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Intervention Review

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Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

  1. Jimmy Chong1,
  2. Bonnie Leung1,
  3. Phillippa Poole2,*

Editorial Group: Cochrane Airways Group

Published Online: 4 NOV 2013

DOI: 10.1002/14651858.CD002309.pub4


How to Cite

Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD002309. DOI: 10.1002/14651858.CD002309.pub4.

Author Information

  1. 1

    Tauranga Hospital, Tauranga, New Zealand

  2. 2

    University of Auckland, Department of Medicine, Auckland, New Zealand

*Phillippa Poole, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. p.poole@auckland.ac.nz.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 4 NOV 2013

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Characteristics of included studies [ordered by study ID]
Cilomilast 039

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 102 centres in Canada, Mexico and the US

2) Participants: 647 (15 mg cilomilast: 431, placebo: 216)

3) 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)

4) Inclusion criteria: FEV1/FVC ≤ 0.7, FEV1 30% to 70% with smoking history > 10 pack-years or current smokers.

5) Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis

6) Total number of participant withdrawals: 137 (32%) and 52 (24%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks, single-blind. Placebo tablets to assess suitability

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary outcomes: lung function; ΔFEV1, SGRQ averaged over 24 weeks

Secondary outcomes: incidence rate of COPD exacerbations, adverse events, FVC at the trough, 6-min walk test, post-exercise dyspnoea


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed 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 riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot 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 useLow risk54% in cilomilast; 58% placebo used ipratropium

Baseline profile: β2 agonist useLow risk99% in cilomilast; 100% placebo used albuterol. 9% in cilomilast; 12% placebo used salmeterol

Baseline profile: corticosteroid useLow risk7% in cilomilast; 8% placebo used triamcinolone. 6% in cilomilast; 7% placebo used beclomethasone

Cilomilast 042

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 98 centres in Australia and New Zealand, Germany, Spain, South Africa and the UK

2) Participants: 700 (15 mg cilomilast: 474, placebo: 226)

3) 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

4) Inclusion criteria: aged 40 to 80 years, FEV1/FVC ≤ 0.7, FEV1 30% to 70% with smoking history > 10 pack-years

5) Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis

6) Total number of participant withdrawals: 122 (26%) and 51 (23%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks, single-blind with placebo

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary outcomes: lung function; ΔFEV1, SGRQ averaged over 24 weeks

Secondary outcomes: incidence rate of COPD exacerbations, summary symptom score, FVC at the trough, 6-min walk test, post-exercise dyspnoea


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskPatients 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 riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal 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 useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 076

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Analysis was done per-protocol population


Participants1) Setting: not stated

2) Participants: 59 (15 mg cilomilast: 29, placebo: 30)

3) Baseline characteristics: mean age: 61 to 62 years, 81% male, 53% active smokers, mean 46 pack-years, 53% to 58% FEV1 predicted

4) Inclusion criteria: aged 40 to 80 years, fixed airflow obstruction, smoking history > 10 pack-years

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 4 (14%) and 2 (7%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks, single-blind with placebo

1) Cilomilast 15 mg twice daily

2) 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%)


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskRandomised to a ratio of 1:1

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot 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 useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 091

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 110 centres in Belgium, Finland, France, Italy, the Netherlands, Norway, Portugal, Spain and the UK

2) Participants: 711 (15 mg cilomilast: 469, placebo: 242)

3) Baseline characteristics: mean age: 64.6 years, 86% male, mean FEV1 % predicted of 53% with 5.0% reversibility. 38% active smokers

4) Inclusion criteria: FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years

5) Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis

6) Total number of participant withdrawals: 121 (26%) and 63 (26%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks, single-blind with placebo

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary outcomes: lung function; ΔFEV1, SGRQ averaged over 24 weeks

Secondary outcomes: incidence rate of COPD exacerbations, summary symptom score, FVC at the trough, 6-min walk test, post-exercise dyspnoea


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed 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 riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal 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 useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 103657

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 103 centres in the US

2) Participants: 613 (15 mg cilomilast: 296, placebo: 317)

3) 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

4) 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

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 105 (35%) and 76 (24%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskRandomised. No other information given

Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 76 (24%) placebo, 105 (35%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 110

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Analysis was done per-protocol population


Participants1) Setting: 10 centres in the US

2) Participants: 65 (15 mg cilomilast: 31, placebo: 34)

3) 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

4) Inclusion criteria: aged 40 to 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

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 1 (3%) and 1 (3%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskAll participants were randomised to receive either cilomilast 15 mg or matching placebo

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 1 (3%) placebo, 1 (3%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 111

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 32 centres in the US, Canada and Australia

2) Participants: 156 (15 mg cilomilast: 79, placebo: 77)

3) Baseline characteristics: mean age: 64.2 years: placebo and 65 years; cilomilast. 66% male: placebo and 65% male: cilomilast. Mean FEV1 % predicted not available

4) Inclusion criteria: aged 40 to 80. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-salbutamol reversibility less than or equal to 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

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 15 (19%) and 14 (18%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary outcomes: change from baseline to endpoint in volume of trapped gas (D)

Secondary outcomes: lung volume measurements, including SVC and RV, 6-min walk test and exertional dyspnoea


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 14 (18%) placebo, 15 (19%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 121

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 22 centres in China

2) Participants: 1018 (15 mg cilomilast: 678, placebo: 340)

3) 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

4) Inclusion criteria: aged 40 to 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 less than or equal to 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

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 124 (18%) and 35 (10%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskParticipants were randomised to a 2:1 ratio for cilomilast 15 mg to placebo

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 35 (10%) placebo, 124 (18%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 156

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 132 centres in US and Canada

2) Participants: 825 (15 mg cilomilast: 418, placebo: 407)

3) 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

4) Inclusion criteria: aged 40 to 80 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-salbutamol reversibility less than or equal to 15% or 200 mL and a post-salbutamol FEV1 at least 1.0 L and between 30% and 70% of predicted

