Methods

Design: randomised, double‐blind, parallel‐group study

12‐Month treatment period

Conducted at 98 research sites in the United States and Canada

Participants

Participants: 797 people were randomly assigned to fluticasone/salmeterol combination (394) and salmeterol alone (403)

Baseline characteristics:

Male %: flut/sal 51, sal 57

Mean age (SD), years: flut/sal 65.4 (9.1), sal 65.3 (8.8)

Smoking history (mean (SD) pack‐years): flut/sal 57.8 (32.7), sal 56.5 (27.8)

Mean % predicted pre‐FEV₁ (SD): 34.1 (11.1), 33.9 (10.6)

Inclusion criteria: ≥ 40 years of age with a diagnosis of COPD (chronic bronchitis and/or emphysema), a cigarette smoking history ≥ 10 pack‐years, a prealbuterol FEV₁/FVC ≤ 0.70, an FEV₁ ≤ 50% of predicted normal and a documented history of at least one COPD exacerbation the year before the study that required treatment with antibiotics or oral corticosteroids and/or hospitalisation
Exclusion criteria: Individuals were excluded if they had a current diagnosis of asthma, a respiratory disorder other than COPD, historical or current evidence of a clinically significant uncontrolled disease or a COPD exacerbation that was not resolved at screening

Interventions

Run‐in: Four‐week run‐in period during which participants received open‐label FSC 250/50 via DISKUS twice daily

Treatments:

1. Fluticasone/salmeterol 250/50 mcg twice daily

2. Salmeterol 50 mcg twice daily

Inhaler device: Diskus

Co‐treatment: Concurrent use of inhaled long‐acting bronchodilators was not allowed during the study period. Oral corticosteroids and antibiotics were allowed for short‐term treatment of a COPD exacerbation

Outcomes

Primary: annual rate of moderate/severe exacerbations

Secondary: time to first moderate/severe exacerbation, annual rate of exacerbations requiring oral corticosteroids, predose FEV₁, time to onset of each moderate/severe exacerbation, diary records of dyspnoea scores, night‐time awakenings due to COPD and use of supplemental albuterol

Notes

Funding: GSK

Clinicaltrials.gov: NCT00115492

Definition of pneumonia: confirmed by chest x‐ray

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Treatments were assigned in blocks using a centre‐based randomisation schedule. As bronchodilator response to FSC 250/50 is generally larger in individuals with COPD who demonstrate FEV₁ reversibility to albuterol, assignment to blinded study medication was stratified on the basis of participants' FEV₁ response to albuterol at screening to provide a similar distribution of albuterol‐responsive and non‐responsive participants in each treatment group

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (assumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Withdrawal rates were very high compared with the numbers of events for different outcomes

Selective reporting (reporting bias)

Low risk

All outcomes stated in the protocol were reported and could be included

Methods

Design: double‐blind, randomised, parallel‐group trial of high‐dose inhaled budesonide versus placebo

Six‐month treatment period (originally intended as 12 months)

Conducted at a single centre in Canada

Participants

Participants: 79 people were randomly assigned to budesonide (39) and placebo (40)
Baseline characteristics:

Male %: bud 84.6, placebo 72.5

Mean age (SD), years: bud 66 (8), placebo 66 (8)

Smoking history (mean (SD) pack‐years): bud 52 (27), placebo 50 (28)

Mean % predicted pre‐FEV₁ (SD): bud 36 (12), placebo 37 (10)

Inclusion criteria: 40 years of age or older; smokers or ex‐smokers; absence of an exacerbation in
respiratory symptoms during the two months before the study; pre‐bronchodilator FEV₁ less than 65% of predicted and FEV₁/forced vital capacity (FVC) less than 0.65; postbronchodilator FEV₁ less than 80%; regular treatment with at least one bronchodilator
Exclusion criteria: history of allergic asthma during childhood or as an adult; inhaled corticosteroids in the previous month or oral corticosteroids in the previous two months; any other active lung disease; diabetes, active peptic ulcer disease, uncontrolled high blood pressure or congestive heart failure; disease other than COPD that might interfere with quality of life

Interventions

Run‐in: All participants were assessed in a single‐blind manner with a two‐week course of oral placebo followed by two weeks of prednisone 40 mg daily. The prednisone was subsequently tapered and was discontinued completely during the third week. Those who did not respond were randomly assigned

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo twice daily

Inhaler device: Turbohaler

Co‐treatment: All medications needed for the well‐being of participants were permitted, except inhaled corticosteroids other than budesonide. In cases of treatment failure, rescue medication with beta₂‐agonists or systemic steroids was available

Outcomes

Primary: change in FEV₁

Secondary: pre‐bronchodilator and postbronchodilator FEV₁ and FVC, pre‐bronchodilator six‐minute walking test, dyspnoea with exercise, quality of life questionnaires, morning and evening PEFR, symptom scores and adverse events

Notes

Funding: Astra Pharma Inc

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central computer‐generated list of random numbers

Allocation concealment (selection bias)

Low risk

Identification of individual treatment assignments was possible only in cases of emergency by breaking the sealed envelope kept by the investigator. The envelopes had to be kept with the case record forms and had to be returned unbroken at the end of the study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

To ensure that outcomes were measured similarly in the treatment groups, both participants and investigators were blinded to the study treatment

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

To ensure that outcomes were measured similarly in the treatment groups, both participants and investigators were blinded to the study treatment

Incomplete outcome data (attrition bias)
All outcomes

High risk

Uneven dropout. Much higher in placebo group (25% vs 7.7% in the ICS group)

Selective reporting (reporting bias)

High risk

Key outcomes missing (mortality, adverse events). No reply from study author

Methods

Design: randomised, double‐blind, parallel‐group, placebo‐controlled trial

Three‐month treatment period

Conducted at two respiratory centres in Canada

Participants

Participants: 41 people were randomly assigned to fluticasone (20) and placebo (21)
Baseline characteristics:

Male %: flut 84.6, placebo 72.5

Mean age (SD), years: flut 66 (8), placebo 66 (8)

Smoking history (mean (SD) pack‐years): flut 52 (27), placebo 50 (28)

Mean % predicted FEV₁ (SD): flut 36 (12), placebo 37 (10)

Inclusion criteria: Age > 40 and < 75 years; smoking history (> 10 pack‐years); postbronchodilator FEV₁ > 25% of predicted
value and FEV₁/forced vital capacity (FVC) < 0.70
Exclusion criteria: history of asthma, atopy (as assessed by an allergy skin prick test during screening) or any other active lung disease. Individuals receiving home oxygen or with raised carbon dioxide tension (.44 mm Hg), α₁‐antitrypsin deficiency, recent exacerbation (in the last 4 weeks), uncontrolled medical condition or hypersensitivity to inhaled corticosteroids and bronchodilators were not eligible for the study

Interventions

Run‐in: unclear duration

Treatments:

1. Fluticasone 500 mcg twice daily

2. Placebo twice daily

Participants were also randomly assigned to fluticasone/salmeterol combination, but this was not included in the present review because no salmeterol arm was available for comparison

Inhaler device: Diskus

Co‐treatment: short‐acting bronchodilators, short‐ and long‐acting anticholinergics or theophylline was allowed throughout the study. Oral corticosteroids and/or antibiotics could be given only in short courses for exacerbation treatment

Outcomes

Primary: treatment difference in the numbers of CD8+ T lymphocytes and CD68+ macrophages on bronchial biopsies

Secondary: numbers of neutrophils and eosinophils in bronchial biopsies

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central computer‐generated list of random numbers

Allocation concealment (selection bias)

Low risk

Set up by a data management/randomisation company (GEREQ, Montreal, Quebec). A procedure was established by GEREQ, which was in possession of the treatment code, to ensure that the treatment code would be broken only in accordance with the protocol and the criteria set up for unbinding of the study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Observers and participants were blinded to drug treatment

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Observers were blinded to whether the biopsies were performed post‐treatment or pretreatment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout uneven but low in both groups (5% ICS and 14% placebo)

Selective reporting (reporting bias)

High risk

Key outcomes not reported. No reply from study author

Methods

Design: double‐blind, placebo‐controlled study

Three‐year treatment period

Conducted at 18 hospitals in the UK

Participants

Participants: 740 people were randomly assigned to fluticasone (372) and placebo (370)Baseline characteristics:

Male %: flut 75.0, placebo 74.1

Mean age (SD), years: flut 63.7 (7.1), placebo 63.8 (7.1)

Smoking history (mean (SD) pack‐years): flut 44 (30), placebo 44 (34)

Mean % predicted FEV₁ (SD): flut 50.3 (14.9), placebo 50.0 (14.9)

Inclusion criteria: current or former smokers 40 to 75 years of age with non­asthmatic chronic obstructive pulmonary disease. Baseline FEV₁ after bronchodilator was at least 0.8 L but less than 85% of predicted normal, and the ratio of FEV₁ to forced vital capacity was less than 70%. Previous use of inhaled and oral corticosteroids was permitted
Exclusion criteria: Individuals were excluded if their FEV₁ response to 400 mcg salbutamol exceeded 10% of predicted normal, if they had a life expectancy of less than five years from concurrent disease or if they used beta blockers

Interventions

Run‐in: eight‐week run­in period after withdrawal from any oral or inhaled corticosteroids

Treatments:

1. Fluticasone propionate 500 mcg daily

2. Placebo twice daily

Inhaler device: metered‐dose inhaler with a spacer device

Co‐treatment: Nasal and ophthalmic corticosteroids, theophyllines and all other bronchodilators were allowed during the study

Outcomes

Primary: decline (mL/y) in FEV₁ after bronchodilator

Secondary: frequency of exacerbations, changes in health status, withdrawals due to respiratory disease, morning serum cortisol concentrations and adverse events

Notes

Funding: GlaxoWellcome Research and Development

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated allocation (block size of six)

Allocation concealment (selection bias)

Low risk

Participants were randomly assigned sequentially from a list comprising treatment numbers only

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Three‐year double‐blind phase using an identical placebo inhaler

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Very high dropout in both groups (43% and 53%)

Selective reporting (reporting bias)

Unclear risk

No outcomes appear to be missing, but protocol could not be located to ensure that all were reported. Author attempted contact with GSK statistician, but no data were provided in time for publication

Methods

Design: multi‐centre, randomised, double‐blind, parallel‐group, placebo‐controlled study

12‐Month treatment period

Conducted at 196 hospitals in 25 countries

Participants

Participants: 1465 people were randomly assigned to fluticasone/salmeterol combination (358), fluticasone (374), salmeterol (372) and placebo (361)
Baseline characteristics:

Male %: flut/salm 75, flut 70, salm 70, placebo 75

Mean age (SD), years: flut/salm 62.7 (8.7), flut 63.5 (8.5), salm 63.2 (8.6), placebo 63.4 (8.6)

Smoking history (mean (SD) pack‐years): flut/salm 42.0 (22.4), flut 41.5 (20.7), salm 43.7 (21.9), placebo 43.4 (22.4)

Mean % predicted FEV₁ (SD): flut/salm 44.8 (14.7), flut 45.0 (13.6), salm 44.3 (13.8), placebo 44.2 (13.7)

