roflumilast and inhaled corticosteroid/long‐acting beta2‐agonist on chronic obstructive pulmonary disease exacerbations (RE(2)SPOND). A randomized clinical trial. American Journal of Respiratory and Critical Care Medicine 2016;194(5):559‐67. [CRS: 4900132000033597; PUBMED: 27585384] - PubMed
    1. Rennard SI, Martinez FJ, Rabe KF, Sethi S, Pizzichini E, McIvor A, et al. Effect of roflumilast in COPD patients receiving inhaled corticosteroid/long‐acting beta2‐agonist fixed‐dose combination: RE2SPOND rationale and study design. International Journal of Chronic Obstructive Pulmonary Disease 2016;11(1):1921‐8. [CENTRAL: 1180201; CRS: 4900132000031987; EMBASE: 20160624756; PUBMED: 27574416] - PMC - PubMed
    1. Rennard SI, Martinez FJ, Sethi S, Zhu H, Haberman R, Zovko E. Effects of roflumilast in COPD patients receiving ICS/LABA fixed‐dose combination: rationale and design of a prospective randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2015;191(Meeting Abstracts):A5790. [CENTRAL: 1101144; CRS: 4900132000009979; EMBASE: 72053688]
    1. White WB, Kowey PR, Zhu H, Siddiqui S, Rowe P. Evaluation of major adverse cardiac events (MACE) in a one‐year, placebo‐controlled study of roflumilast in patients with chronic obstructive pulmonary disease (COPD): rationale and design. American Journal of Respiratory and Critical Care Medicine 2013;187(Meeting Abstracts):A1484. [CENTRAL: 870804; CRS: 4900100000087949]