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 143 (34%) and 96 (24%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 96 (24%) placebo, 143 (34%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 157

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 137 centres from 18 countries

2) Participants: 907 (15 mg cilomilast: 455, placebo: 452)

3) Baseline characteristics: mean age: 63.3 years: placebo and 64.6 years; cilomilast. 73% male: placebo and 78% male: cilomilast. 42% current smokers

4) Inclusion criteria: aged 40 to 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% to 70% predicted normal at screening

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 167 (37%) and 121 (27%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily

Method of randomisation described?Unclear riskA randomisation criteria was used. No other information available

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 121 (27%) placebo, 167 (37%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 168

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: not stated


Participants1) Setting: 42 centres in the US

2) Participants: 306 (15 mg cilomilast: 203, placebo: 103)

3) Baseline characteristics: mean age: 64.3 years: placebo and 65.0 years; cilomilast. 64% male: placebo and 70% male: cilomilast.

4) Inclusion criteria: pre-albuterol FEV1/FVC ≤ 0.7. Post-albuterol FEV1 between 30% and 70% of predicted

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 61 (30%) and 14 (14%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary outcomes: no primary efficacy or safety analyses were defined. Descriptive statistics of change from baseline in minimum and maximum heart rate via 24-hour Holter monitoring reported

Secondary outcomes: no secondary efficacy or safety analyses were defined


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskPatients were randomised at 2:1 ratio of cilomilast to placebo

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 14 (14%) placebo, 61 (30%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo other information available

Baseline profile: β2 agonist useUnclear riskNo other information available

Baseline profile: corticosteroid useUnclear riskNo other information available

Cilomilast 180

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 18 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 34 centres in the US, Canada and South America

2) Participants: 199 (15 mg cilomilast: 97, placebo: 102)

3) Baseline characteristics: mean age: 64.7 years: placebo and 63.7 years; cilomilast. 76% male: placebo and 69% male: cilomilast.

4) 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 or less, evidence of hyperinflation defined by RFRC at least 140% of predicted. Exercise limitation, defined as peak symptom limited VO2 < 75%

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 24 (25%) and 13 (13%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available

Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 13 (13%) placebo, 24 (25%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 181

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 13 weeks

Analysis was done per-protocol population


Participants1) Setting: 27 centres in Australia, Canada, Finland, Ireland, Lithuania, Norway, Romania, Slovakia, Slovenia, South Africa, Sweden and the UK

2) Participants: 127 (15 mg cilomilast: 65, placebo: 62)

3) Baseline characteristics: mean age: 63.4 years: placebo and 61.4 years; cilomilast. 76% male: placebo and 72% male: cilomilast

4) Inclusion criteria: aged 40 to 80 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-bronchodilator FEV1 between 40% and 80% predicted normal. Poor reversibility of less than or equal to 10% or 200 mL increase in FEV1

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 8 (12%) and 6 (10%) from treatment and control groups, respectively


InterventionsRun-in: not stated

1) Cilomilast 15 mg twice daily

2) 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskRandomised. No other information available

Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinding

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 6 (10%) placebo, 8 (12%) cilomilast

Baseline profile: anticholingeric useUnclear riskNo other information available

Baseline profile: β2 agonist useUnclear riskNo other information available

Baseline profile: corticosteroid useUnclear riskNo other information available

Compton 2001

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 6 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 60 centres in Austria, France, Germany, the Netherlands and the UK

2) Participants: 424 (5 mg cilomilast: 109, 10 mg cilomilast: 102, 15 mg cilomilast: 107, placebo: 106)

3) Baseline characteristics: mean age: 62 to 63 years, 75% to 78% male, mean FEV1% predicted of 46.8%, mean smoking history of 36 to 43 (SD 22.4) pack-years

4) Inclusion criteria: FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years

5) Exclusion criteria: asthma, poorly controlled COPD needing hospital visit 6 weeks before study, recent COPD exacerbations or recent corticosteroid use

6) Total number of participant withdrawals: 18 (17%) and 17 (16%) from treatment and control groups, respectively


InterventionsRun-in: 2 weeks, single-blind. Placebo tablets to assess compliance

1) Cilomilast 5 mg, 10 mg, 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: 382 (90%) patients 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


OutcomesPrimary outcomes: lung function: ΔFEV1, SGRQ

Secondary outcomes: peak expiratory flow and FVC, the first dose effect of active treatment on FEV1


NotesPost-bronchodilator results not given so pre-bronchodilator values used in analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskDescribed 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 riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot 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 useUnclear riskInformation not available

Baseline profile: β2 agonist useLow risk102 (24%) patients had been taking long-acting ß2- agonists; e.g. salmeterol, formoterol

Baseline profile: corticosteroid useLow risk331 (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

Methods14 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)


ParticipantsSee individual studies


Interventions1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) Placebo once daily


Outcomes


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskSee individual studies

Randomised?Low riskRandomised

Method of randomisation described?Unclear riskSee individual studies

Blinding?Unclear riskDouble-blind

Method of blinding described?Unclear riskSee individual studies

Description of withdrawals and drop-outs?Unclear riskSee individuals studies

Baseline profile: anticholingeric useUnclear riskSee individuals studies

Baseline profile: β2 agonist useUnclear riskSee individuals studies

Baseline profile: corticosteroid useUnclear riskSee individuals studies

Roflumilast FK1 101

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 26 weeks

Intention-to-treat analysis: stated


Participants1) Setting: not stated

2) Participants: 516 (roflumilast 250 µg: 175, roflumilast 500 µg: 169, placebo: 172)

3) Baseline characteristics: median age: 61 to 62 years. 72% male. Mean 38 to 63 pack-years. 53% current smokers

4) Inclusion criteria: aged 40 to 75. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Reversibility < 12% or 200 mL Post-bronchodilator FEV1 35% to 75% predicted

5) Exclusion criteria: not stated

6) Participant withdrawals: not stated


InterventionsRun-in: 2 weeks with placebo

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) 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