Inclusion criteria: All participants had a baseline FEV₁ before bronchodilation that was 25% to 70% of that predicted, an increase of less than 10% of predicted FEV₁ 30 minutes after inhalation of 400 mcg salbutamol and a pre‐bronchodilator FEV₁/forced vital capacity (FVC) ratio of 70% or less. Participants also had a history of at least 10 pack‐years of smoking, chronic bronchitis, at least one episode of acute COPD symptom exacerbation per year in the previous 3 years and at least one exacerbation in the year immediately before trial entry that required treatment with oral corticosteroids, antibiotics or both
Exclusion criteria: We excluded individuals who had respiratory disorders other than COPD, required regular oxygen treatment or had received systemic corticosteroids, high doses of inhaled corticosteroids (> 1000 mcg daily beclomethasone dipropionate, budesonide or flunisolide, or > 500 mcg daily fluticasone) or antibiotics in the 4 weeks before the 2 week run‐in period before the trial began

Interventions

Run‐in: During the 2‐week run‐in, participants stopped taking regular inhaled corticosteroids or long‐acting beta₂‐agonists

Treatments:

1. Fluticasone/salmeterol 500/50 mcg twice daily

2. Fluticasone 500 mcg twice daily

3. Salmeterol 50 mcg twice daily

4. Placebo twice daily

Inhaler device: multi‐dose dry powder inhaler (Diskus or Accuhaler)

Co‐treatment: Inhaled salbutamol was used as relief medication throughout the study, and regular treatment with anticholinergics, mucolytics and theophylline was allowed. All non‐COPD medications could be continued if the dose remained constant when possible, and if their use would not be expected to affect lung function

Outcomes

Primary: FEV₁ at least 6 and 12 hours after study medication

Secondary: pretreatment FVC and post‐treatment FEV₁ and FVC, daily record card symptoms, morning and evening PEF, use of relief medication, night‐time awakenings, acute exacerbations, health‐related quality of life (SGRQ), adverse events and electrocardiology

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A randomisation schedule generated by the participant allocation for clinical trials (PACT) programme to assign participants to study treatment groups

Allocation concealment (selection bias)

Unclear risk

Every participating centre was supplied with a list of participant numbers (assigned to participants at their first visit) and a list of treatment numbers. Participants who satisfied the eligibility criteria were assigned the next sequential treatment number from the list

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Salmeterol and fluticasone combination, salmeterol, fluticasone and placebo were packaged in identical inhaler devices

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Adverse event information was obtained at each clinic visit by recording spontaneously reported complaints from participants and asking general questions about medical troubles and concomitant medications

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawal rates varied from 25% in the combination inhaler group to 39% in the placebo group. These numbers are substantially higher than the numbers of events reported for any of the outcomes. The unknown outcome of participant withdrawal from the study could have a major impact on the result

Selective reporting (reporting bias)

Low risk

All outcomes reported. Checked with study authors

Methods

Design: multi‐centre, randomised, double‐blind, parallel‐group, placebo‐controlled study

12‐Month treatment period

Conducted at 109 centres in 15 countries

Participants

Participants: 1022 people were randomly assigned to budesonide/formoterol combination (254), budesonide (257), formoterol (255) and placebo (256)
Baseline characteristics:

Male %: bud/form 78, bud 74, form 75, placebo 75

Mean age (range), years: bud/form 64 (42 to 86), bud 64 (41 to 85), form 63 (41 to 84), placebo 65 (43 to 85)

Smoking history (mean pack‐years): bud/form 33, bud 39, form 36, placebo 30

Mean % predicted FEV₁ (SD): bud/form 36 (10), bud 36 (10), form 36 (10), placebo 36 (10)

Inclusion criteria: GOLD‐defined COPD (stages III and IV); ≥ 40 years; COPD symptoms > 2 years; smoking history ≥ 10 pack‐years; FEV₁/FVC ≤ 70% pre‐bronchodilator; FEV₁ ≤ 50% predicted; use of short‐acting beta₂‐agonists as reliever medication; ≥ 1 COPD exacerbation requiring oral corticosteroids/antibiotics 2 to 12 months before first clinic visit
Exclusion criteria: history of asthma/rhinitis before 40 years of age; any relevant cardiovascular disorders; exacerbation of COPD requiring medical intervention within 4 weeks of run‐in/during run‐in phase; non‐allowed medications: oxygen therapy; ICS (aside from study medication), disodium cromoglycate, leukotriene‐antagonists, 5‐lipoxygenase inhibitors, bronchodilators (other than study medication and terbutaline 0.5 mg as needed), antihistamines, medication containing ephedrine, beta‐blocking agents

Interventions

Run‐in: All participants received 30 mg oral prednisolone twice daily and 2 × 4.5 mg formoterol twice daily (2 weeks)

Treatments:

1. Budesonide/formoterol 320/9 mcg twice daily

2. Budesonide 400 mcg twice daily

3. Formoterol 9 mcg twice daily

4. Placebo twice daily

Inhaler device: Turbuhaler

Co‐treatment: terbutaline 0.5 mg as needed, courses of oral corticosteroids (maximum 3 weeks per course) and antibiotics in the event of exacerbations, parenteral steroids and/or nebulised treatment (single injections/inhalations) at emergency visits

Outcomes

Primary: time to first exacerbation and change in postmedication FEV₁

Secondary: number of exacerbations, time to and number of oral corticosteroid–treated episodes, change in postdose FEV₁, slow VC, morning and evening PEF, quality of life (SGRQ), symptoms, use of reliever medication and adverse events

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised trial (no other details—funded by AstraZeneca and presumed to adhere to usual methods)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind (assume participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

An intention‐to‐treat analysis was used but dropout was high in all groups (ranging from 29% to 44%)

Selective reporting (reporting bias)

Low risk

All outcomes stated in the industry document were reported in full. Checked with study authors

Methods

Design: multi‐centre, double‐blind, placebo‐controlled, randomised, parallel‐group study

Three‐year treatment period

Conducted at 444 centres in 42 countries

Participants

Participants: 6184 people were randomly assigned to fluticasone/salmeterol combination (1546), fluticasone (1551), salmeterol (1542) and placebo (1545)
Baseline characteristics:

Male %: flut/salm 75, flut 75, salm 76, placebo 76

Mean age (SD), years: flut/salm 65.0 (8.3), flut 65.0 (8.4), salm 65.1 (8.2), placebo 65.0 (8.2)

Smoking history (mean (SD) pack‐years): flut/salm 47.0 (26.5), flut 49.2 (28.6), salm 49.3 (27.7), placebo 48.6 (26.9)

Mean % predicted FEV₁ (SD): flut/salm 44.3 (12.3), flut 44.1 (12.3), salm 43.6 (12.6), placebo 44.1 (12.3)

Inclusion criteria: current or former smokers with at least a 10‐pack‐year history. Eligible individuals were 40 to 80 years of age and had received a diagnosis of COPD, with a pre‐bronchodilator forced expiratory volume in one second (FEV₁) of less than 60% of predicted value, an increase in FEV₁ with the use of 400 mcg of albuterol of less than 10% of the predicted value for that individual and a ratio of pre‐bronchodilator FEV₁ to forced vital capacity (FVC) equal to or less than 0.70
Exclusion criteria: diagnosis of asthma, current respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis, lung fibrosis); chest x‐ray indicating diagnosis other than COPD that might interfere with the study (chest x‐ray to be taken up to six months before entry to the treatment period); lung volume reduction surgery and/or lung transplant, requirement for long‐term oxygen therapy (LTOT is defined as oxygen therapy prescribed for 12 or more hours per day) at start of study; receiving long‐term oral corticosteroid therapy defined as continuous use for longer than 6 weeks; serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study and/or likely to cause death within the 3‐year study duration; received any other investigational drugs in the last 4 weeks before entry to visit one; evidence of alcohol, drug or solvent abuse; known or suspected hypersensitivity to inhaled corticosteroids, bronchodilators or lactose; known deficiency of α₁‐antitrypsin

Interventions

Run‐in: Before the 2 week run‐in period, all use of corticosteroids and inhaled long‐acting bronchodilators was stopped, but participants could continue other medications for COPD

Treatments:

1. Fluticasone/salmeterol 500/50 mcg twice daily

2. Fluticasone 500 mcg twice daily

3. Salmeterol 50 mcg twice daily

4. Placebo twice daily

Inhaler device: multi‐dose dry powder inhaler (Diskus or Accuhaler)

Co‐treatment: all COPD medications except corticosteroids and inhaled long‐acting bronchodilators

Outcomes

Primary: time to death from any cause by three years

Secondary: frequency of exacerbations, health status (SGRQ), postbronchodilator spirometry and adverse events

Notes

Funding: GSK

Clinicaltrials.gov ID: NCT00268216

Definition of pneumonia: Study authors state there was no prospective definition because the finding was unexpected

NOTE: Participants previously enrolled into TRISTAN (SFCB3024) may be recruited to this trial 4 weeks after stopping their previous study medication

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random assignment with permuted blocks with stratification

Allocation concealment (selection bias)

Low risk

Medication was allocated with the use of three numbers as follows.

1. Each participant who was screened was allocated a participant number. This number was unique to each participant and was assigned from a list provided to the site, in chronological order

2. Each participant who satisfied the randomisation criteria was assigned a unique treatment number from the interactive voice response (IVR) system, which is part of the system for central allocation of drug (SCAD). Once a treatment number had been assigned to a participant, it could not be assigned to any other participant. Neither the participant nor the investigator knew to which treatment arm a participant had been allocated

3. At each treatment visit, the participant was provided with a treatment pack. Each pack number was unique and corresponded to the study medication pack dispensed to the participant at the visit

A specialist IVR system company, ClinPhone, managed this system. At the randomisation visit (visit two), the principal investigator or designee contacted the IVR system through an automated 24‐hour telephone number; upon provision of a unique personal identification number (PIN) and answers to a series of questions, the site was provided with the participant's treatment number as well as a pack number

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Neither the subject nor the investigator knew to which treatment arm a participant had been allocated. At each treatment visit, each participant was issued with a treatment pack containing DISKUS/ACCUHALER inhalers. The inhalers contained one of the four treatments (salmeterol/fluticasone propionate combination product, fluticasone propionate, salmeterol or placebo) in accordance with the randomisation schedule. The inhalers were labelled in accordance with all applicable regulatory requirements. Each treatment pack and study treatment inhaler was labelled with the protocol number; storage and dosing instructions were provided by GW Research and Development

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The investigator is responsible for the detection and documentation of events meeting the definition of an AE or SAE as provided in this protocol. However, no prospective definition of pneumonia is provided in the study protocol

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Outcome all‐cause mortality: Participants who prematurely discontinue study drug will be followed up for 156 weeks from randomisation for assessment of survival. The risk of bias due to incomplete outcome data for mortality is low

General

Withdrawal rates were high but fairly even (with the exception of the placebo group, which had an even higher withdrawal rate; placebo 44%, LABA 36%, ICS 38% and ICS/LABA 34%). However, for participants who withdrew from the study prematurely, all data on exacerbations, health status and lung function available at the time of a participant's withdrawal from the study were included in the analysis. All efficacy analyses were performed according to the intention‐to‐treat principle

Selective reporting (reporting bias)

Low risk

All collected data reported. Checked with study authors

Methods

Design: double‐blind, double‐dummy, randomised, active‐controlled, parallel‐group study

11‐Month treatment period (48 weeks)

Conducted at 76 centres in 8 countries across Europe

Participants

Participants: 481 people were randomly assigned to budesonide/formoterol combination (242) and formoterol (239)
Baseline characteristics:

Male %: bud/form 81.5, form 81.1

Mean age (SD), years: bud/form 64.1 (9.1), form 63.7 (8.8)

Smoking history (mean (SD) pack‐years): bud/form 37.8 (14.6), form 39.7 (19.1)

Mean % predicted FEV₁ (SD): bud/form 42.3 (6.0), form 42.5 (5.9)