References to studies excluded from this review

Borker 2003 {published data only}
    1. Borker RD, Morris A, Lim J, Zhu J, Reisner C. Effect of cilomilast on quality of life improvement/deterioration and non‐drug costs in patients with chronic obstructive pulmonary disease. Chest 2003;124(4):170S‐b,171.
Ferguson 2003 {published data only}
    1. Ferguson G, Fischer TL, Morris A, Zhu J, Barnhart F, Reisner C. Cardiovascular safety of cilomilast in patients with chronic obstructive pulmonary disease. Chest 2003;124(4):171S.
Fischer 2003 {published data only}
    1. Fischer T, Borker R, Barnhart F, Morris A, Zhu J. Effect of cilomilast on chronic obstructive pulmonary disease patients with impaired quality of life. Chest 2003;124(4):129S.
Grootendorst 2001 {published data only}
    1. Grootendorst DC, Gauw SA, Kelly J, Murdoch RD, Sterk PJ, Rabe KF. First dose bronchodilating effect of phosphodiesterase‐4 (PDE‐4) inhibition by cilomilast (Ariflo) with or without co‐administration of salbutamol and/or ipratropium in COPD patients. European Respiratory Journal 2001;18(Suppl 33):1:35s.
Grootendorst 2002 {published data only}
    1. Grootendorst DC, Gauw SA, Verhoosel R, Veen H, Linden A, Moesker H, et al. Effect of a PDE4 inhibitor (Bay 19‐8004) on FEV1 and airway inflammation in patients with COPD. American Journal of Respiratory and Critical Care Medicine 2002;165(8 Suppl):A226.
Grootendorst 2003 {published data only}
    1. Grootendorst DC, Gauw SA, Baan R, Kelly J, Murdoch RD, Sterk PJ, et al. Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?. Pulmonary Pharmacology and Therapeutics 2003;16(2):115‐20. - PubMed
Grootendorst 2007 {published data only}
    1. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbröker D, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62(12):1081‐7. - PMC - PubMed
GSK256066 {published data only}
    1. Lazaar AL, Mistry S, Barrett C, Lulic‐Burns Z. A four‐week randomized study of the safety and tolerability of the inhaled PDE4 inhibitor GSK256066 in COPD. American Journal of Respiratory and Critical Care Medicine 2010;181 (Meeting Abstracts):A4444.
Kelsen 2002 {published data only}
    1. Kelsen SG, Rennard SI, Chodosh S, Schryver B, Vleisides C, Zhu J. COPD exacerbation in a 6‐month trial of cilomilast (Ariflo) a potent, selective phosphodiesterase 4 inhibitor. American Journal of Respiratory and Critical Care Medicine 2002;165 (Suppl 8):A271.
Knobil 2003 {published data only}
    1. Knobil K, Morris A, Zhu J, Fischer T, Reisner C. Cilomilast is efficacious in chronic obstructive pulmonary disease. American Thoracic Society 99th International Conference; 2003 May 16‐21; Seattle. 2003:A035; Poster D92.
    1. Reisner C, Morris A, Zhu J, Fischer T, Knobil K. Cilomilast is efficacious in chronic obstructive pulmonary disease. European Respiratory Journal 2003;22(Suppl 45):Abstract No: P530.
Lim 2004 {published data only}
    1. Lim S, Zhu J, Lake P. Cilomilast decreases exacerbations and maintains lung function in patients with poorly reversible COPD. European Respiratory Journal 2004;24(Suppl 48):88s.
Nieman 1999 {unpublished data only}
    1. Nieman RB, Taneja DT, Amit O, Benincosa LJ, Compton CH, Bethala VK, et al. The effects of low dose SB207499, a second generation, oral PDE4 inhibitor, in patients with COPD. European Respiratory Society Congress; 1999 Oct 9‐13; Madrid. 1999:P2236.
Pascoe 2007 {unpublished data only}
    1. Pascoe SJ, Bonner J, Hauffe S, Bohnemeier H. Gradual dose escalation of QAK423, a novel PDE4 inhibitor, significantly improves the tolerability. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco. 2007:Poster C31.
Reisner 2003 {published data only}
    1. Reisner C, Morris A, Barnhart F, Fischer TL, Acusta A, Darken P. Cilomilast reduces exacerbations in patients with chronic obstructive pulmonary disease. Chest 2003;124:4.
Roflumilast JP708 {unpublished data only}
    1. Brown P. Clinical pharmacology and biopharmaceutics review(s) [Application number 022522Orig1s000]. https:// www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000PharmR.pdf (accessed prior to 28 June 2017).
Sadigov 2014 {published data only}
    1. Sadigov A, Akhundov S, Bagirov R. Analysis of chronic obstructive pulmonary disease exacerbations with the triple therapy compared with dual and single bronchodilator therapy: which treatment is better for patients with severe disease?. Chest 2014;145(3):425A. [CENTRAL: 991341; CRS: 4900126000011438; EMBASE: 71429002]
    1. Sadigov AS, Bagirov R, Abbasov C. Analysis of chronic obstructive pulmonary disease exacerbations with the triple therapy compared with dual treatment: is it better treatment tool for patients with severe disease?. American Journal of Respiratory and Critical Care Medicine 2014;189:A3770. [CENTRAL: 1035664; CRS: 4900126000023131; EMBASE: 72043281]
Sadigov 2015 {published data only}
    1. Sadigov A, Huseynova S. Efficacy and safety of dual anti‐inflammatory combination of fluticasone and roflumilast for the treatment of COPD: is dual better than single?. American Journal of Respiratory and Critical Care Medicine 2015;191(Meeting Abstracts):A3968. [CENTRAL: 1101148; CRS: 4900132000009983; EMBASE: 72051845]
SB207499/040 {unpublished data only}
    1. 207499/040. A multicentre, open‐label extension study to evaluate the safety, tolerability and efficacy of oral SB‐207499 (15 mg twice daily) in patients with chronic obstructive pulmonary disease. www.gsk‐clinicalstudyregister.com/files/pdf/24044.pdf (first received 28 September 2008).
SB207499/041 {unpublished data only}
    1. 207499/041. A multicenter open‐label extension study to evaluate the safety, tolerability and efficacy of oral cilomilast (15 mg twice daily) in patients with chronic obstructive pulmonary disease. www.gsk‐clinicalstudyregister.com/files/pdf/24045.pdf (first received 28 September 2008).
Song 2005 {published data only}
    1. Song Y, Wang C, Liao X, Wang Y, Li Q, Zhao Z, et al. Improvement in lung residual volume in patients with COPD roles of anti‐inflammation activity of cilomilast. Respiratory 2005;10 (Suppl 3):A135.
Spencer 2002 {published data only}
    1. Spencer MD, Zhu J, Izard D. The direct costs of exacerbations in COPD and the effect of cilomilast treatment. European Respiratory Journal 2002;20 (Suppl 38):245s.
Vestbo 2007 {published data only}
    1. Vestbo J, Tan L, Atkinson G. A 6 week study of the efficacy and safety of UK 500,001 dry powder for inhalation (DPI) in adults with chronic obstructive pulmonary disease. European Respiratory Journal 2007;30 (Suppl 51):612s [P3598].
Vestbo 2009 {published data only}
    1. Vestbo J, Tan L, Atkinson G, Ward J. A controlled trial of 6‐weeks' treatment with a novel inhaled phosphodiesterase type‐4 inhibitor in COPD. European Respiratory Journal 2009;33(5):1039‐44. - PubMed
Wang 2005 {published data only}
    1. Wang C, Song Y, Liao X. Efficacy and anti‐inflammation activity of a selective phospodiesterase‐4 inhibitor cilomilast in treatment of COPD. Chest 2005;128(4):262S‐a.
Watz 2013 {published data only}
    1. Watz H, Mistry SJ, Lazaar AL, IPC101939 investigators. Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulmonary Pharmacology and Therapeutics 2013;26(5):588‐95. [CENTRAL: 872117; CRS: 4900100000088401; EMBASE: 2013527752; PUBMED: 23701917] - PubMed