OutcomesPrimary outcomes: post-bronchodilator FEV1 and FEF between 25% to 75% of vital capacity

Secondary outcomes: number of moderate or severe COPD exacerbations which required treatment with oral steroids


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskRandomised. No other information available

Randomised?Low riskPatients randomised in either roflumilast 250 µg, roflumilast 500 µg or placebo groups

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?High riskNot stated

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast FK1 103

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: not stated

2) Participants: 518 (roflumilast 500 µg: 200, placebo: 186)

3) Baseline characteristics: mean age: 60 years. 75% male. 62% current smokers. Average of 35 pack-years

4) Inclusion criteria: aged 40 to 75 years. FEV1/FVC ≤ 0.7. Post-bronchodilator FEV1 35% to 75% of predicted. FEV1 reversibility ≤ 12% and ≤ 200 mL. Pre-bronchodilator FEV1/FVC ≤ 70%

5) Exclusion criteria: not stated

6) Participant withdrawals not stated


InterventionsRun-in: 2 weeks with placebo

1) Roflumilast 500 µg once daily for 24 weeks

2) 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)


OutcomesPrimary outcomes: results for 12/24 week post-bronchodilator FEV1


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNo 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 riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?High riskNot stated

Baseline profile: anticholingeric useUnclear riskNo further information available

Baseline profile: β2 agonist useUnclear riskNo further information available

Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast IN-108

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: not stated


Participants1) Setting: 5 centres in India

2) Participants: 118 recruited (roflumilast 500 µg: 47; roflumilast 200 µg: 46, placebo: 25)

3) Baseline characteristics: mean age: 60 years. 98% male. 41% current smokers. Post-bronchodilator FEV1 of 57% to 61%. Average of 25 pack-years

4) Inclusion criteria: not stated

5) Exclusion criteria: not stated

6) Participant withdrawals: roflumilast 500 µg: 13 (28%); roflumilast 200 µg: 7 (15%) and 10 (40%) from control group


Interventions1) Roflumilast 250 µg once daily

2) Roflumilast 500 µg once daily

3) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: not stated
  • Short-acting β2 agonist: not stated
  • Corticosteroid: none
  • Long-acting β2 bronchodilator: not stated


Outcomes1) To study the safety and tolerability of roflumilast 250 μg versus roflumilast 500 μg versus placebo
2) To investigate the effect of roflumilast 250 μg versus roflumilast 500 μg versus placebo on pulmonary function, efficacy rating and exacerbation rate
3) 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot stated

Randomised?Low riskRandomised

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blind

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskData as above

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast JP-706

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: not stated


Participants1) Setting: Japanese study

2) Participants: 600 (roflumilast 250 µg: 205, roflumilast 500 µg: 204, placebo: 191)

3) Baseline characteristics: mean age: 70 years. 96% male. Post-bronchodilator FEV1 not stated. Average of 56 pack-years. 37% current smokers

4) Inclusion criteria: not stated

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: not stated


InterventionsRun-in: single-blind 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) 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(1) To investigate the efficacy and safety after 24-week treatment of APTA-2217 (roflumilast) at doses of 500 µg and 250 µg in patients with COPD using placebo as a control

(2) 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot stated

Randomised?Low riskRandomised

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blind

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?High riskNot described

Baseline profile: anticholingeric useLow riskConstant dose of short anticholinergics used in 35% (roflumilast 500 µg), 33% (roflumilast 200 µg) and 33% (placebo), respectively

Baseline profile: β2 agonist useUnclear riskNot described

Baseline profile: corticosteroid useUnclear riskNot described

Roflumilast M2-107

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 159 centres in Australia, Austria, Belgium, Canada, France, Germany, Hungary, Ireland, South Africa, Spain and the UK

2) Participants: 1411 (roflumilast 250 µg: 576, roflumilast 500 µg: 555, placebo: 280)

3) Baseline characteristics: median age: 64 years. 74% male. Post-bronchodilator FEV1 is 51% for both groups. Average of 42 pack-years. 45% current smokers

4) 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% to 80% predicted

5) 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

6) Total number of participant withdrawals: 124 (22%) and 32 (11%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) 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


OutcomesPrimary 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% to 75% of vital capacity and number of moderate or severe COPD exacerbations


NotesThere 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

BiasAuthors' judgementSupport 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 riskDouble-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 risk100 patients 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 useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast M2-110

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: not stated


Participants1) Setting: 36 centres in Argentina, Canada, Columbia, Mexico, Peru and the USA

2) Participants: estimated enrolment of 1000 participants

3) Baseline characteristics: not stated

4) Inclusion criteria:

  • Clinical diagnosis of COPD
  • Currently stable COPD with no change in COPD treatment in the prior 4 weeks


5) Exclusion criteria:

  • Clinical diagnosis of asthma
  • Poorly controlled COPD
  • Regular need for daily oxygen therapy


6) Total number of participant withdrawals: not stated


InterventionsRoflumilast 500 µg daily versus placebo


OutcomesPrimary outcomes: pulmonary function
Secondary outcomes: exacerbation rate, quality of life, symptoms, use of rescue medication, safety and tolerability


NotesClinicalTrials.gov Identifier: nCT00062582


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot stated

Randomised?Low riskRandomised

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blind

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Unclear riskNot stated

Baseline profile: anticholingeric useUnclear riskNot stated

Baseline profile: β2 agonist useUnclear riskNot stated

Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-111

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated


Participants1) Setting: m2-111 was conducted in 188 centres in 6 countries, and M2-112 in 159 centre in 14 countries
2) Participants: data combined with M2-112 showing 2686 (roflumilast 500 µg: 1327, placebo: 1359)
3) Baseline characteristics: severe COPD according to GOLD criteria grades III and IV. Mean age: 64 to 65 years. 72% male

4) 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 to 48 pack-years

5) Exclusion criteria: history of asthma, lung cancer or bronchiectasis, need for long-term oxygen therapy, known α1antitrypsin deficiency or clinically significant cardiopulmonary co-morbidity

