Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

Jimmy Chong; Bonnie Leung; Phillippa Poole

doi:10.1002/14651858.CD002309.pub5

Les inhibiteurs de la phosphodiestérase 4 dans le traitement de la bronchopneumopathie chronique obstructive

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Referencias

References to studies included in this review

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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]

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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.

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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]

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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).

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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]

References to studies awaiting assessment

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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]

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References to ongoing studies

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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]

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]

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Additional references

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References to other published versions of this review

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Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2013, Issue 11. [DOI: 10.1002/14651858.CD002309.pub4]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Cilomilast 039

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 102 centres in Canada, Mexico and the USA Participants: 647 (15 mg cilomilast: 431, placebo: 216) Baseline characteristics: mean age: 65 years, 62% male, mean FEV₁% predicted of 49.7%, mean smoking history of 59.9 pack‐years for cilomilast and 56.1 pack‐years for placebo, or current smokers (44% and 47%, respectively) Inclusion criteria: FEV₁/FVC ≤ 0.7, FEV₁ 30% ‐70% with smoking history > 10 pack‐years or current smokers Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis Total number of participant withdrawals: 137 (32%) and 52 (24%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks, single‐blind. Placebo tablets to assess suitability Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: "The only other permitted medications for the treatment of airways disease were stable doses of Ipratropium, via a metered‐dose inhaler, and mucolytic agents." Short‐acting β2 agonist: "...the short‐acting ß₂‐agonist Albuterol, which was administered via a metered‐ dose inhaler, was supplied for the relief of acute respiratory symptoms." Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: lung function; change in FEV₁, SGRQ averaged over 24 weeks Secondary outcomes: incidence rate of COPD exacerbations, adverse events, FVC at the trough, 6‐MWT, post‐exercise dyspnoea
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	"Eligible subjects were randomised in a 2:1 ratio to receive oral cilomilast, 15 mg bid, or placebo for 24 weeks."
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	"The primary reasons for the withdrawal of subjects from the study prior to randomisation were the failure to meet inclusion/exclusion criteria (15.4%) and the presence of adverse effects, including COPD exacerbations (8.5%). More subjects receiving cilomilast than placebo withdrew from the double‐blind phase of study (31.8% (n = 137) versus 24.1% (n = 52)."
Baseline profile: anticholingeric use	Low risk	54% in cilomilast; 58% placebo used ipratropium
Baseline profile: β2 agonist use	Low risk	99% in cilomilast; 100% placebo used albuterol. 9% in cilomilast; 12% placebo used salmeterol
Baseline profile: corticosteroid use	Low risk	7% in cilomilast; 8% placebo used triamcinolone. 6% in cilomilast; 7% placebo used beclomethasone

Cilomilast 042

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 98 centres in Australia and New Zealand, Germany, Spain, South Africa and the UK Participants: 700 (15 mg cilomilast: 474, placebo: 226) Baseline characteristics: mean age: 64.6 years, 80% male, mean FEV₁% predicted of 49% with 5.1% reversibility, DLCO was 71% predicted, also with higher rates of chronic bronchitis 80.1%. 45% active smokers Inclusion criteria: aged 40‐80 years, FEV₁/FVC ≤ 0.7, FEV₁ 30%‐70% with smoking history > 10 pack‐years Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis Total number of participant withdrawals: 122 (26%) and 51 (23%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks, single‐blind with placebo Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: 2% in cilomilast; 3% placebo used salbutamol. 3% in cilomilast; 1% placebo used ipratropium Short‐acting β2 agonist: "Albuterol MDI was used as rescue medication" Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: lung function; change in FEV₁, SGRQ averaged over 24 weeks Secondary outcomes: incidence rate of COPD exacerbations, summary symptom score, FVC at the trough, 6‐MWT, post‐exercise dyspnoea
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised in a 2:1 ratio to receive oral cilomilast, 15 mg twice daily, or placebo for 24 weeks
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 51 (23%) placebo, 122 (26%) cilomilast, primarily due to adverse events, of which most were not from COPD exacerbations
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 076

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Analysis was done per‐protocol population
Participants	Setting: not stated Participants: 59 (15 mg cilomilast: 29, placebo: 30) Baseline characteristics: mean age: 61‐62 years, 81% male, 53% active smokers, mean 46 pack‐years, 53%‐58% FEV₁ predicted Inclusion criteria: aged 40‐80 years, fixed airflow obstruction, smoking history > 10 pack‐years Exclusion criteria: not stated Total number of participant withdrawals: 4 (14%) and 2 (7%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks, single‐blind with placebo Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: "14 of 59 used ipratropium bromide at a constant dosage (eight in the placebo group, six in the cilomilast group)." Short‐acting β2 agonist: "All patients were given albuterol for use as required" Corticosteroid: none Long‐acting β2 bronchodilator: none Used alongside short‐acting ß2 agonists (available to all) and anticholingeric drugs (offered to 24%)
Outcomes	Primary outcomes: change in neutrophil percentage in induced sputum Secondary outcomes: FEV₁, numbers of subepithelial CD8+ cells, CD 68+ cells, epithelial and subepithelial neutrophils
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Randomised to a ratio of 1:1
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	"One patient was lost to follow‐up 3 days after randomisation and another withdrawn for non‐compliance 32 days after randomisation. Four patients were withdrawn after adverse events."
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 091

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 110 centres in Belgium, Finland, France, Italy, the Netherlands, Norway, Portugal, Spain and the UK Participants: 711 (15 mg cilomilast: 469, placebo: 242) Baseline characteristics: mean age: 64.6 years, 86% male, mean FEV₁ % predicted of 53% with 5.0% reversibility. 38% active smokers Inclusion criteria: FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis Total number of participant withdrawals: 121 (26%) and 63 (26%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks, single‐blind with placebo Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: 0.9% in cilomilast; 4% placebo used salbutamol. 1% in cilomilast; 3% placebo used ipratropium Short‐acting β2 agonist: "Albuterol MDI was used as rescue medication" Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: lung function; change in FEV₁, SGRQ averaged over 24 weeks Secondary outcomes: incidence rate of COPD exacerbations, summary symptom score, FVC at the trough, 6‐MWT, post‐exercise dyspnoea
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	"Eligible patients were randomised to receive either SB 207499 or matching placebo ina ratio of 2:1 for 24 weeks."
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 63 (26%) placebo, 121 (26%) cilomilast, primarily due to adverse events, of which most were not from COPD exacerbations
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 103657

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 103 centres in the USA Participants: 613 (15 mg cilomilast: 296, placebo: 317) Baseline characteristics: mean age: 63.2 years: placebo and 63.1 years; cilomilast. 47% male: placebo and 46% male: cilomilast. Mean FEV₁ % predicted not available Inclusion criteria: aged ≥ 40 years of age. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. ≤ 70%, post‐albuterol reversibility ≤ 15% or ≤ 200 mL (or both), post‐albuterol FEV₁ ≤ 70% of predicted normal and at least 1 COPD exacerbation within the 12 months prior to screening Exclusion criteria: not stated Total number of participant withdrawals: 105 (35%) and 76 (24%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: change from baseline to endpoint in trough pre‐bronchodilator FEV₁. Change in total score of SGRQ averaged over 24 weeks Secondary outcomes: changes from baseline in clinic trough FVC, time to first level 2 or level 3 COPD exacerbation
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Randomised. No other information given
Randomised?	Low risk	Participants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 76 (24%) placebo, 105 (35%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 110

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Analysis was done per‐protocol population
Participants	Setting: 10 centres in the USA Participants: 65 (15 mg cilomilast: 31, placebo: 34) Baseline characteristics: mean age: 64.4 years: placebo and 66.1 years: cilomilast. 67% male: placebo and 84% male: cilomilast. Mean FEV₁ % predicted not available Inclusion criteria: aged 40‐80 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Post‐salbutamol reversibility ≤ 15% or 200 mL and a post‐salbutamol FEV₁ at least 1.0 L and between 30% and 70% of predicted Exclusion criteria: not stated Total number of participant withdrawals: 1 (3%) and 1 (3%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: change from baseline at endpoint in neutrophils as a percentage of total cells in induced sputum Secondary outcomes: FVC at the trough, sputum macrophages, eosinophils and lymphocytes as a percentage of total cells in induced sputum. Total cell counts in induced sputum
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	All participants were randomised to receive either cilomilast 15 mg or matching placebo
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 1 (3%) placebo, 1 (3%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 111

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 32 centres in the USA, Canada and Australia Participants: 156 (15 mg cilomilast: 79, placebo: 77) Baseline characteristics: mean age: 64.2 years: placebo and 65 years; cilomilast. 66% male: placebo and 65% male: cilomilast. Mean FEV₁ % predicted not available Inclusion criteria: aged 40‐80 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Post‐salbutamol reversibility ≤ 15% or 200 mL and a post‐salbutamol FEV₁ at least 1.0 L and between 30% and 70% of predicted. Baseline RV (from plethysmography) ≥ 120% of predicted RV Exclusion criteria: not stated Total number of participant withdrawals: 15 (19%) and 14 (18%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: change from baseline to endpoint in volume of trapped gas (D) Secondary outcomes: lung volume measurements, including SVC and RV, 6‐MWT and exertional dyspnoea
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised to receive either 15 mg of cilomilast or matching placebo
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 14 (18%) placebo, 15 (19%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 121

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 22 centres in China Participants: 1018 (15 mg cilomilast: 678, placebo: 340) Baseline characteristics: mean age: 63.9 years: placebo and 64.6 years; cilomilast. 91% male: placebo and 93% male: cilomilast. Mean FEV₁ % predicted not available Inclusion criteria: aged 40‐75 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Documented history of COPD exacerbations each year for 3 years prior to screening. At least 1 exacerbation in the last year that required oral corticosteroids or antibiotics. Post‐salbutamol reversibility ≤ 15% or 200 mL and a post‐salbutamol FEV₁ at least 1.0 L and between 25% and 70% of predicted. % predicted FRC of ≥ 120% from plethysmography Exclusion criteria: not stated Total number of participant withdrawals: 124 (18%) and 35 (10%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: change from baseline to endpoint in trough pre‐bronchodilator FEV₁ Secondary outcomes: time to first level 2 or level 3 COPD exacerbation. Level 2 is defined as acute worsening of COPD that requires additional treatment or hospital outpatient visit. Level 3 is hospital admission for treatment. Change from baseline to endpoint RV and FRC. Change from baseline total score of SGRQ
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised to a 2:1 ratio for cilomilast 15 mg to placebo
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 35 (10%) placebo, 124 (18%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 156

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 132 centres in USA and Canada Participants: 825 (15 mg cilomilast: 418, placebo: 407) Baseline characteristics: mean age: 64.4 years: placebo and 64.5 years; cilomilast. 62% male: placebo and 56% male: cilomilast > 50% predicted FEV₁ for both groups Inclusion criteria: aged 40‐80 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Post‐salbutamol reversibility ≤ 15% or 200 mL and a post‐salbutamol FEV₁ at least 1.0 L and between 30% and 70% of predicted Exclusion criteria: not stated Total number of participant withdrawals: 143 (34%) and 96 (24%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: 8.1% in cilomilast; 8.6% placebo used salbutamol. 1.7% in cilomilast; 2% placebo used ipratropium bromide Short‐acting β2 agonist: "Albuterol MDI was used as rescue medication" Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: change from baseline to endpoint in trough pre‐bronchodilator FEV₁. Change in total score of SGRQ averaged over 24 weeks Secondary outcomes: post‐exercise breathlessness, clinic trough FVC, time to first level 2 or level 3 COPD exacerbation
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 96 (24%) placebo, 143 (34%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 157

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 137 centres from 18 countries Participants: 907 (15 mg cilomilast: 455, placebo: 452) Baseline characteristics: mean age: 63.3 years: placebo and 64.6 years; cilomilast. 73% male: placebo and 78% male: cilomilast. 42% current smokers Inclusion criteria: aged 40‐80 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Poor reversibility of airway obstruction, defined by ≤ 10% of predicted normal or ≤ 200 mL (or both) increase in FEV₁ after administration of salbutamol 400 µg via MDI at screening; post‐salbutamol FEV₁ of between 30%‐70% predicted normal at screening Exclusion criteria: not stated Total number of participant withdrawals: 167 (37%) and 121 (27%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: mean change from baseline in trough pre‐bronchodilator FEV₁ averaged over 52 weeks. Incidence rate of level 2 (moderate) and level 3 (severe) COPD exacerbations during the treatment period Secondary outcomes: time to first level 2 or level 3 COPD exacerbation. Quality of life determined by SGRQ
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?	Unclear risk	A randomisation criteria was used. No other information available
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 121 (27%) placebo, 167 (37%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 168

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: not stated
Participants	Setting: 42 centres in the USA Participants: 306 (15 mg cilomilast: 203, placebo: 103) Baseline characteristics: mean age: 64.3 years: placebo and 65.0 years; cilomilast. 64% male: placebo and 70% male: cilomilast Inclusion criteria: pre‐albuterol FEV₁/FVC ≤ 0.7. Post‐albuterol FEV₁ between 30% and 70% of predicted Exclusion criteria: not stated Total number of participant withdrawals: 61 (30%) and 14 (14%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: no primary efficacy or safety analyses were defined. Descriptive statistics of change from baseline in minimum and maximum heart rate via 24‐h Holter monitoring reported Secondary outcomes: no secondary efficacy or safety analyses were defined
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised at 2:1 ratio of cilomilast to placebo
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 14 (14%) placebo, 61 (30%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No other information available
Baseline profile: β2 agonist use	Unclear risk	No other information available
Baseline profile: corticosteroid use	Unclear risk	No other information available