References to studies awaiting assessment

Barnes 2014 {published data only}
    1. Barnes NC, Saetta M, Rabe KF. Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. BMC Pulmonary Medicine. United Kingdom: BioMed Central Ltd. (Floor 6, 236 Gray's Inn Road, London WC1X 8HB, United Kingdom), 2014; Vol. 14, issue 1:9. [CENTRAL: 973300; CRS: 4900126000005305; EMBASE: 2014126619; PUBMED: 24484726] - PMC - PubMed
Mahmud 2013 {published data only}
    1. Mahmud AM, Hossain A, Hassan R, Khan AS, Bennoor KS, Shaheen M, et al. Placebo controlled study of roflumilast in Bangladeshi COPD patients. Respirology (Carlton, Vic.). Blackwell Publishing, 2013; Vol. 18, issue Suppl 4:125 [PS160]. [CENTRAL: 980913; CRS: 4900126000008659; EMBASE: 71371785]

References to ongoing studies

NCT02451540 2015 {published data only}
    1. 2015‐000053‐21. Placebo controlled study to assess the effect of Roflumilast in hyperinflated COPD patients in addition to LABA/LAMA therapy using Functional Respiratory Imaging. clinicaltrialsregister.eu/ctr‐search/trial/2015‐000053‐21/BE (first received 14 April 2015). [CRS: 4900132000033606]
    1. NCT02451540. Evaluation of the effect of roflumilast in hyperinflated COPD patients using functional respiratory imaging [Placebo controlled study to assess the effect of roflumilast in hyperinflated COPD patients in addition to LABA/LAMA therapy using functional respiratory imaging]. clinicaltrials.gov/show/NCT02451540 (first received 7 May 2015). [CRS: 4900132000033604]
NCT02671942 2016 {published data only}
    1. NCT02671942. A multicenter randomized double‐blind clinical study evaluated the safety, pharmacokinetic and pharmacodynamic characteristics of roflumilast in COPD patients. clinicaltrials.gov/show/NCT02671942 (first received 25 January 2016). [CRS: 4900132000033602]

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