6) Total number of participant withdrawals: data combined with M2-112 showing 433 (33%) and 348 (26%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) 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)


OutcomesPrimary 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% to 75% of vital capacity and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year


Notes


Risk of bias

BiasAuthors' judgementSupport 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 riskDouble-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 riskData combined with M2-112

Baseline profile: anticholingeric useLow riskData combined with M2-112 showing 1604 (60%) patients used anticholinergics

Baseline profile: β2 agonist useLow risk1463 (55%) patients on short-acting β2-agonists

Baseline profile: corticosteroid useLow risk1622 (61%) on concomitant inhaled corticosteroids

Roflumilast M2-111+M2-112

MethodsAs described in separate studies above and below


Participants


Interventions


Outcomes


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskSee individual trials

Randomised?Low riskSee individual trials

Method of randomisation described?Low riskSee individual trials

Blinding?Low riskSee individual trials

Method of blinding described?Low riskSee individual trials

Description of withdrawals and drop-outs?Low riskSee individual trials

Baseline profile: anticholingeric useLow riskSee individual trials

Baseline profile: β2 agonist useLow riskSee individual trials

Baseline profile: corticosteroid useLow riskSee individual trials

Roflumilast M2-112

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 159 centres in 14 countries

2) Participants: 1513 (roflumilast 500 µg: 760, placebo: 753)

3) Baseline characteristics: severe COPD according to GOLD criteria grades III and IV. Mean age: 65 years. 75% male

4) 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

5) Exclusion criteria: history of asthma, lung cancer or bronchiectasis, need for long-term oxygen therapy, known α1antitrypsin deficiency or clinically significant cardiopulmonary co-morbidity

6) Total number of participant withdrawals: 217 (29%) and 163 (22%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) 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)


OutcomesPrimary 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% to 75% of vital capacity and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year


Notes


Risk of bias

BiasAuthors' judgementSupport 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 riskDouble-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 useLow risk739 patients used anticholinergics

Baseline profile: β2 agonist useLow risk820 patients on short-acting β2-agonists

Baseline profile: corticosteroid useLow risk727 on beclomethasone dipropionate 2000 µg or less

Roflumilast M2-118

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 22 centres in 4 countries

2) Participants: 250 (roflumilast 500 µg: 127, placebo: 123)

3) 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

4) Inclusion criteria: participants were clinically stable patients 40 years of age and above with a smoking history of greater than 10 pack-years and a 12-month history of COPD. Other inclusion criteria included: post-bronchodilator FEV1 30% to 80% predicted, FEV1/forced vital capacity (FVC) < 0.7 and set plethysmographic functional residual capacity (FRC) and peak oxygen uptake requirements

5) 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

6) Total number of participant withdrawals: 16 (13%) and 12 (10%) from treatment and control groups, respectively


Interventions1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: patients could use ipratropium bromide in regular stable doses as needed
  • Short-acting β2 agonist: patients could use short-acting β2-agonists as needed
  • Corticosteroid: inhaled corticosteroids (ICS) were permitted throughout the study if taken at a constant dosage for greater than 3 months prior to the study
  • Long-acting β2 bronchodilator: none


OutcomesActivity-related dyspnoea (TDI). Spirometry and body plethysmography. Symptom-limited exercise tests


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot stated

Randomised?Low riskA 1:1 randomisation ratio was used

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskOf the 250 randomised participants, 16 from the roflumilast group and 12 from the placebo group discontinued prematurely

Baseline profile: anticholingeric useUnclear riskNot stated

Baseline profile: β2 agonist useUnclear riskNot stated

Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-119

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 32 centres in 5 countries

2) Participants: 410 (roflumilast 500 µg: 203, placebo: 207)

3) Baseline characteristics: mean age: 68 years. 93% male. Post-bronchodilator FEV1 50.5% predicted. Average of 44 pack-years. 69% current smokers

4) 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% to 80%. Clinically stable COPD within 4 weeks prior to baseline

5) 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

6) Total number of participant withdrawals: 40 (20%) and 18 (9%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) 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


OutcomesPrimary 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 patients experiencing exacerbations, time to study withdrawal and adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot stated

Randomised?Low riskRandomised

Method of randomisation described?Low riskComputer-generated randomisation list used

Blinding?Low riskDouble-blinded

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Low riskPatient numbers at different stages of the study described in figure

Baseline profile: anticholingeric useUnclear riskNot stated

Baseline profile: β2 agonist useUnclear riskNot stated

Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-121

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 16 centres in 6 countries

2) Participants: estimated enrolment 550 participants

3) Baseline characteristics: not stated

4) Inclusion criteria: patients with a history of chronic obstructive pulmonary disease 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

5) 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

6) Total number of participant withdrawals: not stated


Interventions500 µg roflumilast tablets once daily versus placebo


OutcomesPrimary outcome: lung function parameters indicative of hyperinflation in patients 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


NotesClinicalTrials.gov Identifier: nCT00108823


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskNot stated

Randomised?Low riskRandomised

Method of randomisation described?Unclear riskNot stated

Blinding?Low riskDouble-blind

Method of blinding described?Unclear riskNot stated

Description of withdrawals and drop-outs?Unclear riskNot stated

Baseline profile: anticholingeric useUnclear riskNot stated

Baseline profile: β2 agonist useUnclear riskNot stated

Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-124

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 246 centres in 10 countries

2) Participants: 1513 (roflumilast 500 µg: 760, placebo: 753)

3) Baseline characteristics: mean age: 64 years. 71% male. Post-bronchodilator FEV1 37.6% predicted. Average of 47 pack-years. 48% current smokers

4) 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

5) Exclusion criteria: available in the online web appendix (pg 11)

6) Total number of participant withdrawals: 264 (34%) and 234 (31%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) 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%


OutcomesPrimary 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


NotesAdverse event data are pooled with numbers from study M2-125 that followed an identical study design