Cilomilast 180

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 18 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 34 centres in the USA, Canada and South America 2) Participants: 199 (15 mg cilomilast: 97, placebo: 102) Baseline characteristics: mean age: 64.7 years: placebo and 63.7 years; cilomilast. 76% male: placebo and 69% male: cilomilast Inclusion criteria: age at least 40 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Baseline FEV₁ < 70% predicted normal. Moderate to severe chronic dyspnoea defined by baseline Dyspnoea Index focal score ≤ 7, evidence of hyperinflation defined by RFRC at least 140% of predicted. Exercise limitation, defined as peak symptom limited VO₂ < 75% Exclusion criteria: not stated Total number of participant withdrawals: 24 (25%) and 13 (13%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcomes: change from baseline at endpoint in RFRC Secondary outcomes: change from baseline at endpoint in IC during exercise, exertional dyspnoea as measured by the modified Borg scale
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	Participants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 13 (13%) placebo, 24 (25%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Cilomilast 181

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 13 weeks Analysis was done per‐protocol population
Participants	Setting: 27 centres in Australia, Canada, Finland, Ireland, Lithuania, Norway, Romania, Slovakia, Slovenia, South Africa, Sweden and the UK Participants: 127 (15 mg cilomilast: 65, placebo: 62) Baseline characteristics: mean age: 63.4 years: placebo and 61.4 years; cilomilast. 76% male: placebo and 72% male: cilomilast Inclusion criteria: aged 40‐80 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Post‐bronchodilator FEV₁ between 40% and 80% predicted normal. Poor reversibility of ≤ 10% or 200 mL increase in FEV₁ Exclusion criteria: not stated Total number of participant withdrawals: 8 (12%) and 6 (10%) from treatment and control groups, respectively
Interventions	Run‐in: not stated Cilomilast 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: no information available Short‐acting β2 agonist: no information available Corticosteroid: no information available Long‐acting β2 bronchodilator: no information available
Outcomes	Primary outcome: change from baseline at endpoint in CD68+ (macrophages) and CD8+ (cytotoxic T‐lymphocytes) per unit area of tissue Secondary outcome: change from baseline in numbers of sub‐epithelial cells per unit area in biopsy for neutrophil elastase positive (ne+) cells, CD4+, IL‐8 mRNA positive cells, TNF‐alpha mRNA positive cells
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Randomised. No other information available
Randomised?	Low risk	Participants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinding
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Total number of participants withdrawn 6 (10%) placebo, 8 (12%) cilomilast
Baseline profile: anticholingeric use	Unclear risk	No other information available
Baseline profile: β2 agonist use	Unclear risk	No other information available
Baseline profile: corticosteroid use	Unclear risk	No other information available

Compton 2001

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 6 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 60 centres in Austria, France, Germany, the Netherlands and the UK Participants: 424 (5 mg cilomilast: 109, 10 mg cilomilast: 102, 15 mg cilomilast: 107, placebo: 106) Baseline characteristics: mean age: 62‐63 years, 75%‐78% male, mean FEV₁% predicted of 46.8%, mean smoking history of 36‐43 (SD 22.4) pack‐years Inclusion criteria: FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years Exclusion criteria: asthma, poorly controlled COPD needing hospital visit 6 weeks before study, recent COPD exacerbations or recent corticosteroid use Total number of participant withdrawals: 18 (17%) and 17 (16%) from treatment and control groups, respectively
Interventions	Run‐in: 2 weeks, single‐blind. Placebo tablets to assess compliance Cilomilast 5 mg, 10 mg, 15 mg twice daily Placebo twice daily Concomitant medication Short‐acting anticholingeric: 382 (90%) participants were given concomitant treatment for COPD during the study; 267 (70%) salbutamol and 115 (30%) ipratropium bromide Short‐acting β2 agonist: salbutamol used in 70% Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: lung function: change in FEV1, SGRQ Secondary outcomes: peak expiratory flow and FVC, the first dose effect of active treatment on FEV₁
Notes	Post‐bronchodilator results not given so pre‐bronchodilator values used in analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Described as randomised. No other information available
Randomised?	Low risk	"Eligible patients were randomly assigned to receive a 5, 10, or 15 mg tablet of cilomilast twice daily (morning and evening) or matching placebo for 6 weeks."
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	"14 patients (13%) taking cilomilast 15 mg had adverse events leading to patient withdrawal, as did 12 each in the 5 and 10 mg groups (11 and 12%, respectively) and eight (8%) in the placebo group."
Baseline profile: anticholingeric use	Unclear risk	Information not available
Baseline profile: β2 agonist use	Low risk	102 (24%) participants had been taking long‐acting ß₂‐ agonists; e.g. salmeterol, formoterol
Baseline profile: corticosteroid use	Low risk	331 (78%) individuals had taken other medications for their COPD, the most common being inhaled steroids. 229 (54%) took beclomethasone, budesonide or fluticasone

COPD safety pool

Methods	14 double‐blind and placebo‐controlled studies (Roflumilast FK1 101; Roflumilast FK1 103; Roflumilast IN‐108; Roflumilast M2‐107; Roflumilast M2‐110; Roflumilast M2‐111; Roflumilast M2‐112; Roflumilast M2‐118; Roflumilast M2‐119; Roflumilast M2‐121; Roflumilast M2‐124; Roflumilast M2‐125; Roflumilast M2‐127; Roflumilast M2‐128)
Participants	See individual studies
Interventions	Roflumilast 500 µg once daily Roflumilast 250 µg once daily Placebo once daily
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	See individual studies
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	See individual studies
Blinding?	Unclear risk	Double‐blind
Method of blinding described?	Unclear risk	See individual studies
Description of withdrawals and drop‐outs?	Unclear risk	See individuals studies
Baseline profile: anticholingeric use	Unclear risk	See individuals studies
Baseline profile: β2 agonist use	Unclear risk	See individuals studies
Baseline profile: corticosteroid use	Unclear risk	See individuals studies

RO‐2455‐301‐RD (ACROSS)

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 43 centres in mainland China, Hong Kong and Singapore Participants: 626 (500 µg roflumilast: 313, placebo: 313) Baseline characteristics: mean age: 64 years, 91% male, mean FEV₁% predicted of 36%, mean smoking history of 37.2 pack‐years for roflumilast and 37.5 pack‐years for placebo) or current smokers (24% and 29%, respectively) Inclusion criteria: Chinese, Malay or Indian ethnicity, age 40‐80 years with severe‐very severe COPD FEV₁/FVC ≤ 0.7, and post‐bronchodilator FEV₁ ≤ 50%. Current smokers or ex‐smokers with smoking history > 10 pack‐years or current smokers. 12‐month history of COPD and ≥ 14 puffs of rescue medication during the week prior to randomisation Exclusion criteria: primary bronchiectasis, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease, or active TB, lower respiratory tract infection, diagnosis of asthma at < 40 years of age, or a₁‐antitrypsin deficiency Total number of participant withdrawals: 67 (21.4%) and 50 (16%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks, single‐blind. Placebo tablets to assess suitability Roflumilast 500 µg once daily Placebo once daily Concomitant medication Participants were allowed to continue taking fixed combinations of ICS plus LABA or LAMA monotherapy (e.g. tiotropium) if taken at a stable dose for at least 6 months prior to the run‐in period. SAMAs (e.g., ipratropium) were allowed at a constant daily dose as concomitant medication if taken on a regular basis for at least 4 weeks prior to study inclusion. All other COPD treatments were not allowed
Outcomes	Primary outcomes: lung function; change in pre‐bronchodilator FEV₁ Secondary outcomes: change in post‐bronchodilator FEV_1, FVC, incidence rate of COPD exacerbations, time to first COPD exacerbation, transition dyspnoea index, proportional of participants experiencing a COPD exacerbation, adverse events, changes in body weight, laboratory values, vital signs and physical examination findings
Notes	NCT number: NCT01313494 Funded by Takeda
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling.
Randomised?	Low risk	The investigators used an automated, interactive voice‐response system to randomly assign participants.
Method of randomisation described?	Low risk	The sponsor generated a list of participant numbers using a pseudorandom number generator
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	Tablets were identical in appearance.
Description of withdrawals and drop‐outs?	Unclear risk	Total number of participants that discontinued 50 (16%) placebo, 67 (21.4%) roflumilast
Baseline profile: anticholingeric use	Low risk	LAMA: 17.9% for placebo; 20.4% for roflumilast SAMA: 18.2% for placebo; 17.3% for roflumilast
Baseline profile: β2 agonist use	Unclear risk	No information available. SABA allowed
Baseline profile: corticosteroid use	Low risk	ICS/LABA: 55.9% for placebo; 59.7% for roflumilast

RO‐2455‐404‐RD (REACT)

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 203 centres in 21 countries (see online appendix) Participants: 1945 (500 µg roflumilast: 969; placebo: 966) Baseline characteristics: mean age: 65 years, 75% male, mean FEV₁% predicted of 35%, mean smoking history of 48 pack‐years for roflumilast and 48 pack‐years for placebo) or current smokers (42% and 45%, respectively) Inclusion criteria: ≥ 40 years with a smoking history of at least 20 pack‐years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation (confirmed by a post‐bronchodilator FEV₁/FVC ratio < 0·70 and a post‐bronchodilator FEV₁ of ≤ 50% predicted), symptoms of chronic bronchitis, and a history of at least two exacerbations in the previous year Participants must have been taking an ICS–LABA combination for 12 months before the study and a constant dose of an ICS–LABA fixed combination for at least 3 months before enrolment, with placebo tablet compliance of 80%–125% during the 4‐week baseline observation period and with a total cough and sputum score of ≥ 14 (in which the score was a sum of daily scores on 4‐point scales for cough and sputum) recorded in a daily diary during the week preceding the randomisation visit Exclusion criteria: chronic obstructive pulmonary disease exacerbation that was ongoing during the baseline period, or had a diagnosis of asthma or other major lung disease Total number of participant withdrawals: 269 (28%) and 192 (20%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks, single‐blind. Placebo tablets to assess suitability Roflumilast 500 µg once daily Placebo once daily Concomitant medication All participants used a fixed‐dose ICS–LABA combination during the baseline and treatment period. If a participant had an exacerbation that needed additional treatment during the study, the investigator could give them up to 40 mg prednisolone, administered systemically, per day for 7–14 days. In the case of purulent sputum or suspected bacterial infection, additional antibiotic therapy was allowed The use of the following treatments was not allowed: oral and parenteral glucocorticosteroids (except to treat acute exacerbations), LABA or ICS mono therapy, SAMA, and any short‐acting β2 agonists (with the exception of salbutamol) or oral β2 agonists Participants already taking inhaled tiotropium bromide (a LAMA) were allowed to continue this treatment
Outcomes	Primary outcomes: rate of moderate‐to‐severe chronic obstructive pulmonary disease exacerbations per patient per year. This was assessed in several ways: rate of exacerbations; % with exacerbation; time to first, second or third exacerbation; NNTB to avoid 1 moderate to severe exacerbation Secondary outcomes: change in post‐bronchodilator FEV_1, rate of severe chronic obstructive pulmonary disease exacerbations per patient per year, laboratory values, vital signs, physical examination findings, changes in bodyweight and body‐mass index, and reported adverse events, including mortality
Notes	NCT number: NCT01329029 Sponsored by Takeda
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	All parties involved in the study were masked to treatment assignment
Randomised?	Low risk	Randomised
Method of randomisation described?	Low risk	Enrolled participants were randomly assigned in a 1:1 ratio, with a block size of 4, by a computerised central randomisation system, the Interactive Voice Response System–Interactive Web Response System (PPD Global Limited, Cambridge, UK)
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	Roflumilast and placebo were supplied as identical yellow triangular tablets in wallet cards containing 40 tablets
Description of withdrawals and drop‐outs?	Unclear risk	269 participants (28%) discontinued from study in the roflumilast group and 192 (20%) discontinued from the placebo group
Baseline profile: anticholingeric use	Unclear risk	LAMA: 69% for placebo; 70% for roflumilast
Baseline profile: β2 agonist use	Unclear risk	No group differences stated; however 1900 (98%) of 1935 participants were using a combination of ICS–LABA according to the protocol
Baseline profile: corticosteroid use	Unclear risk	As above

Roflumilast DAL‐MD‐01

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: stated
Participants	Setting: single centre in USA Participants: 27 (500 µg roflumilast: 11, placebo: 16) Baseline characteristics: mean age: 62 years, 64% male, mean FEV₁% predicted of 45%, mean smoking history of 44 pack‐years for roflumilast and 47 pack‐years for placebo) or current smokers (63% and 55%, respectively) Inclusion criteria: > 40 years old with a diagnosis of moderate‐to‐severe COPD as defined by Global Initiative for Chronic Obstructive Lung Disease criteria, current or former cigarette smokers with more than 10 pack‐years of total consumption, chronic bronchitis defined by chronic cough and sputum production lasting at least 3 months for 2 consecutive years Exclusion criteria: asthma as defined by the American Thoracic Society/European Respiratory Society guidelines, clinically significant bronchiectasis, known sensitivity to roflumilast, the use of other methylxanthines (specifically theophylline) within 1 month of screening, changes to maintenance COPD therapy within 1 month of screening Total number of participant withdrawals: 1 (9%) and 1 (6%) from treatment and control groups, respectively
Interventions	Run‐in: no run in Roflumilast 500 µg once daily Placebo once daily Concomitant medication Allowed, except for theophylline. For roflumilast and placebo groups respectively: LAMA was used by 8 (50%) and 6 (55%); ICS or LABA/ICS was used by 10 (63%) 6 (55%)
Outcomes	Primary outcomes: change in induced sputum AcPGP at 12 weeks post‐randomisation in an intention‐to‐treat analysis Secondary outcomes: changes in plasma AcPGP, sputum neutrophil counts, additional sputum biomarkers, 6MWT, the Breathlessness Cough and Sputum Scale, SGRQ scores, and changes in post‐bronchodilator FEV₁ at the 12‐week visit
Notes	NCT number: NCT01572948
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Unclear risk	Randomised
Method of randomisation described?	Unclear risk	Sealed envelope. Block randomisation schema using a block size of four and an allocation ratio of 1:1. Block randomization was stratified by current smoking status and ICS use
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	Identical white tablets containing a 30‐day supply of either roflumilast, 500 mg or placebo
Description of withdrawals and drop‐outs?	Low risk	No withdrawals described
Baseline profile: anticholingeric use	Unclear risk	Not stated
Baseline profile: β2 agonist use	Unclear risk	Not stated
Baseline profile: corticosteroid use	Unclear risk	Not stated