Inclusion criteria: hospital outpatients with severe stable COPD according to the GOLD guidelines; 40 years of age with a diagnosis of symptomatic COPD for > 2 years, at least a 20‐pack‐year smoking history, a postbronchodilator FEV₁ between 30% and 50% of predicted normal and at least 0.7 L absolute value and a predose FEV₁/forced vital capacity (FVC) of 0.7; at least one exacerbation requiring medical intervention (oral corticosteroid and/or antibiotic treatment and/or need for a visit to an emergency department and/or hospitalisation) within 2 to 12 months before the screening visit and the need to be clinically stable for the 2 months before study entry; change in FEV₁ < 12% of predicted normal value 30 minutes following inhalation of 200 mg of salbutamol pMDI
Exclusion criteria: history of asthma, allergic rhinitis or other atopic disease, variability of symptoms from day to day and frequent symptoms at night and early morning (suggestive of asthma); receiving long‐term oxygen therapy or having a lower respiratory tract infection or having been hospitalised for an acute COPD exacerbation within two months before screening or during the run‐in period. Treatments with oral, injectable or depot corticosteroids and antibiotics, long‐acting antihistamines and changes in the dose of an oral modified‐release theophylline in the two months before screening and during the run‐in period were excluded

Interventions

Run‐in: During the 4‐week run‐in period, all non‐permitted COPD treatments were discontinued and eligible participants were treated with combination ipratropium/salbutamol (20/100 mg, two inhalations three times daily)

Treatments:

1. Budesonide/formoterol 400/12 mcg twice daily

2. Formoterol 12 mcg twice daily

Inhaler device: dry powder inhaler

Co‐treatment: not described

Outcomes

Primary: change in predose morning FEV₁ and mean rate of COPD exacerbations per participant per year

Secondary: FVC, PEF, SGRQ total score, six‐minute walking test, BMI, BODE index, safety evaluations including ECG

Notes

Funding: Chiesi Farmaceutici

Clinicaltrials.gov ID: NCT00476099

Definition of pneumonia: not defined

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The randomisation scheme followed a balanced‐block centre‐stratified design and was prepared via a computerised system

Allocation concealment (selection bias)

Low risk

Participants were centrally assigned, in each centre, to one of the three treatment arms at the end of the run‐in period through an Interactive voice/web response System (IXRS)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

On each study day, participants took both active medications and matched placebo twice daily, to maintain blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

On each study day, participants took both active medications and matched placebo twice daily, to maintain blinding. In cases of emergency, unbinding of the treatment code was done through IXRS

Incomplete outcome data (attrition bias)
All outcomes

Low risk

12.3% withdrew from the combination group and 14.2% from the formoterol group. Judged to be relatively low and even between groups, and for the intention‐to‐treat population, last observation carried forward was used

Selective reporting (reporting bias)

Low risk

All outcomes stated in the prospectively registered protocol were reported in full

Methods

Design: randomised, double‐blind, placebo‐controlled trial

12‐Month treatment period in total, but participants/clinicians could stop study inhalers and return to usual (prerandomisation) steroid inhalers at any point during the study. These participants remained in the study, continued completing their diary cards and were followed up

Conducted at 31 general practices in East London and Essex, UK

Participants

Participants: 260 people were randomly assigned to fluticasone (128) and placebo (132)
Baseline characteristics:

Male %: flut 48, placebo 56

Mean age (SD), years: flut 67.6 (8.9), placebo 67.3 (9.0)

Smoking history (mean (SD) pack‐years): flut 40.0 (24.2), placebo 38.8 (22.3)

Mean % predicted FEV₁ (SD): flut 53.2 (18.2), placebo 55.0 (17.1)

Inclusion criteria: Investigators searched the medical record database at each practise to identify people 40 years of age and older, with a history of smoking, who had been prescribed ICS for a minimum of six months. We invited people who fulfilled these criteria to attend a recruitment interview. Individuals with lung function consistent with international guidelines for the diagnosis of COPD were invited to join the study: postbronchodilator FEV₁ less than 80% predicted, FEV₁/FVC ratio less than 70% and a pre‐bronchodilator to postbronchodilator change in FEV₁ of less than 15%. Participants with an FEV₁ greater than 15% but with a volume change of less than 200 mL were also included
Exclusion criteria: At interview, we excluded people if they were on long‐term oral corticosteroids, were not taking their prescribed ICS for at least four days a week or had other chronic active lung disease or lung cancer

Interventions

Run‐in: two‐week run‐in period before randomisation, when participants stopped their regular ICS

Treatments:

1. Fluticasone propionate 500 mcg twice daily

2. Placebo twice daily

Inhaler device: Accuhaler

Co‐treatment: General practitioners were advised to manage exacerbations according to usual guidance with antibiotics and/or oral steroids. Decisions about stopping study inhalers and returning to usual (prerandomisation) steroid inhalers were made by the general practitioner and the participant. Participants who did return to their usual steroid inhaler after randomisation remained in the study, continued completing their diary cards and were followed up for one year

Outcomes

Primary: COPD exacerbation frequency

Secondary: time to first exacerbation (from diary cards and medical records), reported symptoms, peak expiratory flow rate and reliever inhaler use (from diary cards) and lung function and health=related quality of life (at follow‐up visits)

Notes

Funding: The British Lung Foundation and Newham National Health Service Trust Research and Development funded the study. GlaxoSmithKline provided the study inhalers free of charge but was not involved in study design, data collection or analysis or interpretation of results

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were allocated with minimisation to intervention or control using the programme MINIM v1.3. Minimisation factors were age, smoking status, pretrial weekly dose of ICS, self reported COPD exacerbation frequency and percentage predicted FEV₁

Allocation concealment (selection bias)

Low risk

Inhalers were given an alphanumerical code to conceal allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study nurses and regular clinicians were blind to allocation throughout the study. Inhalers were given an alphanumerical code to conceal allocation