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskAll 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 riskDouble-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 risk264 patients discontinued from study in the roflumilast group and 234 discontinued from the placebo group

Baseline profile: anticholingeric useUnclear riskNo other information available

Baseline profile: β2 agonist useUnclear riskNo other information available

Baseline profile: corticosteroid useHigh riskPretreatment of 44% in both roflumilast and placebo groups

Roflumilast M2-124+M2-125

MethodsAs described in separate studies above and below


Participants


Interventions


Outcomes


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskSee individual studies

Randomised?Low riskSee individual studies

Method of randomisation described?Low riskSee individual studies

Blinding?Low riskSee individual studies

Method of blinding described?Low riskSee individual studies

Description of withdrawals and drop-outs?Low riskSee individual studies

Baseline profile: anticholingeric useLow riskSee individual studies

Baseline profile: β2 agonist useLow riskSee individual studies

Baseline profile: corticosteroid useHigh riskSee individual studies

Roflumilast M2-125

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 221 centres in 8 countries

2) Participants: 1571 (roflumilast 500 µg: 773, placebo: 798)

3) Baseline characteristics: mean age: 64 years. 80% male. Average of 48 pack-years. 35% current smokers

4) 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

5) Exclusion criteria: available in the online web appendix (pg 11)

6) Total number of participant withdrawals: 246 (32%) and 248 (31%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) 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%


OutcomesPrimary 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


NotesAdverse event data are pooled with numbers from study M2-124 that followed an identical study design


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskAll 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 riskDouble-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 risk246 patients discontinued from study in the roflumilast group and 248 discontinued from the placebo group

Baseline profile: anticholingeric useLow riskNo other information available

Baseline profile: β2 agonist useLow riskNo other information available

Baseline profile: corticosteroid useHigh riskPretreatment of 40% in both roflumilast and placebo groups

Roflumilast M2-127

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 135 centres in 10 countries

2) Participants: 1221 (roflumilast 500 µg: 467, placebo: 468)

3) 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

4) 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

5) Exclusion criteria: available in the online web appendix (pg 10)

6) Total number of participant withdrawals: 107 (23%) and 82 (18%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo once a day

1) Roflumilast 500 µg and salmeterol once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: none
  • Short-acting β2 agonist: patients used short-acting β2 as rescue medication
  • Corticosteroid: none
  • Long-acting β2 bronchodilator: none


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskAll 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 riskDouble-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 risk107 patients discontinued from study in the roflumilast group and 82 discontinued from the placebo group

Baseline profile: anticholingeric useUnclear riskNo other information available

Baseline profile: β2 agonist useUnclear riskNo other information available

Baseline profile: corticosteroid useUnclear riskNo other information available

Roflumilast M2-128

MethodsParallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated


Participants1) Setting: 85 centres in 7 countries

2) Participants: 910 (roflumilast 500 µg: 372, placebo: 372)

3) 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

4) 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

5) Exclusion criteria: available in the online web appendix (pg 10)

6) Total number of participant withdrawals: 62 (17%) and 39 (11%) from treatment and control groups, respectively


InterventionsRun-in: 4 weeks with placebo once a day

1) Roflumilast 500 µg and tiotropium once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: none
  • Short-acting β2 agonist: patients used short-acting β2 as rescue medication
  • Corticosteroid: none
  • Long-acting β2 bronchodilator: none


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskAll 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 riskDouble-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 risk62 patients discontinued from study in the roflumilast group and 39 discontinued from the placebo group

Baseline profile: anticholingeric useUnclear riskNo information available

Baseline profile: β2 agonist useUnclear riskNo information available

Baseline profile: corticosteroid useUnclear riskNo information available

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Borker 2003Insufficient data. Only RR of QOL improvement provided

Ferguson 2003Integrated results from four 24-week cilomilast trials

Fischer 2003Analysis focused on patients with a baseline SGRQ score of ≥ the median SGRQ score only

Grootendorst 2001Endpoint: first dose-bronchodilator effects only

Grootendorst 2002Treatment Bayer BAY 19-8004; 11 patients only 1 week in duration

Grootendorst 2003Endpoint: first-dose bronchodilator effects only

Grootendorst 2007Cross-over design

GSK256066Phase II trial. No primary outcome measure investigating lung function. Only one trial to date

Kelsen 2002No study ID or group numbers identified

Knobil 2003No SD or SE given

Lim 2004Combining results from 2 pivotal European phase III cilomilast trials

Nieman 1999Study 038. Insufficient data available for changes in lung function and exacerbation rates

Pascoe 2007Treatment QAK423 (Novartis), discontinued. Only 1 trial available

Reisner 2003Combined results. Individual studies already included in review

Rennard 2008SE not provided for exacerbation rates

Roflumilast JP708JP108 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 patients enrolled in JP106 continued onto the JP108 study

SB207499/040Open-label study. Males or females 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

SB207499/041Open-label study. Males or females 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 2005Although quoted as significant, mean and SD figures not provided

Spencer 2002No study ID or group numbers identified

Vestbo 2007Treatment UK-500,001 (Pfizer). Discontinued

Vestbo 2009Treatment UK-500,001 (Pfizer). Discontinued

Wang 2005Although quoted as significant, mean and SD figures not provided

 
Characteristics of ongoing studies [ordered by study ID]
Calverley 2012

Trial name or titleRoflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment

Methods1-year, randomised, double-blind, multicentre, phase III/IV study

ParticipantsCOPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis and at least 2 exacerbations in the previous year will be recruited

InterventionsRoflumilast 500 µg once daily or placebo on top of a fixed long-acting β2 agonist/inhaled corticosteroid combination

OutcomesThe primary outcome is the rate of moderate or severe COPD exacerbations

Starting dateMay 2011

Contact information

NotesIdentification number RO-2455-404-RD, clinicaltrials.gov identifier NCT01329029

Ferguson 2012

Trial name or titleRoflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Dose Combinations of Long-acting β2-agonist (LABA) and Inhaled Corticosteroid (ICS)