Roflumilast FK1 101

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 26 weeks Intention‐to‐treat analysis: stated
Participants	Setting: not stated Participants: 516 (roflumilast 250 µg: 175, roflumilast 500 µg: 169, placebo: 172) Baseline characteristics: median age: 61‐62 years. 72% male. Mean 38 to 63 pack‐years. 53% current smokers Inclusion criteria: aged 40‐75 years. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Reversibility < 12% or 200 mL post‐bronchodilator FEV₁ 35%‐75% predicted Exclusion criteria: not stated Participant withdrawals: not stated
Interventions	Run‐in: 2 weeks with placebo Roflumilast 500 µg once daily Roflumilast 250 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: allowed at a constant daily dose for those treated before with anticholinergics on a constant dosage Short‐acting β2 agonist: salbutamol was allowed as rescue medication Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: post‐bronchodilator FEV₁ and FEF between 25%‐75% of vital capacity Secondary outcomes: number of moderate or severe COPD exacerbations which required treatment with oral steroids
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Randomised. No other information available
Randomised?	Low risk	Participants randomised in either roflumilast 250 µg, roflumilast 500 µg or placebo groups
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	High risk	Not stated
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Roflumilast FK1 103

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: not stated Participants: 518 (roflumilast 500 µg: 200, placebo: 186) Baseline characteristics: mean age: 60 years. 75% male. 62% current smokers. Average of 35 pack‐years Inclusion criteria: aged 40‐75 years. FEV₁/FVC ≤ 0.7. Post‐bronchodilator FEV₁ 35%‐75% of predicted. FEV₁ reversibility ≤ 12% and ≤ 200 mL. Pre‐bronchodilator FEV₁/FVC ≤ 70% Exclusion criteria: not stated Participant withdrawals not stated
Interventions	Run‐in: 2 weeks with placebo Roflumilast 500 µg once daily for 24 weeks Roflumilast 500 µg once daily for 12 weeks. Placebo once daily for following 12 weeks Concomitant medication Short‐acting anticholingeric: all medications were withdrawn except constant dose short‐acting anticholinergics Short‐acting β2 agonist: as rescue medication Corticosteroid: none Long‐acting β2 bronchodilator: none Used alongside short‐acting ß₂ agonists (available to all)
Outcomes	Primary outcomes: results for 12/24 week post‐bronchodilator FEV₁
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	No information available
Randomised?	Low risk	"After randomisation, patients received placebo or roflumilast 500 µg once daily for 24 weeks or roflumilast 500 µg for 12 weeks followed by placebo for 12 weeks"
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	High risk	Not stated
Baseline profile: anticholingeric use	Unclear risk	No further information available
Baseline profile: β2 agonist use	Unclear risk	No further information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Roflumilast FLUI‐2011‐77

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 6 months Intention‐to‐treat analysis: stated Responder analysis for the most part
Participants	Setting: 2 centres Participants: 41 (500 µg roflumilast: 30, placebo: 11) Baseline characteristics: not stated Inclusion criteria: not stated Exclusion criteria: not stated Total number of participant withdrawals: not stated
Interventions	Run‐in: not stated Concomitant medication: not stated
Outcomes	Primary outcomes: postbronchodilation: spirometry, body plethysmography, 6MWT, Patient reported outcomes Secondary outcomes: not stated
Notes	NCT number: NCT01480661 Funded by Takeda
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Unclear risk	Not stated
Baseline profile: anticholingeric use	Unclear risk	Not stated
Baseline profile: β2 agonist use	Unclear risk	Not stated
Baseline profile: corticosteroid use	Unclear risk	Not stated

Roflumilast IN‐108

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: not stated
Participants	Setting: 5 centres in India Participants: 118 recruited (roflumilast 500 µg: 47; roflumilast 200 µg: 46, placebo: 25) Baseline characteristics: mean age: 60 years. 98% male. 41% current smokers. Post‐bronchodilator FEV₁ of 57%‐61%. Average of 25 pack‐years Inclusion criteria: not stated Exclusion criteria: not stated Participant withdrawals: roflumilast 500 µg: 13 (28%); roflumilast 200 µg: 7 (15%) and 10 (40%) from control group
Interventions	Roflumilast 250 µg once daily Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: not stated Short‐acting β2 agonist: not stated Corticosteroid: none Long‐acting β2 bronchodilator: not stated
Outcomes	To study the safety and tolerability of roflumilast 250 μg versus roflumilast 500 μg versus placebo To investigate the effect of roflumilast 250 μg versus roflumilast 500 μg versus placebo on pulmonary function, efficacy rating and exacerbation rate To evaluate plasma levels of roflumilast and its major metabolite roflumilast N‐oxide Note: only the third objective is discussed here
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blind
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Data as above
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Roflumilast JP‐706

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: not stated
Participants	Setting: Japan Participants: 600 (roflumilast 250 µg: 205, roflumilast 500 µg: 204, placebo: 191) Baseline characteristics: mean age: 70 years. 96% male. Post‐bronchodilator FEV₁ not stated. Average of 56 pack‐years. 37% current smokers Inclusion criteria: not stated Exclusion criteria: not stated Total number of participant withdrawals: not stated
Interventions	Run‐in: single‐blind 4 weeks with placebo Roflumilast 500 µg once daily Roflumilast 250 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: used at a constant daily dose Short‐acting β2 agonist: not stated Corticosteroid: not stated Long‐acting β2 bronchodilator: not stated
Outcomes	To investigate the efficacy and safety after 24‐week treatment of APTA‐2217 (roflumilast) at doses of 500 µg and 250 µg in people with COPD using placebo as a control To investigate the pharmacokinetics of roflumilast and roflumilast N‐oxide after repeated administration of APTA‐2217 at doses of 500 µg and 250 µg
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blind
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	High risk	Not described
Baseline profile: anticholingeric use	Low risk	Constant dose of short anticholinergics used in 35% (roflumilast 500 µg), 33% (roflumilast 200 µg) and 33% (placebo), respectively
Baseline profile: β2 agonist use	Unclear risk	Not described
Baseline profile: corticosteroid use	Unclear risk	Not described

Roflumilast M2‐107

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 159 centres in Australia, Austria, Belgium, Canada, France, Germany, Hungary, Ireland, South Africa, Spain and the UK Participants: 1411 (roflumilast 250 µg: 576, roflumilast 500 µg: 555, placebo: 280) Baseline characteristics: median age: 64 years. 74% male. Post‐bronchodilator FEV₁ is 51% for both groups. Average of 42 pack‐years. 45% current smokers Inclusion criteria: aged ≥ 40 with history of COPD > 12 months. FEV₁ < 50% predicted, FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. Reversibility < 12% or 200 mL. Mean post‐bronchodilator FEV₁ 30%‐80% predicted Exclusion criteria: asthma, lung cancer or bronchiectasis, long‐term oxygen treatment, recent exacerbation that required a course of systemic corticosteroids, emergency room treatment or hospital admission within 4 weeks before the run‐in period Total number of participant withdrawals: 124 (22%) and 32 (11%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo Roflumilast 500 µg once daily Roflumilast 250 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: used at a constant daily dose Short‐acting β2 agonist: salbutamol as rescue medication Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: post‐bronchodilator FEV₁ and SGRQ total score Secondary outcomes: change from baseline in pre‐bronchodilator FEV₁, post‐bronchodilator FVC, post‐bronchodilator FEV in 6 seconds and FVC, FEF rate between 25%‐75% of vital capacity and number of moderate or severe COPD exacerbations
Notes	There is inconsistency in the quoting of statistical errors. Within the text and Table 2, data are quoted as "least squares means and SD", however in Figures 2 and 3, SE bars are shown. It is more likely that the results represent SE and not SD
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	"No person involved in data analysis had knowledge of the randomisation sequence"
Randomised?	Low risk	"Treatment was assigned by the investigators with sequential study numbers according to a block randomisation list in ratios of 2:2:1 (Roflumilast 250 µg, Roflumilast 500 µg, Placebo)."
Method of randomisation described?	Low risk	"The randomisation sequence was generated by ALTANA Pharma AG in a blinded manner"
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"Medication boxes were labelled with the study protocol number, randomisation number, and visit code; coding prevented the investigator and people at the study centre from knowing which medication was given."
Description of withdrawals and drop‐outs?	Low risk	100 participants discontinued from study from the roflumilast 250 µg group, 124 from the roflumilast 500 µg group and 32 from the placebo group
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Roflumilast M2‐110

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: not stated
Participants	Setting: 36 centres in Argentina, Canada, Columbia, Mexico, Peru and the USA Participants: estimated enrolment of 1000 participants Baseline characteristics: not stated Inclusion criteria: Clinical diagnosis of COPD Currently stable COPD with no change in COPD treatment in the prior 4 weeks Exclusion criteria: Clinical diagnosis of asthma Poorly controlled COPD Regular need for daily oxygen therapy Total number of participant withdrawals: not stated
Interventions	Roflumilast 500 µg daily versus placebo
Outcomes	Primary outcomes: pulmonary function Secondary outcomes: exacerbation rate, quality of life, symptoms, use of rescue medication, safety and tolerability
Notes	ClinicalTrials.gov Identifier: nCT00062582
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blind
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Unclear risk	Not stated
Baseline profile: anticholingeric use	Unclear risk	Not stated
Baseline profile: β2 agonist use	Unclear risk	Not stated
Baseline profile: corticosteroid use	Unclear risk	Not stated

Roflumilast M2‐111

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: M2‐111 was conducted in 188 centres in 6 countries, and M2‐112 in 159 centres in 14 countries Participants: data combined with M2‐112 showing 2686 (roflumilast 500 µg: 1327, placebo: 1359), suggesting total n for this study was 1173. Baseline characteristics: severe COPD according to GOLD criteria grades III and IV. Mean age: 64‐65 years. 72% male Inclusion criteria: aged ≥ 40 years. Post‐bronchodilator FEV₁ < 50% predicted. Reversibility < 15%. Mean post‐bronchodilator FEV₁ 42%. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. 40% current smokers, 60% ex‐smokers; average 46‐48 pack‐years Exclusion criteria: history of asthma, lung cancer or bronchiectasis, need for long‐term oxygen therapy, known α₁antitrypsin deficiency or clinically significant cardiopulmonary co‐morbidity Total number of participant withdrawals: data combined with M2‐112 showing 433 (33%) and 348 (26%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: 891 patients on short‐acting anticholinergics Short‐acting β2 agonist: salbutamol as rescue medication Corticosteroid: 943 patients continued corticosteroid use Long‐acting β2 bronchodilator: none Used alongside corticosteroids, anticholinergics and rescue short‐acting ß₂ agonists 54% overall (available to all)
Outcomes	Primary outcomes: change from baseline to endpoint in post‐bronchodilator FEV₁ and the number of moderate or severe exacerbations per patient per year Secondary outcomes: change from baseline in SGRQ total score, change from baseline in prebronchial FEV₁, post‐bronchodilator FEV in 6 seconds and FVC, FEF rate between 25%‐75% of vital capacity and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	"Each study participant who qualified was assigned a number in sequential order. Code labelling prevented the investigator and the patient from knowing which drug was administered."
Randomised?	Low risk	"randomised (1:1)"
Method of randomisation described?	Low risk	"The randomisation list was generated using a multiplicative congruential pseudorandom number generator (program RANDOM, based on Fishman and Moore)."
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"There was a stratification of patients according to smoking status (current smokers/ex‐smokers) and treatment with inhaled corticosteroids (yes/no)."
Description of withdrawals and drop‐outs?	Low risk	Data combined with M2‐112
Baseline profile: anticholingeric use	Low risk	Data combined with M2‐112 showing 1604 (60%) participants used anticholinergics
Baseline profile: β2 agonist use	Low risk	1463 (55%) participants on short‐acting β₂‐agonists
Baseline profile: corticosteroid use	Low risk	1622 (61%) on concomitant ICS

Roflumilast M2‐111+M2‐112

Methods	As described in separate studies above and below
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	See individual trials
Randomised?	Low risk	See individual trials
Method of randomisation described?	Low risk	See individual trials
Blinding?	Low risk	See individual trials
Method of blinding described?	Low risk	See individual trials
Description of withdrawals and drop‐outs?	Low risk	See individual trials
Baseline profile: anticholingeric use	Low risk	See individual trials
Baseline profile: β2 agonist use	Low risk	See individual trials
Baseline profile: corticosteroid use	Low risk	See individual trials