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Study nurses performed the measurements and were blind to allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Decisions about stopping study inhalers and returning to usual (prerandomisation) steroid inhalers were made by the general practitioner and the participant. Participants who did return to their usual steroid inhaler after randomisation remained in the study, continued completing their diary cards and were followed up for one year

Selective reporting (reporting bias)

High risk

Key outcomes were not reported (e.g. total mortality, breakdown of all and serious adverse events). No reply from study authors

Methods

Design: randomised, double‐blind, parallel‐group, pilot study

12‐Month treatment period

Conducted at a single centre in Italy

Participants

Participants: 12 people were randomly assigned to fluticasone/salmeterol combination (6) and salmeterol alone (6)
Baseline characteristics:

Male %: flut/salm 83.3, salm 100

Age range (mean not reported), years: flut/salm 53 to 77, salm 55 to 78

Smoking history (mean (SD) pack‐years): flut/salm 40.1 (6.3), salm 43.1 (5.3)

Mean % predicted FEV₁ (SD): flut/salm 50 (2.0), salm 48 (5.6)

Inclusion criteria: basal FEV₁ < 80% predicted normal value, but > 800 mL; FEV₁/FVC ratio < 70% predicted; FEV₁ change of < 12% as a percentage of predicted normal
value following salbutamol 400 mg; regular treatment with oral theophylline 200 mg bid and short‐acting beta₂‐adrenergics prn for a period of at least six months; current smokers or ex‐smokers with a smoking history of at least 10 pack‐years
Exclusion criteria: current evidence of asthma or other pulmonary diseases; regular treatment with ICS; unstable respiratory disease requiring oral/parenteral corticosteroids within four weeks before the beginning of the study; changes in COPD medication in the last four weeks before entering the run‐in period; upper or lower respiratory tract infection within four weeks before the screening visit; unstable angina or unstable arrhythmias; recent myocardial infarction or hearth failure; insulin‐dependent diabetes mellitus; neuropsychiatric disorders; concurrent use of medications that affected COPD (e.g. beta‐blockers) or interacted with methylxanthine products such as macrolides or fluoroquinolones; known or suspected hypersensitivity to ICS, beta₂‐agonist or lactose; evidence of alcohol abuse

Interventions

Run‐in: Patients entered a two‐week run‐in period during which they assumed their regular treatment with theophylline and salbutamol as required

Treatments:

1. Fluticasone/salmeterol 250/50 mcg twice daily

2. Salmeterol 50 mcg twice daily

Participants were also randomly assigned to placebo (6), but this group was not included in the current review because no group received fluticasone monotherapy

Inhaler device: Diskus

Co‐treatment: theophylline and salbutamol as required

Outcomes

Unclear which outcome was primary

Exacerbations per year, FEV₁, morning PEF, daily symptom scores, use of rescue medication and adverse events

Notes

Funding: unclear

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

At the end of the run‐in, eligible participants will be randomly assigned to receive one of the three double‐blind treatments (no other details and does not appear to be industry funded)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Assigned to receive one of the three double‐blind treatments, all via Diskus

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropout

Selective reporting (reporting bias)

High risk

Several key outcomes not reported (mortality, adverse events). Difficulty contacting study authors

Methods

Design: two replicate double‐blind parallel‐group trials

12‐Month treatment period

Study one was conducted at 167 centres in 15 countries (Argentina, Australia, Canada, Chile, Estonia, Germany, Italy, Mexico, Netherlands, Peru, Phillipines, South Africa, Sweden, the United Kingdom and the United States). Study two was conducted at 183 centres in 15 countries

Participants

Participants: 1622 people were randomly assigned in study one and 1633 in study two to vilanterol 25 (818), fluticasone/vilanterol combination 50/25 (820), 100/25 (806) and 200/25 (811)
Baseline characteristics:

Male %: Vil 58.0, F/Vil 50/25 58.0, F/Vil 100/25 56.2, F/Vil 200/25 57.6

Mean age, years: Vil 63.6, F/Vil 50/25 63.7, F/Vil 100/25 63.8, F/Vil 200/25 63.7

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁: Vil 45.2, F/Vil 50/25 45.4, F/Vil 100/25 46.1, F/Vil 200/25 45.2

Inclusion criteria: Eligible patients were 40 years of age or older and had a history of COPD, a smoking history of 10 or more pack‐years, a ratio of forced expiratory volume in one second (FEV₁) to forced vital capacity of 0.70 or less after bronchodilators (and an FEV₁ of 70% or less of predicted) and a documented history of one or more moderate or severe disease exacerbations in the year before screening
Exclusion criteria: Appendix listing the exclusion criteria and the drugs that were and were not permissible for the study duration could not be located

Interventions

Run‐in: four weeks during which participants received open‐label combination fluticasone propionate (250) and salmeterol (50) twice daily to establish adherence to treatment and a stable baseline

Treatments:

1. Fluticasone furoate/vilanterol 50/25 mcg daily

2. Fluticasone furoate/vilanterol 100/25 mcg daily

3. Fluticasone furoate/vilanterol 200/25 mcg daily

4. Vilanterol 25 daily

Inhaler device: dry powder inhaler

Co‐treatment: Appendix listing the exclusion criteria and the drugs that were and were not permissible for the study duration could not be located

Outcomes

Primary: annual rate of moderate and severe exacerbations

Secondary: time to first moderate or severe exacerbation; annual rate of exacerbations requiring oral corticosteroids; predose AM FEV₁

Notes

Funding: GSK

Clinicaltrials.gov ID: NCT01009463 and NCT01017952

Definition of pneumonia: confirmed by chest x‐ray

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The central randomisation schedule was generated by the GSK statistics group, which used a validated computerised system (RandAll; GSK, London, UK)

Allocation concealment (selection bias)