MethodsA 52-week, double-blind, randomised, placebo-controlled, parallel-group study

ParticipantsMale or female patients at least 40 years of age, history of COPD (according to GOLD 2010) for at least 12 months prior to screening (Visit 1) associated with chronic productive cough for 3 months in each of 2 consecutive years (with other causes of productive cough excluded). Only patients with chronic bronchitis will be included (concomitant emphysema is permitted). FEV1 (post-bronchodilator) ≤ 50% of predicted at screening with at least 2 documented moderate or severe COPD exacerbations within 12 months prior. Patients must be on FDC LABA/ICS treatment ≥ 3 months prior

InterventionsRoflumilast 500 µg, oral administration, once per day. Other name: Daliresp

Dose-matched placebo, oral administration, once per day

OutcomesPrimary outcome measures: rate of moderate or severe COPD exacerbations per participant per year
Secondary outcome measures: pre-bronchodilator forced expiratory volume in 1 second (FEV1) in litres

Starting dateSeptember 2011

Contact information

NotesClinicalTrials.gov Identifier: nCT01443845

 
Comparison 1. PDE4 inhibitor versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 FEV1 (by drug)2215670Mean Difference (IV, Fixed, 95% CI)45.60 [39.45, 51.75]

    1.1 Roflumilast 500 μg
129315Mean Difference (IV, Fixed, 95% CI)52.58 [43.61, 61.56]

    1.2 Roflumilast 250 μg
31033Mean Difference (IV, Fixed, 95% CI)56.88 [24.38, 89.38]

    1.3 Cilomilast 15 mg
105322Mean Difference (IV, Fixed, 95% CI)38.15 [29.41, 46.90]

 2 FEV1 (by mean COPD severity)1611744Mean Difference (IV, Fixed, 95% CI)49.18 [41.35, 57.01]

    2.1 GOLD grade I + II (FEV1 ≥ 50% predicted)
94647Mean Difference (IV, Fixed, 95% CI)51.79 [38.99, 64.59]

    2.2 GOLD grade III + IV (FEV1 < 50% predicted)
77097Mean Difference (IV, Fixed, 95% CI)47.62 [37.72, 57.52]

 3 FEV1 (Roflumilast 500 μg by mean COPD severity)108827Mean Difference (IV, Fixed, 95% CI)53.08 [43.85, 62.32]

    3.1 GOLD grade I + II (FEV1 ≥ 50% predicted)
63187Mean Difference (IV, Fixed, 95% CI)69.86 [53.34, 86.38]

    3.2 GOLD grade III + IV (FEV1 < 50% predicted)
45640Mean Difference (IV, Fixed, 95% CI)45.46 [34.32, 56.60]

 4 FEV1 (by study duration)2214870Mean Difference (IV, Fixed, 95% CI)45.19 [38.92, 51.45]

    4.1 Duration ≤ 12 weeks
61010Mean Difference (IV, Fixed, 95% CI)107.25 [75.44, 139.07]

    4.2 Duration 24 to 26 weeks
117419Mean Difference (IV, Fixed, 95% CI)42.03 [33.86, 50.20]

    4.3 Duration 52 weeks
56441Mean Difference (IV, Fixed, 95% CI)43.71 [33.46, 53.97]

 5 FEV1 (additional medication)2214650Mean Difference (IV, Fixed, 95% CI)45.18 [38.92, 51.44]

    5.1 Long-acting bronchodilator
21645Mean Difference (IV, Fixed, 95% CI)60.52 [40.57, 80.46]

    5.2 Corticosteroids
32904Mean Difference (IV, Fixed, 95% CI)42.26 [25.46, 59.05]

    5.3 PDE4i treatment only
1710101Mean Difference (IV, Fixed, 95% CI)43.73 [36.56, 50.90]

 6 FEV1 (published versus unpublished)2214870Mean Difference (IV, Fixed, 95% CI)45.39 [39.13, 51.66]

    6.1 Published
1410329Mean Difference (IV, Fixed, 95% CI)53.92 [45.50, 62.34]

    6.2 Unpublished
84541Mean Difference (IV, Fixed, 95% CI)34.82 [25.44, 44.19]

 7 FEV1 (random-effects model)2214870Mean Difference (IV, Random, 95% CI)48.42 [38.22, 58.63]

 8 FEV1 (roflumilast 500 μg versus 250 μg)31560Mean Difference (IV, Fixed, 95% CI)22.61 [-5.95, 51.16]

 9 FVC1310861Mean Difference (IV, Fixed, 95% CI)84.66 [68.33, 100.99]

 10 PEF54245Mean Difference (IV, Fixed, 95% CI)6.54 [3.95, 9.13]

    10.1 Roflumilast 500 μg
43685Mean Difference (IV, Fixed, 95% CI)5.46 [2.74, 8.17]

    10.2 Roflumilast 250 μg
1347Mean Difference (IV, Fixed, 95% CI)7.0 [-4.05, 18.05]

    10.3 Cilomilast 15 mg
1213Mean Difference (IV, Fixed, 95% CI)34.0 [20.14, 47.86]

 11 SGRQ total score107618Mean Difference (IV, Fixed, 95% CI)-1.04 [-1.66, -0.41]