Roflumilast M2‐112

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 159 centres in 14 countries Participants: 1513 (roflumilast 500 µg: 760, placebo: 753) Baseline characteristics: severe COPD according to GOLD criteria grades III and IV. Mean age: 65 years. 75% male Inclusion criteria: aged ≥ 40 years. Post‐bronchodilator FEV₁ < 50% predicted. Reversibility < 15%. Mean post‐bronchodilator FEV₁ 41%. FEV₁/FVC ≤ 0.7 with smoking history > 10 pack‐years. 37% current smokers, 63% ex‐smokers; average 44 pack‐years Exclusion criteria: history of asthma, lung cancer or bronchiectasis, need for long‐term oxygen therapy, known α₁antitrypsin deficiency or clinically significant cardiopulmonary co‐morbidity Total number of participant withdrawals: 217 (29%) and 163 (22%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: 891 participants on short‐acting anticholinergics Short‐acting β2 agonist: salbutamol as rescue medication Corticosteroid: 943 participants continued corticosteroid use Long‐acting β2 bronchodilator: none Used alongside corticosteroids, anticholinergics and rescue short‐acting ß₂ agonists 54% overall (available to all)
Outcomes	Primary outcomes: change from baseline to endpoint in post‐bronchodilator FEV₁ and the number of moderate or severe exacerbations per patient per year Secondary outcomes: change from baseline in SGRQ total score, change from baseline in prebronchial FEV₁, post‐bronchodilator FEV in 6 seconds and FVC, FEF rate between 25%‐75% of vital capacity and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	"Each study participant who qualified was assigned a number in sequential order. Code labelling prevented the investigator and the patient from knowing which drug was administered."
Randomised?	Low risk	"randomised (1:1)"
Method of randomisation described?	Low risk	"The randomisation list was generated using a multiplicative congruential pseudorandom number generator (program RANDOM, based on Fishman and Moore)."
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"There was a stratification of patients according to smoking status (current smokers/ex‐smokers) and treatment with inhaled corticosteroids (yes/no)."
Description of withdrawals and drop‐outs?	Low risk	"Over 70% of patients completed the study. The reasons for withdrawal were similar between groups except for adverse events, which occurred more frequently with roflumilast." "Withdrawal due to COPD exacerbations was reported in 3.5 and 3.2% of patients in roflumilast and placebo groups, respectively."
Baseline profile: anticholingeric use	Low risk	739 participants used anticholinergics
Baseline profile: β2 agonist use	Low risk	820 participants on short‐acting β₂‐agonists
Baseline profile: corticosteroid use	Low risk	727 participants on beclomethasone dipropionate 2000 µg or less

Roflumilast M2‐118

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 22 centres in 4 countries Participants: 250 (roflumilast 500 µg: 127, placebo: 123) Baseline characteristics: mean age: 60 years. 73% (roflumilast) versus 84% (placebo) male. Post‐bronchodilator FEV₁ 55% predicted. Average of 41 pack‐years. 53% current smokers Inclusion criteria: participants were clinically stable patients ≥ 40 years with a smoking history of > 10 pack‐years and a 12‐month history of COPD. Other inclusion criteria included: post‐bronchodilator FEV₁ 30%‐80% predicted, FEV₁/forced vital capacity (FVC) < 0.7 and set plethysmographic FRC and peak oxygen uptake requirements Exclusion criteria: asthma or a lung disease other than COPD; a1‐antitrypsin deficiency; participation in a pulmonary rehabilitation programme within 2 months; supplemental oxygen therapy; a significant medical comorbidity that may influence exercise tolerance Total number of participant withdrawals: 16 (13%) and 12 (10%) from treatment and control groups, respectively
Interventions	Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: participants could use ipratropium bromide in regular stable doses as needed Short‐acting β2 agonist: participants could use short‐acting β₂‐agonists as needed Corticosteroid: ICS were permitted throughout the study if taken at a constant dosage for > 3 months prior to the study Long‐acting β2 bronchodilator: none
Outcomes	Activity‐related dyspnoea (TDI). Spirometry and body plethysmography. Symptom‐limited exercise tests
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	A 1:1 randomisation ratio was used
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Of the 250 randomised participants, 16 from the roflumilast group and 12 from the placebo group discontinued prematurely
Baseline profile: anticholingeric use	Unclear risk	Not stated
Baseline profile: β2 agonist use	Unclear risk	Not stated
Baseline profile: corticosteroid use	Unclear risk	Not stated

Roflumilast M2‐119

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 32 centres in 5 countries Participants: 410 (roflumilast 500 µg: 203, placebo: 207) Baseline characteristics: mean age: 68 years. 93% male. Post‐bronchodilator FEV₁ 50.5% predicted. Average of 44 pack‐years. 69% current smokers Inclusion criteria: former or current smokers with at least a 10 pack‐year history. Aged ≥ 40 years. Post‐bronchodilator FEV₁/FVC ≤ 0.7 and FEV₁ of 30%‐80%. Clinically stable COPD within 4 weeks prior to baseline Exclusion criteria: history of asthma or other relevant lung disease, COPD exacerbation with the 4 weeks prior to baseline, need for long‐term oxygen therapy, known α₁antitrypsin deficiency or clinically significant cardiopulmonary co‐morbidity Total number of participant withdrawals: 40 (20%) and 18 (9%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: "Short‐acting anticholinergics at a constant daily dosage as concomitant medication if already taken on a regular basis at a constant dosage for at least 4 weeks prior to the study." Short‐acting β2 agonist: patients could use short‐acting β₂ agonists as needed Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcome: mean change in post‐bronchodilator FEV₁ from baseline Secondary outcomes: mean change in pre‐bronchodilator FEV₁ from baseline, change in other lung function measures, time to COPD exacerbation, proportion of participants experiencing exacerbations, time to study withdrawal and adverse effects
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Low risk	Computer‐generated randomisation list used
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Low risk	Participant numbers at different stages of the study described in figure
Baseline profile: anticholingeric use	Unclear risk	Not stated
Baseline profile: β2 agonist use	Unclear risk	Not stated
Baseline profile: corticosteroid use	Unclear risk	Not stated

Roflumilast M2‐121

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 12 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 16 centres in 6 countries Participants: estimated enrolment 550 participants Baseline characteristics: not stated Inclusion criteria: people with a history of COPD for at least 12 months as defined by the GOLD criteria, age ≥ 40 years, FEV1/FVC ratio (post‐bronchodilator) ≤ 70%, FEV₁ (post‐bronchodilator) ≤ 65% of predicted, FRC (post‐bronchodilator) ≤ 120% of predicted Exclusion criteria: COPD exacerbation indicated by a treatment with systemic glucocorticosteroids not stopped at least 4 weeks prior to the baseline visit, non‐smoker, current smoker or ex‐smoker (smoking cessation at least 1 year ago) with a smoking history of < 10 pack‐years, or suffering from any concomitant disease that might interfere with study procedures or evaluation Total number of participant withdrawals: not stated
Interventions	500 µg roflumilast tablets once daily versus placebo
Outcomes	Primary outcome: lung function parameters indicative of hyperinflation in people with COPD Secondary outcomes: Mean change from randomisation to endpoint in additional pre‐ and post‐bronchodilator spirometric and lung volume parameters Measurement of quality of life parameters and dyspnoea
Notes	ClinicalTrials.gov Identifier: NCT00108823
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double‐blind
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Unclear risk	Not stated
Baseline profile: anticholingeric use	Unclear risk	Not stated
Baseline profile: β2 agonist use	Unclear risk	Not stated
Baseline profile: corticosteroid use	Unclear risk	Not stated

Roflumilast M2‐124

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 246 centres in 10 countries Participants: 1513 (roflumilast 500 µg: 760, placebo: 753) Baseline characteristics: mean age: 64 years. 71% male. Post‐bronchodilator FEV₁ 37.6% predicted. Average of 47 pack‐years. 48% current smokers Inclusion criteria: former or current smokers with at least a 20 pack‐year history. Aged ≥ 40 years. Post‐bronchodilator FEV₁/FVC ≤ 0.7. Chronic cough and sputum production. Post‐bronchodilator FEV₁ < 50% predicted. At least 1 recorded COPD exacerbation requiring systemic glucocorticosteroids or treatment in hospital in previous year Exclusion criteria: available in the online web appendix (pg 11) Total number of participant withdrawals: 264 (34%) and 234 (31%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: 31% of those in the roflumilast group and 32% on placebo Short‐acting β2 agonist: "Patients could use short acting β₂ agonists as needed" Corticosteroid: none Long‐acting β2 bronchodilator: "Eligible patients were stratified according to their use of long acting β2 agonists and smoking status." Roflumilast 49%, placebo 51%
Outcomes	Primary outcomes: mean change in pre‐bronchodilator FEV₁ from baseline to each post‐randomisation visit during the treatment period. Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids or requiring hospitalisation or leading to death, per patient per year Secondary outcomes: mean change in post‐bronchodilator FEV₁ from baseline to each post‐randomisation visit during the treatment period. Time to mortality due to any reason. Natural log‐transformed C Reactive Protein (mg/L), Mean TDI focal score during the treatment period
Notes	Adverse event data are pooled with numbers from study M2‐125 that followed an identical study design
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	All individuals involved in the studies were unaware of treatment assignment
Randomised?	Low risk	"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?	Low risk	"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"All individuals involved in the studies were unaware of treatment assignment. Tablets were identical in appearance. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling."
Description of withdrawals and drop‐outs?	Low risk	264 participants discontinued from study in the roflumilast group and 234 discontinued from the placebo group
Baseline profile: anticholingeric use	Unclear risk	No other information available
Baseline profile: β2 agonist use	Unclear risk	No other information available
Baseline profile: corticosteroid use	High risk	Pretreatment of 44% in both roflumilast and placebo groups

Roflumilast M2‐124+M2‐125

Methods	As described in separate studies above and below
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	See individual studies
Randomised?	Low risk	See individual studies
Method of randomisation described?	Low risk	See individual studies
Blinding?	Low risk	See individual studies
Method of blinding described?	Low risk	See individual studies
Description of withdrawals and drop‐outs?	Low risk	See individual studies
Baseline profile: anticholingeric use	Low risk	See individual studies
Baseline profile: β2 agonist use	Low risk	See individual studies
Baseline profile: corticosteroid use	High risk	See individual studies

Roflumilast M2‐125

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 221 centres in 8 countries Participants: 1571 (roflumilast 500 µg: 773, placebo: 798) Baseline characteristics: mean age: 64 years. 80% male. Average of 48 pack‐years. 35% current smokers Inclusion criteria: former or current smokers with at least a 20 pack‐year history. Aged ≥ 40 years. Post‐bronchodilator FEV₁/FVC ≤ 0.7. Chronic cough and sputum production. Post‐bronchodilator FEV₁ < 50% predicted. At least 1 recorded COPD exacerbation requiring systemic glucocorticosteroids or treatment in hospital in previous year Exclusion criteria: available in the online web appendix (pg 11) Total number of participant withdrawals: 246 (32%) and 248 (31%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo Roflumilast 500 µg once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: 38% of those in the roflumilast group and 41% on placebo Short‐acting β2 agonist: "Patients could use short acting β₂ agonists as needed" Corticosteroid: none Long‐acting β2 bronchodilator: "Eligible patients were stratified according to their use of long acting β2 agonists and smoking status." Roflumilast 48%, placebo 51%
Outcomes	Primary outcomes: mean change in pre‐bronchodilator FEV₁ from baseline to each post‐randomisation visit during the treatment period. Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids or requiring hospitalisation or leading to death, per patient per year Secondary outcomes: mean change in post‐bronchodilator FEV₁ from baseline to each post‐randomisation visit during the treatment period. Time to mortality due to any reason. Natural log‐transformed CRP (mg/L), Mean TDI focal score during the treatment period
Notes	Adverse event data are pooled with numbers from study M2‐124 that followed an identical study design
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	All individuals involved in the studies were unaware of treatment assignment
Randomised?	Low risk	"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?	Low risk	"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"All individuals involved in the studies were unaware of treatment assignment. Tablets were identical in appearance. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling."
Description of withdrawals and drop‐outs?	Low risk	246 patients discontinued from study in the roflumilast group and 248 discontinued from the placebo group
Baseline profile: anticholingeric use	Low risk	No other information available
Baseline profile: β2 agonist use	Low risk	No other information available
Baseline profile: corticosteroid use	High risk	Pretreatment of 40% in both roflumilast and placebo groups

Roflumilast M2‐127

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 135 centres in 10 countries Participants: 1221 (roflumilast 500 µg: 467, placebo: 468) Baseline characteristics: mean age: 65 years. 71% male. Post‐bronchodilator FEV₁ 54.7% and 55.3% predicted (roflumilast and placebo). Average of 43 pack‐years. 39% current smokers Inclusion criteria: former or current smokers with (≥ 1 year smoking cessation) and at least a 10 pack‐year history. Aged ≥ 40 years. Post‐bronchodilator FEV₁/FVC ≤ 0.7. Post‐bronchodilator FEV₁ 40% to 70% predicted. Partial reversibility to albuterol with increase from baseline FEV₁ of ≤ 12% or 200 mL Exclusion criteria: available in the online web appendix (pg 10) Total number of participant withdrawals: 107 (23%) and 82 (18%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo once a day Roflumilast 500 µg and salmeterol once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: none Short‐acting β2 agonist: participants used short‐acting β₂ as rescue medication Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: change in mean pre‐bronchodilator FEV₁ from baseline to each post‐randomisation visit Secondary outcomes: post‐bronchodilator FEV₁ and FVC, TDI score, SOBQ, rate of COPD exacerbations, and use of rescue medication
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	All individuals involved in the studies were unaware of treatment assignment
Randomised?	Low risk	"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?	Low risk	"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"All individuals involved in the studies were unaware of treatment assignment. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling. Tablets were identical in appearance."
Description of withdrawals and drop‐outs?	Low risk	107 participants discontinued from study in the roflumilast group and 82 discontinued from the placebo group
Baseline profile: anticholingeric use	Unclear risk	No other information available
Baseline profile: β2 agonist use	Unclear risk	No other information available
Baseline profile: corticosteroid use	Unclear risk	No other information available