Unclear risk

The statistician entered the parameters for the randomisation but was masked to treatment assignment and did not have access to the master randomisation schedule until the study was unmasked at database lock. The Registration and Medication Ordering System (RAMOS; GSK, London, UK) was used to register and randomly assign participants and assign drugs

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and investigators were masked to allocation, and the Ellipta dry powder inhalers were identical in appearance. Every effort was made to ensure that the statistics and programming department of GSK was not unmasked to any treatment allocations ahead of the database freeze

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Participants and investigators were masked to allocation, and the Ellipta dry powder inhalers were identical in appearance. Every effort was made to ensure that the statistics and programming department of GSK was not unmasked to any treatment allocations ahead of the database freeze

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout quite high but even between groups (ranging from 23% to 31%). A generalised linear model was used for the intention‐to‐treat analyses of each study, including all randomly assigned participants receiving at least one dose of study drug (representing 100% of those randomly assigned)

Selective reporting (reporting bias)

Low risk

All outcomes stated in the prospectively registered protocol were reported in the published paper

Methods

Design: randomised, double‐blind, parallel‐group study

12‐Month study period

Conducted at 94 research sites in the United States and Canada

Participants

Participants: 782 people were randomly assigned to fluticasone/salmeterol combination (394) and salmeterol alone (388)
Baseline characteristics:

Male %: flut/salm 58, salm 52

Mean age (SD), years: flut/salm 64.9 (9.0), salm 65.0 (9.1)

Smoking history (mean (SD) pack‐years): flut/salm 58.5 (30.6), salm 54.4 (25.7)

Mean % predicted FEV₁ (SD): flut/salm 32.8 (11.0), salm 32.8 (10.1)

Inclusion criteria: 40 years of age or older with a diagnosis of COPD, a cigarette smoking history of greater than or equal to 10 pack‐years, a prealbuterol FEV₁/FVC of 0.70 or less, an FEV₁ of 50% of predicted normal or less and a history of 1 or more exacerbations of COPD in the year before the study, which required treatment with oral corticosteroids or antibiotics, or hospitalisation
Exclusion criteria: diagnosis of asthma, a significant lung disease other than COPD, a clinically significant and uncontrolled medical disorder including but not limited to cardiovascular, endocrine or metabolic, neurological, psychiatric, hepatic, renal, gastric and neuromuscular diseases, or had a COPD exacerbation that was not resolved at screening

Interventions

Run‐in: four‐week run‐in period during which participants received open‐label fluticasone/salmeterol 250/50 via Diskus twice daily

Treatments:

1. Fluticasone/salmeterol 250/50 mcg twice daily

2. Salmterol 50 mcg twice daily

Inhaler device: Diskus

Co‐treatment: As‐needed albuterol was provided for use throughout the study. Concurrent inhaled long‐acting bronchodilators (beta₂‐agonist and anticholinergic), ipratropium/albuterol combination products, oral beta‐agonists, inhaled corticosteroids and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the short‐term treatment of COPD exacerbations

Outcomes

Primary: annual rate of moderate to severe exacerbations

Secondary: time to first moderate to severe exacerbation, annual rate of exacerbations requiring oral corticosteroids, predose FEV₁, diary records of dyspnoea, night‐time awakenings due to COPD and use of supplemental albuterol

Notes

Funding: GSK (ID SCO40043)

Clinicaltrials.gov ID: NCT00144911

Definition of pneumonia: no objective definition given

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centre‐based randomisation schedule

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropout high and fairly even (30% vs 38%). Method of imputation described only for the primary outcome (‘Endpoint was defined as the last scheduled measurement of predose AM FEV₁ during the 52‐week treatment period’)

Selective reporting (reporting bias)

Low risk

Checked GSK documents—all stated and expected outcomes are reported

Methods

Design: randomised, double‐blind, parallel‐group study

Three‐month study period

Conducted at 163 centres in 9 countries (India, Japan, Republic of Korea, Phillipines, Poland, Russian Federation, Taiwan, Ukraine and Vietnam)

Participants

Participants: 1293 people were randomly assigned to budesonide/formoterol combination (636) and formoterol alone (657)
Baseline characteristics:

Male %: bud/form 87.6, form 90.3

Mean age (range), years: bud/form 64.5 (40 to 89), form 65.6 (40 to 87)

Smoking history (mean (range) pack‐years): bud/form 43.4 (10 to 160), form 44.7 (0 to 300)

Mean % predicted FEV₁ (range): bud/form 40.9 (12 to 79), form 40.8 (8‐84)

Inclusion criteria: male and female individuals, 40 years of age or older with a diagnosis of moderate to severe COPD for at least 2 years (pre‐bronchodilator forced expiratory volume in one second (FEV₁) 50% of predicted normal or less, postbronchodilator FEV₁/forced vital capacity (FVC) < 70%), current or previous smoking history of 10 or more pack‐years and having at least one COPD exacerbation in 12 months
Exclusion criteria: history or current clinical diagnosis of asthma or atopic disease such as allergic rhinitis; significant or unstable ischaemic heart disease, arrhythmia, cardiomyopathy, heart failure, uncontrolled hypertension or any other relevant cardiovascular disorder; experiencing a COPD exacerbation during the run‐in period or within 4 weeks before randomisation that required hospitalisation and/or a course of oral or parenteral steroids; and requiring regular oxygen therapy

Interventions

Run‐in: 1‐ to 2‐week run‐in period during which participants received open‐label formoterol 4.5 mg two inhalations twice daily and all other COPD medications were discontinued, with the exception of salbutamol 100 mg/actuation via pMDI

Treatments:

1. Budesonide/formoterol combination 320/9 mcg twice daily

2. Formoterol 9 mcg twice daily

Inhaler device: Turbuhaler

Co‐treatment: Salbutamol 100 mg/actuation was available as reliever medication throughout the treatment period. During the randomised treatment period, participants were not permitted to take any other medication for their COPD, including beta₂‐agonists, anticholinergics, leukotriene receptor antagonists, medications containing ephedrine or xanthine‐containing derivatives or inhaled corticosteroids