    11.1 Roflumilast 500 μg
22208Mean Difference (IV, Fixed, 95% CI)-0.69 [-2.07, 0.69]

    11.2 Roflumilast 250 μg
1716Mean Difference (IV, Fixed, 95% CI)-1.60 [-3.56, 0.36]

    11.3 Cilomilast 15 mg
84694Mean Difference (IV, Fixed, 95% CI)-1.06 [-1.81, -0.31]

 12 SGRQ total score (by mean COPD severity)74824Mean Difference (IV, Fixed, 95% CI)-1.53 [-2.36, -0.70]

    12.1 GOLD grade I and II
32042Mean Difference (IV, Fixed, 95% CI)-1.62 [-2.80, -0.44]

    12.2 GOLD grade III and IV
42782Mean Difference (IV, Fixed, 95% CI)-1.44 [-2.61, -0.27]

 13 SGRQ total score (by published versus unpublished)107042Mean Difference (IV, Fixed, 95% CI)-0.97 [-1.63, -0.31]

    13.1 Published
43052Mean Difference (IV, Fixed, 95% CI)-1.93 [-3.02, -0.83]

    13.2 Unpublished
63990Mean Difference (IV, Fixed, 95% CI)-0.43 [-1.26, 0.40]

 14 SGRQ total score (by duration)107042Mean Difference (IV, Fixed, 95% CI)-0.97 [-1.63, -0.31]

    14.1 Duration < 12 weeks
1213Mean Difference (IV, Fixed, 95% CI)-3.90 [-7.50, -0.30]

    14.2 Duration 24 to 26 weeks
74600Mean Difference (IV, Fixed, 95% CI)-1.18 [-1.94, -0.42]

    14.3 Duration 52 weeks
22229Mean Difference (IV, Fixed, 95% CI)0.26 [-1.18, 1.69]

 15 No. people with one or more exacerbations (by drug)2015035Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.71, 0.83]

    15.1 Roflumilast 500 μg
109507Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.71, 0.87]

    15.2 Cilomilast
105528Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.67, 0.85]

 16 Exacerbation rate (inverse variance)7Rate Ratio (Fixed, 95% CI)0.87 [0.81, 0.93]

    16.1 Roflumilast
6Rate Ratio (Fixed, 95% CI)0.86 [0.80, 0.92]

    16.2 Cilomilast
1Rate Ratio (Fixed, 95% CI)0.95 [0.78, 1.17]

 17 Exacerbation rate11691Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.48, -0.02]

    17.1 Roflumilast 500 μg
1835Mean Difference (IV, Fixed, 95% CI)-0.38 [-0.70, -0.06]

    17.2 Roflumilast 250 μg
1856Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.44, 0.24]

 18 Exacerbation rate (roflumilast 500 μg versus 250 μg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 19 Number of people on roflumilast with one or more exacerbations (additional medication)109507Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.71, 0.87]

    19.1 Long-acting bronchodilators
21676Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.54, 0.88]

    19.2 Corticosteroids
12686Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.70, 0.95]

    19.3 Treatment only
75145Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.67, 0.93]

 20 SGRQ symptom score21048Mean Difference (IV, Fixed, 95% CI)-1.53 [-4.11, 1.06]

    20.1 Roflumilast
1835Mean Difference (IV, Fixed, 95% CI)1.00 [-3.78, 1.78]

    20.2 Cilomilast
1213Mean Difference (IV, Fixed, 95% CI)-4.80 [-11.73, 2.13]

 21 Borg Scale62860Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.33, -0.05]

    21.1 Cilomilast
62860Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.33, -0.05]

 22 Summary symptom score31899Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.25, 0.13]

    22.1 Cilomilast
31899Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.25, 0.13]

 23 Shortness of breath questionnaire21633Mean Difference (IV, Fixed, 95% CI)-1.09 [-2.47, 0.28]

 24 6-minute walk test41948Mean Difference (IV, Fixed, 95% CI)1.92 [-7.58, 11.41]

    24.1 Cilomilast
41948Mean Difference (IV, Fixed, 95% CI)1.92 [-7.58, 11.41]

 25 No. of patients experiencing an adverse effect2316048Odds Ratio (M-H, Fixed, 95% CI)1.27 [1.19, 1.36]

    25.1 Roflumilast 500 μg
99506Odds Ratio (M-H, Fixed, 95% CI)1.31 [1.20, 1.43]

    25.2 Cilomilast 15 mg
146542Odds Ratio (M-H, Fixed, 95% CI)1.21 [1.08, 1.36]

 26 No of patients experiencing an adverse event (Roflumilast 500 μg versus 250 μg)41977Odds Ratio (M-H, Fixed, 95% CI)1.21 [1.01, 1.46]