Roflumilast M2‐128

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 24 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 85 centres in 7 countries Participants: 910 (roflumilast 500 µg: 372, placebo: 372) Baseline characteristics: mean age: 64 years. 71% male. Post‐bronchodilator FEV₁ 56.0% and 56.2% predicted (roflumilast and placebo). Average of 44 pack‐years. 40% current smokers Inclusion criteria: former or current smokers with (≥ 1 year smoking cessation) and at least a 10 pack‐year history. Aged ≥ 40 years. Post‐bronchodilator FEV₁/FVC ≤ 0.7. Post‐bronchodilator FEV₁ 40% to 70% predicted. Partial reversibility to albuterol with increase from baseline FEV₁ of ≤ 12% or 200 mL Exclusion criteria: available in the online web appendix (pg 10) Total number of participant withdrawals: 62 (17%) and 39 (11%) from treatment and control groups, respectively
Interventions	Run‐in: 4 weeks with placebo once a day Roflumilast 500 µg and tiotropium once daily Placebo once daily Concomitant medication Short‐acting anticholingeric: none Short‐acting β2 agonist: participants used short‐acting β₂ as rescue medication Corticosteroid: none Long‐acting β2 bronchodilator: none
Outcomes	Primary outcomes: change in mean pre‐bronchodilator FEV₁ from baseline to each post‐randomisation visit Secondary outcomes: post‐bronchodilator FEV₁ and FVC, TDI score, SOBQ, rate of COPD exacerbations and use of rescue medication
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	All individuals involved in the studies were unaware of treatment assignment
Randomised?	Low risk	"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?	Low risk	"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?	Low risk	Double‐blinded
Method of blinding described?	Low risk	"All individuals involved in the studies were unaware of treatment assignment. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling. Tablets were identical in appearance."
Description of withdrawals and drop‐outs?	Low risk	62 participants discontinued from study in the roflumilast group and 39 discontinued from the placebo group
Baseline profile: anticholingeric use	Unclear risk	No information available
Baseline profile: β2 agonist use	Unclear risk	No information available
Baseline profile: corticosteroid use	Unclear risk	No information available

Roflumilast ROF‐MD‐07(RE2SPOND)

Methods	Parallel‐group study Randomisation: randomised, double‐blind, placebo‐controlled trial Trial duration: 52 weeks Intention‐to‐treat analysis: stated
Participants	Setting: 338 locations across Australia, Argentina, Canada, Chile, Columbia, Italy, Malaysia, Peru, Phillippines, Romania, Russia, Serbia, Spain, Taiwan, Ukraine Participants: 2354 (500 µg roflumilast: 1178; placebo: 1176) Baseline characteristics: mean age: 64 years, 68% male, mean FEV₁% predicted of 33%, mean smoking history of 52.2 pack‐years for roflumilast and 53.1 pack‐years for placebo) or current smokers (39% and 40%, respectively) Inclusion criteria: ≥ 40 years with severe‐very severe COPD, chronic bronchitis, ≥ 2 exacerbations and/or hospitalisations in the previous year, and were receiving ICS/LABA with or without LAMA daily for ≥ 3 months Exclusion criteria: participants were excluded if, within the 4 weeks prior to enrolment, they had a moderate or severe COPD exacerbation and/or COPD exacerbation treated with antibiotics or systemic corticosteroids or a lower respiratory tract infection. Other exclusionary criteria included diagnoses of other lung diseases, moderate‐to‐severe liver impairment (Child‐Pugh B or C), HIV or hepatitis infection, current diagnosis of asthma, cancer in the past 5 years, α1‐antitrypsin deficiency, a clinically significant cardiovascular condition, a resting QTc interval > 470 ms, or a body mass index ≥ 45 kg/m Total number of participant withdrawals: 337 (29%) and 254 (21%) from treatment and control groups, respectively
Interventions	Run‐in: 2 weeks, single‐blind. Placebo tablets to assess suitability Roflumilast 500 µg once daily Placebo once daily Concomitant medication ICS/LABA FDC (fluticasone propionate/salmeterol, 250/50 mg (1 inhalation twice a day), or budesonide/formoterol, 160/4.5 mg (2 inhalations twice a day) Participants taking fluticasone propionate/salmeterol, 500/50 mg, at study entry were required to switch to the lower dosage (250/50 mg) before entry. Up to 60% of participants were allowed concomitant LAMA (e.g. tiotropium) if administered for ≥3 months before screening, with no dose change. Those not on LAMA were allowed a SAMA.
Outcomes	Primary outcomes: rate of moderate or severe COPD exacerbations per patient per year Secondary outcomes: rate of severe exacerbations, rate of moderate or severe antibiotic‐treated COPD exacerbations, and mean change from baseline in predose FEV₁ over 52 weeks, frequency of moderate or severe COPD exacerbations, median time to first moderate or severe exacerbation, mean changes from baseline in predose FVC, mean changes from baseline over time in the COPD Assessment Test (CAT), and daily symptoms measured via EXAcerbation of Chronic Pulmonary Disease Tool–Patient Reported Outcomes (EXACT‐PRO), adverse events, Columbia‐Suicide Severity Rating Scale, laboratory parameters and vital signs
Notes	NCT01443845 Sponsored by Activas and Astra Zeneca
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	Not stated
Randomised?	Low risk	Randomised
Method of randomisation described?	Unclear risk	Not stated
Blinding?	Low risk	Double blind
Method of blinding described?	Unclear risk	Not stated
Description of withdrawals and drop‐outs?	Unclear risk	337 participants (29%) discontinued from study in the roflumilast group and 254 (22%) discontinued from the placebo group
Baseline profile: anticholingeric use	Unclear risk	LAMA: 47% for placebo; 47% for roflumilast
Baseline profile: β2 agonist use	Unclear risk	Combined LABA/ICS Fluticasone propionate/salmeterol FDC 65% for placebo; 65% for roflumilast Budesonide/formoterol FDC 35% for placebo; 35% for roflumilast
Baseline profile: corticosteroid use	Unclear risk	As above

CAT: COPD Assessment Test; COPD: chronic obstructive pulmonary disease; DLCO: diffusing capacity of the lung for carbon monoxide; FDC: fixed dose combination; FEF: forced expiratory flow; FEV₁: forced expiratory volume in one second; FRC: functional residual capacity; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; IC: inspiratory capacity; ICS: inhaled corticosteroid; L: litre; LABA: Long‐acting beta‐2 agonist; LAMA: Long acting muscarinic antagonist; MDI: metered dose inhaler; mL: millilitre; RFRC: resting functional residue capacity; RV: residual volume; SAMA: Short acting muscarinic antagonist; SD: standard deviation; SE: standard error; SGRQ: St George's Respiratory Questionnaire
SOBQ: Shortness of Breath Questionnaire; SVC: slow vital capacity; TDI: transition dyspnoea index; 6MWT: 6‐minute walk test

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos
estudios a la espera de clasificación
estudios en curso

Study	Reason for exclusion
Borker 2003	Insufficient data. Only RR of QOL improvement provided
Ferguson 2003	Integrated results from four 24‐week cilomilast trials
Fischer 2003	Analysis focused on participants with a baseline SGRQ score of ≥ the median SGRQ score only
Grootendorst 2001	Endpoint: first dose‐bronchodilator effects only
Grootendorst 2002	Treatment Bayer BAY 19‐8004; 11 participants only 1 week in duration
Grootendorst 2003	Endpoint: first‐dose bronchodilator effects only
Grootendorst 2007	Cross‐over design
GSK256066	Phase II trial. No primary outcome measure investigating lung function. Only 1 trial to date
Kelsen 2002	No study ID or group numbers identified
Knobil 2003	No SD or SE given
Lim 2004	Combining results from 2 pivotal European phase III cilomilast trials
Nieman 1999	Study 038. Insufficient data available for changes in lung function and exacerbation rates
Pascoe 2007	Treatment QAK423 (Novartis), discontinued. Only 1 trial available
Reisner 2003	Combined results. Individual studies already included in review
Roflumilast JP708	JP108 is an extension study of APTA‐2217‐06 study. After the key‐open of APTA‐2217‐06 study, administration to placebo group would be terminated. Not all participants enrolled in JP106 continued onto the JP108 study
Sadigov 2014	No placebo group
Sadigov 2015	Open label. No placebo group
SB207499/040	Open‐label study. Men or women with COPD who successfully completed study 042 or 091 where participants received cilomilast 15 mg twice daily or placebo for 24 weeks in study 042 and 26 weeks in study 091 without tolerability problems. Concomitant COPD medication use allowed, given placebo or placebo/Ariflo during study period
SB207499/041	Open‐label study. Men or women with COPD who successfully completed study 039 where participants received cilomilast 15 mg twice daily or placebo for 24 weeks without tolerability problems. Concomitant COPD medication use allowed, given placebo or placebo/Ariflo during study period
Song 2005	Abstract only. Unable to contact study author
Spencer 2002	No study ID or group numbers identified
Vestbo 2007	Treatment UK‐500,001 (Pfizer). Discontinued
Vestbo 2009	Treatment UK‐500,001 (Pfizer). Discontinued
Wang 2005	Although quoted as significant, mean and SD figures not provided
Watz 2013	Inhaled therapy

COPD: chronic obstructive pulmonary disease
RR: risk ratio
QOL: quality of life
SD: standard deviation
SE: standard error

Characteristics of studies awaiting assessment [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos
estudios en curso

Barnes 2014

Methods	An international, 16‐week, randomised, 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
Participants	150 participants with COPD and chronic bronchitis for at least 12 months will be recruited into the study and randomized in a 1:1 ratio to receive either roflumilast or placebo
Interventions	Roflumilast and placebo
Outcomes	The primary endpoint will be the number of CD8+ cells in bronchial biopsy tissue specimens (sub‐mucosa) and the key secondary endpoint will be the number of CD68+ cells assessed by indirect immunohistochemistry
Notes	Completed awaiting results

Mahmud 2013

Methods	Single‐blind, randomised, placebo‐controlled study was carried out in the Department of Respiratory Medicine at National Institute of Diseases of the Chest and Hospital (NIDCH), Dhaka, Bangladesh
Participants	130 participants were recruited initially and randomly distributed into Group‐A where they got conventional therapy (inhaled salmeterol + fluticasone and tiotropium) and roflumilast (0.5 mg once daily) and Group‐ B where participants got placebo with conventional therapy. Study duration was 3 months
Interventions	As above
Outcomes	The primary outcome variable was change in mean FEV₁ and secondary outcome variable was change in mean CAT score from baseline
Notes	No data provided. Study authors contacted

CAT: COPD Assessment Test
COPD: chronic obstructive pulmonary disease

Characteristics of ongoing studies [ordered by study ID]

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estudios incluidos
estudios excluidos
estudios a la espera de clasificación

NCT02451540 2015

Trial name or title	Evaluation of the effect of roflumilast in hyperinflated COPD patients using functional respiratory imaging
Methods	Parallel RCT
Participants	40 people who are stable on LABA/LAMA therapy and who are prone to dynamics hyperinflation
Interventions	Roflumilast and placebo
Outcomes	Radiological (CT) changes in airway measures Changes in spirometry and body plethysmography
Starting date	September 2015
Contact information	University Hospital of Antwerp
Notes	Other Study ID Numbers: FLUI‐2014‐134, EudraCT Estimated study completion date: January 2017

NCT02671942 2016

Trial name or title	A multicenter randomized double‐blind clinical study evaluated the safety, pharmacokinetic and pharmacodynamic characteristics of roflumilast in COPD patients
Methods	Parallel RCT
Participants	People with COPD in China
Interventions	Roflumilast and placebo
Outcomes	Area under the plasma concentration after versus drug dose Percentage of participants with adverse events of interest Change in pre‐bronchodilator FEV₁ during the down titration period
Starting date	March 2016
Contact information	Contact: Zheng Jinping
Notes	Estimated enrolment: 120 Estimated study completion date: August 2017

COPD: chronic obstructive pulmonary disease
FEV₁: forced expiratory volume in first second
RCT: randomised controlled trial