 27 Diarrhoea2115241Odds Ratio (M-H, Fixed, 95% CI)3.07 [2.66, 3.53]

    27.1 Roflumilast
78699Odds Ratio (M-H, Fixed, 95% CI)3.96 [3.20, 4.89]

    27.2 Cilomilast
146542Odds Ratio (M-H, Fixed, 95% CI)2.47 [2.05, 2.98]

 28 Nausea2015687Odds Ratio (M-H, Fixed, 95% CI)4.06 [3.40, 4.86]

    28.1 Roflumilast 500 μg
68289Odds Ratio (M-H, Fixed, 95% CI)3.54 [2.63, 4.78]

    28.2 Roflumilast 250 μg
1856Odds Ratio (M-H, Fixed, 95% CI)3.97 [0.91, 17.39]

    28.3 Cilomilast 15 mg
146542Odds Ratio (M-H, Fixed, 95% CI)4.37 [3.49, 5.47]

 29 Headache1914690Odds Ratio (M-H, Fixed, 95% CI)1.67 [1.42, 1.96]

    29.1 Roflumilast 500 μg
89040Odds Ratio (M-H, Fixed, 95% CI)2.48 [1.90, 3.25]

    29.2 Roflumilast 250 μg
1347Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.24, 3.99]

    29.3 Cilomilast 15 mg
115303Odds Ratio (M-H, Fixed, 95% CI)1.32 [1.08, 1.62]

 30 Vomiting115828Odds Ratio (M-H, Fixed, 95% CI)4.01 [2.80, 5.74]

    30.1 Roflumilast
1835Odds Ratio (M-H, Fixed, 95% CI)1.52 [0.06, 37.37]

    30.2 Cilomilast
104993Odds Ratio (M-H, Fixed, 95% CI)4.06 [2.83, 5.82]

 31 Dyspepsia125621Odds Ratio (M-H, Fixed, 95% CI)3.13 [2.30, 4.27]

    31.1 Cilomilast
125621Odds Ratio (M-H, Fixed, 95% CI)3.13 [2.30, 4.27]

 32 Abdominal pain115604Odds Ratio (M-H, Fixed, 95% CI)1.97 [1.55, 2.49]

    32.1 Cilomilast
115604Odds Ratio (M-H, Fixed, 95% CI)1.97 [1.55, 2.49]

 33 Weight loss67864Odds Ratio (M-H, Fixed, 95% CI)3.94 [3.11, 5.00]

    33.1 Roflumilast
67864Odds Ratio (M-H, Fixed, 95% CI)3.94 [3.11, 5.00]

 34 Influenza-like symptoms89108Odds Ratio (M-H, Fixed, 95% CI)1.10 [0.86, 1.41]

    34.1 Roflumilast 500 μg
67795Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.87, 1.48]

    34.2 Roflumilast 250 μg
1347Odds Ratio (M-H, Fixed, 95% CI)1.98 [0.18, 22.00]

    34.3 Cilomilast 15 mg
2966Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.44, 1.75]

 35 Upper respiratory tract infection1814523Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.79, 1.03]

    35.1 Roflumilast 500 μg
89040Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.73, 1.09]

    35.2 Roflumilast 250 μg
21203Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]

    35.3 Cilomilast 15 mg
104280Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.13]

 36 Withdrawals due to adverse events2416056Odds Ratio (M-H, Fixed, 95% CI)1.84 [1.66, 2.03]

    36.1 Roflumilast 500 μg
109511Odds Ratio (M-H, Fixed, 95% CI)1.80 [1.58, 2.04]

    36.2 Cilomilast 15 mg
146545Odds Ratio (M-H, Fixed, 95% CI)1.90 [1.61, 2.24]

 37 Non-fatal serious adverse events2114375Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.91, 1.11]

    37.1 Roflumilast 500 μg
77830Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.94, 1.19]

    37.2 Cilomilast 15 mg
146545Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.06]

 38 Mortality2015030Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.69, 1.22]

    38.1 Roflumilast
78698Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.32]

    38.2 Cilomilast
136332Odds Ratio (M-H, Fixed, 95% CI)0.70 [0.34, 1.45]

 39 All psychiatric disorders (roflumilast)1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    39.1 Roflumilast 500 μg
111168Odds Ratio (M-H, Fixed, 95% CI)2.13 [1.79, 2.54]

    39.2 Roflumilast 250 μg
16288Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.56, 1.33]

 40 Insomnia and sleep disorders (roflumilast)1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    40.1 Roflumilast 500 μg
111168Odds Ratio (M-H, Fixed, 95% CI)2.88 [2.15, 3.86]

    40.2 Roflumilast 250 μg
16288Odds Ratio (M-H, Fixed, 95% CI)1.48 [0.81, 2.70]

 41 Anxiety or anxiety disorder (roflumilast)1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    41.1 Roflumilast 500 μg
111168Odds Ratio (M-H, Fixed, 95% CI)1.81 [1.26, 2.62]

    41.2 Roflumilast 250 μg
16288Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.40, 2.21]

 42 Depression (roflumilast)1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

    42.1 Roflumilast 500 μg
111168Odds Ratio (M-H, Fixed, 95% CI)1.59 [1.11, 2.27]

    42.2 Roflumilast 250 μg
16288Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.20, 1.56]

 
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: patients with stable chronic obstructive pulmonary disease
Settings: community-based, randomised, parallel, double-blind, placebo-controlled trials
Intervention: phosphodiesterase 4 inhibitors
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)1
Comments

Assumed riskCorresponding risk

PlaceboPhosphodiesterase IV inhibitors

Change in FEV1 lung function
(mL)
Follow-up: mean 17.5 weeks
The mean change in FEV1 lung function in the control groups was
a fall of 22.5 mL
The mean change in FEV1 lung function in the intervention groups was
45.6 mL better
(39.45 to 51.75 higher)
15,670
(22 studies)
⊕⊕⊕⊝
moderate2,3

Change in quality of life
St George's Respiratory Questionnaire
Follow-up: mean 27.8 weeks
The mean change in quality of life in the control groups was an improvement of
1.81 SGRQ units
The mean change in quality of life in the intervention groups was
1.04 units better
(1.66 to 0.41)
7618
(10 studies)
⊕⊕⊕⊝
moderate2,3
Lower scores on SGRQ represent improved quality of life

COPD exacerbations
No. of patients with exacerbations
Follow-up: 12 to 52 weeks
30 per 10024 per 100
(23 to 26)
OR 0.77
(0.71 to 0.83)
15,035
(20 studies)
⊕⊕⊕⊕
high

Mortality (all-cause)
No. of participants
Follow-up: 6 to 52 weeks
1 per 1001 per 100
(1 to 2)
OR 0.92
(0.69 to 1.22)
15,030
(20 studies)
⊕⊕⊕⊝
moderate4

Adverse events
No. of participants experiencing any adverse event
Follow-up: 6 to 52 weeks
66 per 10071 per 100
(70 to 73)
OR 1.27
(1.19 to 1.36)
16,048
(23 studies)
⊕⊕⊕⊝
moderate5
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 10011 per 100
(10 to 13)
OR 3.07
(2.66 to 3.53)
15,241
(21 studies)
⊕⊕⊕⊕
high
Diarrhoea was the most commonly reported gastrointestinal side effect. Weight loss was more common, and may be a result of diarrhoea

Psychiatric adverse events (roflumilast)
No. of participants
Follow-up: 12 to 52 weeks
35 per 100071 per 1000
(60 to 83)
OR 2.13
(1.79 to 2.54)
11,168
(14 studies)
⊕⊕⊕⊝
moderate6
Pooled data from FDA website, not individual trial reports

*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 (US); 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 were very few events, leading to wide confidence intervals.
5There was high level of heterogeneity between study results (I2 > 50%).
6Based on data from the combined COPD safety pool. Individual study data not obtained.
 
Table 1. Number of references for which we sought full text

Search date:No. of references for which we sought full text

December 200853

January 20105

August 201012

June 201320