Data and analyses

Open in table viewer

Comparison 1. PDE4 inhibitor versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV₁ (by drug) Show forest plot	27	20585	Mean Difference (IV, Random, 95% CI)	51.53 [43.17, 59.90]
Open in figure viewer Analysis 1.1 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 1 FEV₁ (by drug).
1.1 Roflumilast 500 μg	17	14230	Mean Difference (IV, Random, 95% CI)	56.45 [48.01, 64.89]
1.2 Roflumilast 250 μg	3	1033	Mean Difference (IV, Random, 95% CI)	56.88 [24.38, 89.38]
1.3 Cilomilast 15 mg	10	5322	Mean Difference (IV, Random, 95% CI)	41.03 [23.93, 58.13]
2 FEV₁ (by mean COPD severity) Show forest plot	21	16659	Mean Difference (IV, Fixed, 95% CI)	52.77 [46.73, 58.82]
Open in figure viewer Analysis 1.2 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 2 FEV₁ (by mean COPD severity).
2.1 GOLD grade I + II (FEV1 ≥ 50% predicted)	9	4647	Mean Difference (IV, Fixed, 95% CI)	51.79 [38.99, 64.59]
2.2 GOLD grade III + IV (FEV1 < 50% predicted)	12	12012	Mean Difference (IV, Fixed, 95% CI)	53.06 [46.19, 59.92]
3 FEV₁ (Roflumilast 500 μg by mean COPD severity) Show forest plot	15	13742	Mean Difference (IV, Fixed, 95% CI)	55.51 [48.88, 62.14]
Open in figure viewer Analysis 1.3 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 3 FEV₁ (Roflumilast 500 μg by mean COPD severity).
3.1 GOLD grade I + II (FEV1 ≥ 50% predicted)	6	3187	Mean Difference (IV, Fixed, 95% CI)	69.86 [53.34, 86.38]
3.2 GOLD grade III + IV (FEV1 < 50% predicted)	9	10555	Mean Difference (IV, Fixed, 95% CI)	52.75 [45.52, 59.99]
4 FEV₁ (by study duration) Show forest plot	27	19785	Mean Difference (IV, Fixed, 95% CI)	49.08 [43.85, 54.32]
Open in figure viewer Analysis 1.4 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 4 FEV₁ (by study duration).
4.1 Duration ≤ 12 weeks	7	1037	Mean Difference (IV, Fixed, 95% CI)	102.21 [71.26, 133.16]
4.2 Duration 24 to 26 weeks	13	8086	Mean Difference (IV, Fixed, 95% CI)	46.14 [38.44, 53.84]
4.3 Duration 52 weeks	7	10662	Mean Difference (IV, Fixed, 95% CI)	48.77 [41.44, 56.10]
5 FEV₁ (additional medication) Show forest plot	27	19565	Mean Difference (IV, Fixed, 95% CI)	49.08 [43.84, 54.31]
Open in figure viewer Analysis 1.5 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 5 FEV₁ (additional medication).
5.1 Long‐acting bronchodilator	2	1645	Mean Difference (IV, Fixed, 95% CI)	60.52 [40.57, 80.46]
5.2 Corticosteroids	3	2904	Mean Difference (IV, Fixed, 95% CI)	42.26 [25.46, 59.05]
5.3 PDE4i treatment only	19	10169	Mean Difference (IV, Fixed, 95% CI)	44.78 [37.67, 51.90]
5.4 Various concomitant treatments	3	4847	Mean Difference (IV, Fixed, 95% CI)	56.58 [46.91, 66.25]
6 FEV₁ (published versus unpublished) Show forest plot	27	19785	Mean Difference (IV, Fixed, 95% CI)	49.23 [43.99, 54.46]
Open in figure viewer Analysis 1.6 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 6 FEV₁ (published versus unpublished).
6.1 Published	19	15244	Mean Difference (IV, Fixed, 95% CI)	55.75 [49.44, 62.06]
6.2 Unpublished	8	4541	Mean Difference (IV, Fixed, 95% CI)	34.82 [25.44, 44.19]
7 FEV₁ (random‐effects model) Show forest plot	27	19785	Mean Difference (IV, Random, 95% CI)	51.47 [42.68, 60.26]
Open in figure viewer Analysis 1.7 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 7 FEV₁ (random‐effects model).
8 FEV₁ (roflumilast 500 μg versus 250 μg) Show forest plot	3	1560	Mean Difference (IV, Fixed, 95% CI)	22.61 [‐5.95, 51.16]
Open in figure viewer Analysis 1.8 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 8 FEV₁ (roflumilast 500 μg versus 250 μg).
9 FVC Show forest plot	16	21954	Mean Difference (IV, Fixed, 95% CI)	87.28 [74.87, 99.70]
Open in figure viewer Analysis 1.9 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 9 FVC.
10 PEF Show forest plot	5	4245	Mean Difference (IV, Fixed, 95% CI)	6.54 [3.95, 9.13]
Open in figure viewer Analysis 1.10 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 10 PEF.
10.1 Roflumilast 500 μg	4	3685	Mean Difference (IV, Fixed, 95% CI)	5.46 [2.74, 8.17]
10.2 Roflumilast 250 μg	1	347	Mean Difference (IV, Fixed, 95% CI)	7.0 [‐4.05, 18.05]
10.3 Cilomilast 15 mg	1	213	Mean Difference (IV, Fixed, 95% CI)	34.0 [20.14, 47.86]
11 SGRQ total score Show forest plot	11	7645	Mean Difference (IV, Fixed, 95% CI)	‐1.06 [‐1.68, ‐0.43]
Open in figure viewer Analysis 1.11 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 11 SGRQ total score.
11.1 Roflumilast 500 μg	3	2235	Mean Difference (IV, Fixed, 95% CI)	‐0.79 [‐2.16, 0.58]
11.2 Roflumilast 250 μg	1	716	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐3.56, 0.36]
11.3 Cilomilast 15 mg	8	4694	Mean Difference (IV, Fixed, 95% CI)	‐1.06 [‐1.81, ‐0.31]
12 SGRQ total score (by published versus unpublished) Show forest plot	11	7069	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐1.65, ‐0.34]
Open in figure viewer Analysis 1.12 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 12 SGRQ total score (by published versus unpublished).
12.1 Published	5	3079	Mean Difference (IV, Fixed, 95% CI)	‐1.98 [‐3.07, ‐0.89]
12.2 Unpublished	6	3990	Mean Difference (IV, Fixed, 95% CI)	‐0.43 [‐1.26, 0.40]
13 SGRQ total score (by duration) Show forest plot	11	7069	Mean Difference (IV, Fixed, 95% CI)	‐0.99 [‐1.65, ‐0.33]
Open in figure viewer Analysis 1.13 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 13 SGRQ total score (by duration).
13.1 Duration < 12 weeks	2	240	Mean Difference (IV, Fixed, 95% CI)	‐4.19 [‐7.60, ‐0.78]
13.2 Duration 24 to 26 weeks	7	4600	Mean Difference (IV, Fixed, 95% CI)	‐1.18 [‐1.94, ‐0.42]
13.3 Duration 52 weeks	2	2229	Mean Difference (IV, Fixed, 95% CI)	0.26 [‐1.18, 1.69]
14 SGRQ total score (by mean COPD severity) Show forest plot	8	4851	Mean Difference (IV, Fixed, 95% CI)	‐1.56 [‐2.39, ‐0.74]
Open in figure viewer Analysis 1.14 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 14 SGRQ total score (by mean COPD severity).
14.1 GOLD grade I and II	3	2042	Mean Difference (IV, Fixed, 95% CI)	‐1.62 [‐2.80, ‐0.44]
14.2 GOLD grade III and IV	5	2809	Mean Difference (IV, Fixed, 95% CI)	‐1.51 [‐2.67, ‐0.34]
15 SGRQ symptom score Show forest plot	2	1048	Mean Difference (IV, Fixed, 95% CI)	‐1.53 [‐4.11, 1.06]
Open in figure viewer Analysis 1.15 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 15 SGRQ symptom score.
15.1 Roflumilast	1	835	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐3.78, 1.78]
15.2 Cilomilast	1	213	Mean Difference (IV, Fixed, 95% CI)	‐4.80 [‐11.73, 2.13]
16 Number of participants with one or more exacerbations (by drug) Show forest plot	23	19948	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.73, 0.83]
Open in figure viewer Analysis 1.16 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 16 Number of participants with one or more exacerbations (by drug).
16.1 Roflumilast 500 μg	13	14420	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.73, 0.86]
16.2 Cilomilast	10	5528	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.67, 0.85]
17 Number of participants on roflumilast with one or more exacerbations (additional medication) Show forest plot	13	14420	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.73, 0.86]
Open in figure viewer Analysis 1.17 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 17 Number of participants on roflumilast with one or more exacerbations (additional medication).
17.1 Long‐acting bronchodilators	2	1676	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.54, 0.88]
17.2 Corticosteroids	1	2686	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.70, 0.95]
17.3 Treatment only	7	5145	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.67, 0.93]
17.4 Various concomitant treatments	3	4913	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.72, 0.91]
18 Exacerbation rate (inverse variance) Show forest plot	9		Rate Ratio (Fixed, 95% CI)	0.88 [0.83, 0.93]
Open in figure viewer Analysis 1.18 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 18 Exacerbation rate (inverse variance).
18.1 Roflumilast	8		Rate Ratio (Fixed, 95% CI)	0.87 [0.82, 0.92]
18.2 Cilomilast	1		Rate Ratio (Fixed, 95% CI)	0.95 [0.78, 1.17]
19 Borg Scale Show forest plot	6	2860	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.33, ‐0.05]
Open in figure viewer Analysis 1.19 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 19 Borg Scale.
19.1 Cilomilast	6	2860	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.33, ‐0.05]
20 Summary symptom score Show forest plot	5	6186	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.07, 0.03]
Open in figure viewer Analysis 1.20 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 20 Summary symptom score.
20.1 Roflumilast	2	4287	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.08, 0.04]
20.2 Cilomilast	3	1899	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.13, 0.06]
21 Shortness of breath questionnaire Show forest plot	2	1633	Mean Difference (IV, Fixed, 95% CI)	‐1.09 [‐2.47, 0.28]
Open in figure viewer Analysis 1.21 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 21 Shortness of breath questionnaire.
22 6‐minute walk test Show forest plot	5	1975	Mean Difference (IV, Fixed, 95% CI)	2.09 [‐7.39, 11.57]
Open in figure viewer Analysis 1.22 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 22 6‐minute walk test.
22.1 Roflumilast	1	27	Mean Difference (IV, Fixed, 95% CI)	55.0 [‐111.29, 221.29]
22.2 Cilomilast	4	1948	Mean Difference (IV, Fixed, 95% CI)	1.92 [‐7.58, 11.41]
23 Number of participants experiencing an adverse effect Show forest plot	27	20988	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [1.22, 1.37]
Open in figure viewer Analysis 1.23 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 23 Number of participants experiencing an adverse effect.
23.1 Roflumilast 500 μg	13	14446	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.24, 1.42]
23.2 Cilomilast 15 mg	14	6542	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [1.08, 1.36]
24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg) Show forest plot	4	1977	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [1.01, 1.46]
Open in figure viewer Analysis 1.24 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg).
25 Diarrhoea Show forest plot	25	20181	Odds Ratio (M‐H, Fixed, 95% CI)	3.13 [2.76, 3.54]
Open in figure viewer Analysis 1.25 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 25 Diarrhoea.
25.1 Roflumilast	11	13639	Odds Ratio (M‐H, Fixed, 95% CI)	3.72 [3.15, 4.38]
25.2 Cilomilast	14	6542	Odds Ratio (M‐H, Fixed, 95% CI)	2.47 [2.05, 2.98]
26 Nausea Show forest plot	24	20627	Odds Ratio (M‐H, Fixed, 95% CI)	3.78 [3.23, 4.43]
Open in figure viewer Analysis 1.26 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 26 Nausea.
26.1 Roflumilast 500 μg	10	13229	Odds Ratio (M‐H, Fixed, 95% CI)	3.21 [2.57, 4.03]
26.2 Roflumilast 250 μg	1	856	Odds Ratio (M‐H, Fixed, 95% CI)	3.97 [0.91, 17.39]
26.3 Cilomilast 15 mg	14	6542	Odds Ratio (M‐H, Fixed, 95% CI)	4.37 [3.49, 5.47]
27 Headache Show forest plot	21	18977	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [1.47, 1.95]
Open in figure viewer Analysis 1.27 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 27 Headache.
27.1 Roflumilast 500 μg	10	13327	Odds Ratio (M‐H, Fixed, 95% CI)	2.15 [1.76, 2.63]
27.2 Roflumilast 250 μg	1	347	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.24, 3.99]
27.3 Cilomilast 15 mg	11	5303	Odds Ratio (M‐H, Fixed, 95% CI)	1.32 [1.08, 1.62]
28 Vomiting Show forest plot	11	5828	Odds Ratio (M‐H, Fixed, 95% CI)	4.01 [2.80, 5.74]
Open in figure viewer Analysis 1.28 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 28 Vomiting.
28.1 Roflumilast	1	835	Odds Ratio (M‐H, Fixed, 95% CI)	1.52 [0.06, 37.37]
28.2 Cilomilast	10	4993	Odds Ratio (M‐H, Fixed, 95% CI)	4.06 [2.83, 5.82]
29 Dyspepsia Show forest plot	13	6247	Odds Ratio (M‐H, Fixed, 95% CI)	3.17 [2.33, 4.30]
Open in figure viewer Analysis 1.29 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 29 Dyspepsia.
29.1 Roflumilast	1	626	Odds Ratio (M‐H, Fixed, 95% CI)	7.07 [0.36, 137.40]
29.2 Cilomilast	12	5621	Odds Ratio (M‐H, Fixed, 95% CI)	3.13 [2.30, 4.27]
30 Abdominal pain Show forest plot	13	8165	Odds Ratio (M‐H, Fixed, 95% CI)	2.04 [1.63, 2.55]
Open in figure viewer Analysis 1.30 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 30 Abdominal pain.
30.1 Roflumilast	2	2561	Odds Ratio (M‐H, Fixed, 95% CI)	2.76 [1.35, 5.62]
30.2 Cilomilast	11	5604	Odds Ratio (M‐H, Fixed, 95% CI)	1.97 [1.55, 2.49]
31 Weight loss Show forest plot	9	12178	Odds Ratio (M‐H, Fixed, 95% CI)	3.76 [3.11, 4.54]
Open in figure viewer Analysis 1.31 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 31 Weight loss.
31.1 Roflumilast	9	12178	Odds Ratio (M‐H, Fixed, 95% CI)	3.76 [3.11, 4.54]
32 Influenza‐like symptoms Show forest plot	9	11460	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.87, 1.36]
Open in figure viewer Analysis 1.32 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 32 Influenza‐like symptoms.
32.1 Roflumilast 500 μg	7	10147	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.87, 1.41]
32.2 Roflumilast 250 μg	1	347	Odds Ratio (M‐H, Fixed, 95% CI)	1.98 [0.18, 22.00]
32.3 Cilomilast 15 mg	2	966	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.44, 1.75]
33 Upper respiratory tract infection Show forest plot	20	16902	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.79, 1.02]
Open in figure viewer Analysis 1.33 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 33 Upper respiratory tract infection.
33.1 Roflumilast 500 μg	10	11419	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.75, 1.07]
33.2 Roflumilast 250 μg	2	1203	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.54, 1.31]
33.3 Cilomilast 15 mg	10	4280	Odds Ratio (M‐H, Fixed, 95% CI)	0.92 [0.75, 1.13]
34 Withdrawals due to adverse events Show forest plot	28	20996	Odds Ratio (M‐H, Fixed, 95% CI)	1.90 [1.74, 2.09]
Open in figure viewer Analysis 1.34 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 34 Withdrawals due to adverse events.
34.1 Roflumilast 500 μg	14	14451	Odds Ratio (M‐H, Fixed, 95% CI)	1.91 [1.71, 2.13]
34.2 Cilomilast 15 mg	14	6545	Odds Ratio (M‐H, Fixed, 95% CI)	1.90 [1.61, 2.24]
35 Non‐fatal serious adverse events Show forest plot	24	18689	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.91, 1.07]
Open in figure viewer Analysis 1.35 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 35 Non‐fatal serious adverse events.
35.1 Roflumilast 500 μg	10	12144	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.93, 1.11]
35.2 Cilomilast 15 mg	14	6545	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.72, 1.06]
36 Mortality Show forest plot	23	19344	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.76, 1.23]
Open in figure viewer Analysis 1.36 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 36 Mortality.
36.1 Roflumilast	10	13012	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.78, 1.29]
36.2 Cilomilast	13	6332	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.34, 1.45]
37 All psychiatric disorders (roflumilast) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.37 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 37 All psychiatric disorders (roflumilast).
37.1 Roflumilast 500 μg	1	11168	Odds Ratio (M‐H, Fixed, 95% CI)	2.13 [1.79, 2.54]
37.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.56, 1.33]
38 Insomnia and sleep disorders (roflumilast) Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.38 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 38 Insomnia and sleep disorders (roflumilast).
38.1 Roflumilast 500 μg	4	15482	Odds Ratio (M‐H, Fixed, 95% CI)	2.67 [2.11, 3.38]
38.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.81, 2.70]
39 Anxiety or anxiety disorder (roflumilast) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.39 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 39 Anxiety or anxiety disorder (roflumilast).
39.1 Roflumilast 500 μg	1	11168	Odds Ratio (M‐H, Fixed, 95% CI)	1.81 [1.26, 2.62]
39.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.40, 2.21]
40 Depression (roflumilast) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.40 Comparison 1 PDE₄ inhibitor versus placebo, Outcome 40 Depression (roflumilast).
40.1 Roflumilast 500 μg	1	11168	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [1.11, 2.27]
40.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.20, 1.56]

Figure 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.

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Figure 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.

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Figure 3

Study flow diagram

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Figure 4

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Funnel plot of comparison: 1 PDE4 inhibitor versus placebo, outcome: 1.6 FEV1 (published versus unpublished).

Figure 5

Funnel plot of comparison: 1 PDE₄ inhibitor versus placebo, outcome: 1.6 FEV₁ (published versus unpublished).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 1 FEV1 (by drug).

Analysis 1.1

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 1 FEV₁ (by drug).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 2 FEV1 (by mean COPD severity).

Analysis 1.2

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 2 FEV₁ (by mean COPD severity).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 3 FEV1 (Roflumilast 500 μg by mean COPD severity).

Analysis 1.3

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 3 FEV₁ (Roflumilast 500 μg by mean COPD severity).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 4 FEV1 (by study duration).

Analysis 1.4

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 4 FEV₁ (by study duration).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 5 FEV1 (additional medication).

Analysis 1.5

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 5 FEV₁ (additional medication).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 6 FEV1 (published versus unpublished).

Analysis 1.6

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 6 FEV₁ (published versus unpublished).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 7 FEV1 (random‐effects model).

Analysis 1.7

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 7 FEV₁ (random‐effects model).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 8 FEV1 (roflumilast 500 μg versus 250 μg).

Analysis 1.8

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 8 FEV₁ (roflumilast 500 μg versus 250 μg).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 9 FVC.

Analysis 1.9

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 9 FVC.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 10 PEF.

Analysis 1.10

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 10 PEF.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 11 SGRQ total score.

Analysis 1.11

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 11 SGRQ total score.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 12 SGRQ total score (by published versus unpublished).

Analysis 1.12

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 12 SGRQ total score (by published versus unpublished).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 13 SGRQ total score (by duration).

Analysis 1.13

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 13 SGRQ total score (by duration).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 14 SGRQ total score (by mean COPD severity).

Analysis 1.14

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 14 SGRQ total score (by mean COPD severity).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 15 SGRQ symptom score.

Analysis 1.15

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 15 SGRQ symptom score.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 16 Number of participants with one or more exacerbations (by drug).

Analysis 1.16

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 16 Number of participants with one or more exacerbations (by drug).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 17 Number of participants on roflumilast with one or more exacerbations (additional medication).

Analysis 1.17

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 17 Number of participants on roflumilast with one or more exacerbations (additional medication).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 18 Exacerbation rate (inverse variance).

Analysis 1.18

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 18 Exacerbation rate (inverse variance).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 19 Borg Scale.

Analysis 1.19

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 19 Borg Scale.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 20 Summary symptom score.

Analysis 1.20

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 20 Summary symptom score.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 21 Shortness of breath questionnaire.

Analysis 1.21

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 21 Shortness of breath questionnaire.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 22 6‐minute walk test.

Analysis 1.22

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 22 6‐minute walk test.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 23 Number of participants experiencing an adverse effect.

Analysis 1.23

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 23 Number of participants experiencing an adverse effect.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg).

Analysis 1.24

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 25 Diarrhoea.

Analysis 1.25

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 25 Diarrhoea.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 26 Nausea.

Analysis 1.26

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 26 Nausea.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 27 Headache.

Analysis 1.27

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 27 Headache.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 28 Vomiting.

Analysis 1.28

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 28 Vomiting.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 29 Dyspepsia.

Analysis 1.29

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 29 Dyspepsia.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 30 Abdominal pain.

Analysis 1.30

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 30 Abdominal pain.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 31 Weight loss.

Analysis 1.31

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 31 Weight loss.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 32 Influenza‐like symptoms.

Analysis 1.32

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 32 Influenza‐like symptoms.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 33 Upper respiratory tract infection.

Analysis 1.33

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 33 Upper respiratory tract infection.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 34 Withdrawals due to adverse events.

Analysis 1.34

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 34 Withdrawals due to adverse events.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 35 Non‐fatal serious adverse events.

Analysis 1.35

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 35 Non‐fatal serious adverse events.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 36 Mortality.

Analysis 1.36

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 36 Mortality.

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 37 All psychiatric disorders (roflumilast).

Analysis 1.37

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 37 All psychiatric disorders (roflumilast).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 38 Insomnia and sleep disorders (roflumilast).

Analysis 1.38

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 38 Insomnia and sleep disorders (roflumilast).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 39 Anxiety or anxiety disorder (roflumilast).

Analysis 1.39

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 39 Anxiety or anxiety disorder (roflumilast).

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Comparison 1 PDE4 inhibitor versus placebo, Outcome 40 Depression (roflumilast).

Analysis 1.40

Comparison 1 PDE₄ inhibitor versus placebo, Outcome 40 Depression (roflumilast).

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Summary of findings for the main comparison. Phosphodiesterase 4 inhibitors compared to placebo for chronic obstructive pulmonary disease

Phosphodiesterase 4 inhibitors compared to placebo for chronic obstructive pulmonary disease
Patient or population: people with stable chronic obstructive pulmonary disease Settings: community‐based, randomised, parallel, double‐blind, placebo‐controlled trials Intervention: phosphodiesterase 4 inhibitors Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)¹	Comments
	Assumed risk	Corresponding risk
	Placebo	Phosphodiesterase IV inhibitors
Change in FEV₁ lung function (mL) Follow‐up: mean 28.0 weeks	The mean change in FEV₁ lung function in the control groups was a fall of 20.67 mL	The mean change in FEV₁ lung function in the intervention groups was 49.27 mL better (44.11 to 54.44 higher)		20,585 (27 studies)	⊕⊕⊕⊝ moderate^2,3
Change in quality of life St George's Respiratory Questionnaire Follow‐up: mean 24.2 weeks	The mean change in quality of life in the control groups was an improvement of 2.21SGRQ units	The mean change in quality of life in the intervention groups was 1.06 units better (0.43 to 1.68)		7645 (11 studies)	⊕⊕⊕⊝ moderate^2,3	Lower scores on SGRQ represent improved quality of life. This result does not reach the minimum clinically important difference for this scale.
COPD exacerbations No. of participants with exacerbations Follow‐up: 12 to 52 weeks	33 per 100	28 per 100 (26 to 29)	OR 0.78 (0.73 to 0.83)	19,948 (23 studies)	⊕⊕⊕⊕ high	See Figure 1
Adverse events No. of participants experiencing any adverse event Follow‐up: 6 to 52 weeks	64 per 100	69 per 100 (70 to 73)	OR 1.29 (1.22 to 1.37)	20,988 (27 studies)	⊕⊕⊕⊝ moderate⁴	This outcome includes participants who reported COPD exacerbations as an adverse event
Gastrointestinal side effects No. of participants experiencing diarrhoea Follow‐up: 6 to 52 weeks	4 per 100	11 per 100 (10 to 12)	OR 3.13 (2.76 to 3.54)	20,181 (25 studies)	⊕⊕⊕⊕ high	Diarrhoea was the most commonly reported gastrointestinal side effect. See Figure 2 Weight loss was more common, and may be a result of diarrhoea
Psychiatric adverse events (roflumilast 500 µg) No. of participants Follow‐up: 12 to 52 weeks	35 per 1000	71 per 1000 (60 to 83)	OR 2.13 (1.79 to 2.54)	11,168 (14 studies)	⊕⊕⊕⊝ moderate⁵	Pooled data from FDA website, not individual trial reports
Mortality (all‐cause) No. of participants Follow‐up: 6 to 52 weeks	1 per 100	1 per 100 (1 to 2)	OR 0.97 (0.76 to 1.23)	19,344 (23 studies)	⊕⊕⊕⊝ moderate⁶
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDA: Food and Drug Administration (USA); FEV₁: forced expiratory volume in one second; OR: odds ratio; SGRQ: St George's Respiratory Questionnaire
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹There was a greater proportion of participant withdrawals in the treatment (24%) compared with the control group (19%), but not sufficient to warrant downgrading the quality of evidence. ²There was moderate heterogeneity between the studies (I² = 30% to 50%). ³There was a statistically significant difference between published and unpublished studies. ⁴There was high level of heterogeneity between study results (I² > 50%). ⁵Based on data from the combined COPD safety pool. Individual study data not obtained. ⁶There were very few events, leading to wide confidence intervals.

Summary of findings for the main comparison. Phosphodiesterase 4 inhibitors compared to placebo for chronic obstructive pulmonary disease

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Table 1. Number of references for which we sought full text

Search date:	No. of references for which we sought full text
December 2008	53
January 2010	5
August 2010	12
June 2013	20
October 2016	28

Table 1. Number of references for which we sought full text

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Comparison 1. PDE4 inhibitor versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV₁ (by drug) Show forest plot	27	20585	Mean Difference (IV, Random, 95% CI)	51.53 [43.17, 59.90]

1.1 Roflumilast 500 μg	17	14230	Mean Difference (IV, Random, 95% CI)	56.45 [48.01, 64.89]
1.2 Roflumilast 250 μg	3	1033	Mean Difference (IV, Random, 95% CI)	56.88 [24.38, 89.38]
1.3 Cilomilast 15 mg	10	5322	Mean Difference (IV, Random, 95% CI)	41.03 [23.93, 58.13]
2 FEV₁ (by mean COPD severity) Show forest plot	21	16659	Mean Difference (IV, Fixed, 95% CI)	52.77 [46.73, 58.82]

2.1 GOLD grade I + II (FEV1 ≥ 50% predicted)	9	4647	Mean Difference (IV, Fixed, 95% CI)	51.79 [38.99, 64.59]
2.2 GOLD grade III + IV (FEV1 < 50% predicted)	12	12012	Mean Difference (IV, Fixed, 95% CI)	53.06 [46.19, 59.92]
3 FEV₁ (Roflumilast 500 μg by mean COPD severity) Show forest plot	15	13742	Mean Difference (IV, Fixed, 95% CI)	55.51 [48.88, 62.14]

3.1 GOLD grade I + II (FEV1 ≥ 50% predicted)	6	3187	Mean Difference (IV, Fixed, 95% CI)	69.86 [53.34, 86.38]
3.2 GOLD grade III + IV (FEV1 < 50% predicted)	9	10555	Mean Difference (IV, Fixed, 95% CI)	52.75 [45.52, 59.99]
4 FEV₁ (by study duration) Show forest plot	27	19785	Mean Difference (IV, Fixed, 95% CI)	49.08 [43.85, 54.32]

4.1 Duration ≤ 12 weeks	7	1037	Mean Difference (IV, Fixed, 95% CI)	102.21 [71.26, 133.16]
4.2 Duration 24 to 26 weeks	13	8086	Mean Difference (IV, Fixed, 95% CI)	46.14 [38.44, 53.84]
4.3 Duration 52 weeks	7	10662	Mean Difference (IV, Fixed, 95% CI)	48.77 [41.44, 56.10]
5 FEV₁ (additional medication) Show forest plot	27	19565	Mean Difference (IV, Fixed, 95% CI)	49.08 [43.84, 54.31]

5.1 Long‐acting bronchodilator	2	1645	Mean Difference (IV, Fixed, 95% CI)	60.52 [40.57, 80.46]
5.2 Corticosteroids	3	2904	Mean Difference (IV, Fixed, 95% CI)	42.26 [25.46, 59.05]
5.3 PDE4i treatment only	19	10169	Mean Difference (IV, Fixed, 95% CI)	44.78 [37.67, 51.90]
5.4 Various concomitant treatments	3	4847	Mean Difference (IV, Fixed, 95% CI)	56.58 [46.91, 66.25]
6 FEV₁ (published versus unpublished) Show forest plot	27	19785	Mean Difference (IV, Fixed, 95% CI)	49.23 [43.99, 54.46]

6.1 Published	19	15244	Mean Difference (IV, Fixed, 95% CI)	55.75 [49.44, 62.06]
6.2 Unpublished	8	4541	Mean Difference (IV, Fixed, 95% CI)	34.82 [25.44, 44.19]
7 FEV₁ (random‐effects model) Show forest plot	27	19785	Mean Difference (IV, Random, 95% CI)	51.47 [42.68, 60.26]

8 FEV₁ (roflumilast 500 μg versus 250 μg) Show forest plot	3	1560	Mean Difference (IV, Fixed, 95% CI)	22.61 [‐5.95, 51.16]

9 FVC Show forest plot	16	21954	Mean Difference (IV, Fixed, 95% CI)	87.28 [74.87, 99.70]

10 PEF Show forest plot	5	4245	Mean Difference (IV, Fixed, 95% CI)	6.54 [3.95, 9.13]

10.1 Roflumilast 500 μg	4	3685	Mean Difference (IV, Fixed, 95% CI)	5.46 [2.74, 8.17]
10.2 Roflumilast 250 μg	1	347	Mean Difference (IV, Fixed, 95% CI)	7.0 [‐4.05, 18.05]
10.3 Cilomilast 15 mg	1	213	Mean Difference (IV, Fixed, 95% CI)	34.0 [20.14, 47.86]
11 SGRQ total score Show forest plot	11	7645	Mean Difference (IV, Fixed, 95% CI)	‐1.06 [‐1.68, ‐0.43]

11.1 Roflumilast 500 μg	3	2235	Mean Difference (IV, Fixed, 95% CI)	‐0.79 [‐2.16, 0.58]
11.2 Roflumilast 250 μg	1	716	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐3.56, 0.36]
11.3 Cilomilast 15 mg	8	4694	Mean Difference (IV, Fixed, 95% CI)	‐1.06 [‐1.81, ‐0.31]
12 SGRQ total score (by published versus unpublished) Show forest plot	11	7069	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐1.65, ‐0.34]

12.1 Published	5	3079	Mean Difference (IV, Fixed, 95% CI)	‐1.98 [‐3.07, ‐0.89]
12.2 Unpublished	6	3990	Mean Difference (IV, Fixed, 95% CI)	‐0.43 [‐1.26, 0.40]
13 SGRQ total score (by duration) Show forest plot	11	7069	Mean Difference (IV, Fixed, 95% CI)	‐0.99 [‐1.65, ‐0.33]

13.1 Duration < 12 weeks	2	240	Mean Difference (IV, Fixed, 95% CI)	‐4.19 [‐7.60, ‐0.78]
13.2 Duration 24 to 26 weeks	7	4600	Mean Difference (IV, Fixed, 95% CI)	‐1.18 [‐1.94, ‐0.42]
13.3 Duration 52 weeks	2	2229	Mean Difference (IV, Fixed, 95% CI)	0.26 [‐1.18, 1.69]
14 SGRQ total score (by mean COPD severity) Show forest plot	8	4851	Mean Difference (IV, Fixed, 95% CI)	‐1.56 [‐2.39, ‐0.74]

14.1 GOLD grade I and II	3	2042	Mean Difference (IV, Fixed, 95% CI)	‐1.62 [‐2.80, ‐0.44]
14.2 GOLD grade III and IV	5	2809	Mean Difference (IV, Fixed, 95% CI)	‐1.51 [‐2.67, ‐0.34]
15 SGRQ symptom score Show forest plot	2	1048	Mean Difference (IV, Fixed, 95% CI)	‐1.53 [‐4.11, 1.06]

15.1 Roflumilast	1	835	Mean Difference (IV, Fixed, 95% CI)	1.00 [‐3.78, 1.78]
15.2 Cilomilast	1	213	Mean Difference (IV, Fixed, 95% CI)	‐4.80 [‐11.73, 2.13]
16 Number of participants with one or more exacerbations (by drug) Show forest plot	23	19948	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.73, 0.83]

16.1 Roflumilast 500 μg	13	14420	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.73, 0.86]
16.2 Cilomilast	10	5528	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.67, 0.85]
17 Number of participants on roflumilast with one or more exacerbations (additional medication) Show forest plot	13	14420	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.73, 0.86]

17.1 Long‐acting bronchodilators	2	1676	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.54, 0.88]
17.2 Corticosteroids	1	2686	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.70, 0.95]
17.3 Treatment only	7	5145	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.67, 0.93]
17.4 Various concomitant treatments	3	4913	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.72, 0.91]
18 Exacerbation rate (inverse variance) Show forest plot	9		Rate Ratio (Fixed, 95% CI)	0.88 [0.83, 0.93]

18.1 Roflumilast	8		Rate Ratio (Fixed, 95% CI)	0.87 [0.82, 0.92]
18.2 Cilomilast	1		Rate Ratio (Fixed, 95% CI)	0.95 [0.78, 1.17]
19 Borg Scale Show forest plot	6	2860	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.33, ‐0.05]

19.1 Cilomilast	6	2860	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.33, ‐0.05]
20 Summary symptom score Show forest plot	5	6186	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.07, 0.03]

20.1 Roflumilast	2	4287	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.08, 0.04]
20.2 Cilomilast	3	1899	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.13, 0.06]
21 Shortness of breath questionnaire Show forest plot	2	1633	Mean Difference (IV, Fixed, 95% CI)	‐1.09 [‐2.47, 0.28]

22 6‐minute walk test Show forest plot	5	1975	Mean Difference (IV, Fixed, 95% CI)	2.09 [‐7.39, 11.57]

22.1 Roflumilast	1	27	Mean Difference (IV, Fixed, 95% CI)	55.0 [‐111.29, 221.29]
22.2 Cilomilast	4	1948	Mean Difference (IV, Fixed, 95% CI)	1.92 [‐7.58, 11.41]
23 Number of participants experiencing an adverse effect Show forest plot	27	20988	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [1.22, 1.37]

23.1 Roflumilast 500 μg	13	14446	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.24, 1.42]
23.2 Cilomilast 15 mg	14	6542	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [1.08, 1.36]
24 Number of participants experiencing an adverse event (Roflumilast 500 μg versus 250 μg) Show forest plot	4	1977	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [1.01, 1.46]

25 Diarrhoea Show forest plot	25	20181	Odds Ratio (M‐H, Fixed, 95% CI)	3.13 [2.76, 3.54]

25.1 Roflumilast	11	13639	Odds Ratio (M‐H, Fixed, 95% CI)	3.72 [3.15, 4.38]
25.2 Cilomilast	14	6542	Odds Ratio (M‐H, Fixed, 95% CI)	2.47 [2.05, 2.98]
26 Nausea Show forest plot	24	20627	Odds Ratio (M‐H, Fixed, 95% CI)	3.78 [3.23, 4.43]

26.1 Roflumilast 500 μg	10	13229	Odds Ratio (M‐H, Fixed, 95% CI)	3.21 [2.57, 4.03]
26.2 Roflumilast 250 μg	1	856	Odds Ratio (M‐H, Fixed, 95% CI)	3.97 [0.91, 17.39]
26.3 Cilomilast 15 mg	14	6542	Odds Ratio (M‐H, Fixed, 95% CI)	4.37 [3.49, 5.47]
27 Headache Show forest plot	21	18977	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [1.47, 1.95]

27.1 Roflumilast 500 μg	10	13327	Odds Ratio (M‐H, Fixed, 95% CI)	2.15 [1.76, 2.63]
27.2 Roflumilast 250 μg	1	347	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.24, 3.99]
27.3 Cilomilast 15 mg	11	5303	Odds Ratio (M‐H, Fixed, 95% CI)	1.32 [1.08, 1.62]
28 Vomiting Show forest plot	11	5828	Odds Ratio (M‐H, Fixed, 95% CI)	4.01 [2.80, 5.74]

28.1 Roflumilast	1	835	Odds Ratio (M‐H, Fixed, 95% CI)	1.52 [0.06, 37.37]
28.2 Cilomilast	10	4993	Odds Ratio (M‐H, Fixed, 95% CI)	4.06 [2.83, 5.82]
29 Dyspepsia Show forest plot	13	6247	Odds Ratio (M‐H, Fixed, 95% CI)	3.17 [2.33, 4.30]

29.1 Roflumilast	1	626	Odds Ratio (M‐H, Fixed, 95% CI)	7.07 [0.36, 137.40]
29.2 Cilomilast	12	5621	Odds Ratio (M‐H, Fixed, 95% CI)	3.13 [2.30, 4.27]
30 Abdominal pain Show forest plot	13	8165	Odds Ratio (M‐H, Fixed, 95% CI)	2.04 [1.63, 2.55]

30.1 Roflumilast	2	2561	Odds Ratio (M‐H, Fixed, 95% CI)	2.76 [1.35, 5.62]
30.2 Cilomilast	11	5604	Odds Ratio (M‐H, Fixed, 95% CI)	1.97 [1.55, 2.49]
31 Weight loss Show forest plot	9	12178	Odds Ratio (M‐H, Fixed, 95% CI)	3.76 [3.11, 4.54]

31.1 Roflumilast	9	12178	Odds Ratio (M‐H, Fixed, 95% CI)	3.76 [3.11, 4.54]
32 Influenza‐like symptoms Show forest plot	9	11460	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.87, 1.36]

32.1 Roflumilast 500 μg	7	10147	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.87, 1.41]
32.2 Roflumilast 250 μg	1	347	Odds Ratio (M‐H, Fixed, 95% CI)	1.98 [0.18, 22.00]
32.3 Cilomilast 15 mg	2	966	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.44, 1.75]
33 Upper respiratory tract infection Show forest plot	20	16902	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.79, 1.02]

33.1 Roflumilast 500 μg	10	11419	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.75, 1.07]
33.2 Roflumilast 250 μg	2	1203	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.54, 1.31]
33.3 Cilomilast 15 mg	10	4280	Odds Ratio (M‐H, Fixed, 95% CI)	0.92 [0.75, 1.13]
34 Withdrawals due to adverse events Show forest plot	28	20996	Odds Ratio (M‐H, Fixed, 95% CI)	1.90 [1.74, 2.09]

34.1 Roflumilast 500 μg	14	14451	Odds Ratio (M‐H, Fixed, 95% CI)	1.91 [1.71, 2.13]
34.2 Cilomilast 15 mg	14	6545	Odds Ratio (M‐H, Fixed, 95% CI)	1.90 [1.61, 2.24]
35 Non‐fatal serious adverse events Show forest plot	24	18689	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.91, 1.07]

35.1 Roflumilast 500 μg	10	12144	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.93, 1.11]
35.2 Cilomilast 15 mg	14	6545	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.72, 1.06]
36 Mortality Show forest plot	23	19344	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.76, 1.23]

36.1 Roflumilast	10	13012	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.78, 1.29]
36.2 Cilomilast	13	6332	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.34, 1.45]
37 All psychiatric disorders (roflumilast) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

37.1 Roflumilast 500 μg	1	11168	Odds Ratio (M‐H, Fixed, 95% CI)	2.13 [1.79, 2.54]
37.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.56, 1.33]
38 Insomnia and sleep disorders (roflumilast) Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

38.1 Roflumilast 500 μg	4	15482	Odds Ratio (M‐H, Fixed, 95% CI)	2.67 [2.11, 3.38]
38.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.81, 2.70]
39 Anxiety or anxiety disorder (roflumilast) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

39.1 Roflumilast 500 μg	1	11168	Odds Ratio (M‐H, Fixed, 95% CI)	1.81 [1.26, 2.62]
39.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.40, 2.21]
40 Depression (roflumilast) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

40.1 Roflumilast 500 μg	1	11168	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [1.11, 2.27]
40.2 Roflumilast 250 μg	1	6288	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.20, 1.56]

Comparison 1. PDE4 inhibitor versus placebo

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Referencias

References to studies included in this review

Cilomilast 039 {published data only}

Cilomilast 042 {unpublished data only}

Cilomilast 076 {published and unpublished data}

Cilomilast 091 {unpublished data only}

Cilomilast 103657 {unpublished data only}

Cilomilast 110 {unpublished data only}

Cilomilast 111 {published and unpublished data}

Cilomilast 121 {unpublished data only}

Cilomilast 156 {unpublished data only}

Cilomilast 157 {unpublished data only}

Cilomilast 168 {published and unpublished data}

Cilomilast 180 {unpublished data only}

Cilomilast 181 {unpublished data only}

Compton 2001 {published and unpublished data}

COPD safety pool {published data only}

RO‐2455‐301‐RD (ACROSS) {published data only}

RO‐2455‐404‐RD (REACT) {published data only}

Roflumilast DAL‐MD‐01 {published data only}

Roflumilast FK1 101 {published and unpublished data}

Roflumilast FK1 103 {published and unpublished data}

Roflumilast FLUI‐2011‐77 {published data only}

Roflumilast IN‐108 {unpublished data only}

Roflumilast JP‐706 {unpublished data only}

Roflumilast M2‐107 {published and unpublished data}

Roflumilast M2‐110 {unpublished data only}

Roflumilast M2‐111 {published data only}

Roflumilast M2‐111+M2‐112 {published data only}

Roflumilast M2‐112 {published and unpublished data}

Roflumilast M2‐118 {published data only}

Roflumilast M2‐119 {published data only}

Roflumilast M2‐121 {unpublished data only}

Roflumilast M2‐124 {published and unpublished data}

Roflumilast M2‐124+M2‐125 {published data only}

Roflumilast M2‐125 {published data only}

Roflumilast M2‐127 {published data only}

Roflumilast M2‐128 {published data only}

Roflumilast ROF‐MD‐07(RE2SPOND) {published data only}

References to studies excluded from this review

Borker 2003 {published data only}

Ferguson 2003 {published data only}

Fischer 2003 {published data only}

Grootendorst 2001 {published data only}

Grootendorst 2002 {published data only}

Grootendorst 2003 {published data only}

Grootendorst 2007 {published data only}

GSK256066 {published data only}

Kelsen 2002 {published data only}

Knobil 2003 {published data only}

Lim 2004 {published data only}

Nieman 1999 {unpublished data only}

Pascoe 2007 {unpublished data only}

Reisner 2003 {published data only}

Roflumilast JP708 {unpublished data only}

Sadigov 2014 {published data only}

Sadigov 2015 {published data only}

SB207499/040 {unpublished data only}

SB207499/041 {unpublished data only}

Song 2005 {published data only}

Spencer 2002 {published data only}

Vestbo 2007 {published data only}

Vestbo 2009 {published data only}

Wang 2005 {published data only}

Watz 2013 {published data only}

References to studies awaiting assessment

Barnes 2014 {published data only}

Mahmud 2013 {published data only}

References to ongoing studies

NCT02451540 2015 {published data only}

NCT02671942 2016 {published data only}

Additional references

Agusti 2005

Barnes 2000

Barnes 2003

Barnes 2005

Boswell‐Smith 2006

Calverley 2007