Outcomes

Primary: change in predose FEV₁ from baseline to treatment period

Secondary: 1 hour postdose FEV₁, predose and one hour postdose FVC, COPD symptoms, time to first COPD exacerbation, number of COPD exacerbations, health‐related quality of life on the SGRQ, morning and evening PEF, adverse events and vital signs

Notes

Funding: AstraZeneca (ID: D589DC00007)

Clinicaltrials.gov ID: NCT01069289

Definition of pneumonia: pneumonia, brochopneumonia and bacterial pneumonia counted as serious adverse events. Diagnosis not given

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly assigned 1:1 to study treatment. No details of sequence generation methods, but presumed to adhere to usual AstraZeneca methods

Allocation concealment (selection bias)

Unclear risk

No details

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

From clinicaltrials.gov: masking: double‐blind (participant, caregiver, investigator, outcomes assessor)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

From clinicaltrials.gov: masking: double‐blind (participant, caregiver, investigator, outcomes assessor)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout low and even between groups

Selective reporting (reporting bias)

Low risk

All outcomes were fully reported on clinical.trials.gov and in the published report

Methods

Design: multi‐centre, randomised, placebo‐controlled, double‐blind trial

Three‐month treatment period

Conducted at 32 centres in Germany

Participants

Participants: 140 people were randomly assigned to salmeterol plus fluticasone (68) and salmeterol plus placebo (69)
Baseline characteristics:

Male %: flut+salm 60.6, salm+placebo 71.2

Mean age (SD), years: flut+salm 61 (8), salm+placebo 63 (10)

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: documented history of COPD; male and female subjects 40 to 79 years of age; smokers and ex‐smokers with a smoking history of ≥ 10 pack‐years; FEV₁ 40% to 80% of predicted, FEV₁/FVC < 70% at visit 1 or 2; low reversibility of airway obstruction at visit 1 or 2: increase in FEV₁ (normal value) < 10% at 30 minutes after inhalation of 200 mcg salbutamol; symptomatic COPD during run‐in as documented in the participant diary: on ≥ 5 days, symptom score was > 5 and/or salbutamol inhalation; ability to correctly use the Mini‐Wright Peak‐Flow‐Meter and the Diskus™ inhaler
Exclusion criteria: long‐term oxygen therapy; use of inhaled or systemic corticosteroids during the 8 weeks before study entry; acute exacerbation, antibiotic treatment or hospital stay within 4 weeks before study entry; use of beta blockers within two weeks before study entry

Interventions

Run‐in: 2 weeks during which all participants received salmeterol 50 mcg twice daily as bronchodilator treatment and salbutamol as rescue medication

Treatments:

1. Salmeterol 50 mcg plus fluticasone 500 mcg twice daily (and placebo tablets for 2 weeks)

2. Salmeterol 50 mcg plus placebo inhaler twice daily (and placebo tablets for 2 weeks)

A third group receiving oral prednisolone in combination with salmeterol was not included in this review

Inhaler device: Diskus

Co‐treatment: salbutamol as rescue medication

Outcomes

Primary: change in FEV₁

Secondary: Participants' self assessment of exercise capacity and morning serum cortisol concentrations

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Described as randomised (presumed to adhere to usual GSK methodology)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout relatively low and even between groups (17.6% vs 14.5%). Full analysis set (FAS) and per‐protocol analyses were reported, but only the FAS was extracted

Selective reporting (reporting bias)

Unclear risk

All outcomes stated were reported. Pneumonia‐related outcomes were not reported. GSK data request was not successful at the time of publication

Methods

Design: randomised, double‐blind, parallel‐group, comparative trial

Six‐month treatment period

Conducted at 55 centres in the United States

Participants

Participants: 640 people were randomly assigned to fluticasone 250 (216), fluticasone 500 (218) and placebo (206)
Baseline characteristics:

Male %: flut250 72.2, flut500 66.1, placebo 68.0

Mean age (SD), years: flut250 65.2 (8.7), flut500 63.3 (10.0), placebo 64.8 (9.5)

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: Male or female individuals were eligible if they were diagnosed with COPD; were at least 40 years of age; had a current or prior history of at least 20 pack‐years of cigarette smoking; had a history of cough productive of sputum on most days for at least 3 months of the year, for at least 2 years that was not attributable to another disease process; had a baseline FEV₁ < 65% of predicted normal but > 0.70 L or FEV₁ ≤ 0.70 L and > 40% of predicted normal and FEV₁/forced vital capacity (FVC) ratio of < 0.70; had a score of ≥ 2 on the Modified Medical Research Council (MMRC) Dyspnea Scale at screening and a score of ≥ 4 on the CBSQ at randomisation and had not received systemic corticosteroids or high‐dose inhaled corticosteroid therapy for at least 6 months before screening
Exclusion criteria: current diagnosis of asthma, concurrent participation in a pulmonary rehabilitation programme, respiratory disease other than COPD or other significant concurrent disease, an abnormal and clinically significant ECG at screening and the occurrence of a moderate or severe COPD exacerbation during the run‐in period

Interventions

Run‐in: 2‐week placebo run‐in period

Treatments:

1. Fluticasone propionate 250 mcg twice daily

2. Fluticasone propionate 500 mcg twice daily

3. Placebo twice daily

Inhaler device: Diskus

Co‐treatment: Concurrent use of the following respiratory medications was not allowed: beta‐agonists (other than salbutamol), cromolyns, corticosteroids (oral, inhaled and intranasal), anti‐leukotrienes and ipratropium. Concurrent use of theophylline was allowed. Use of antibiotics for the treatment of up to three COPD exacerbations was allowed

Outcomes

Primary: morning predose FEV₁

Secondary: Chronic Bronchitis Symptoms Questionnaire (CBSQ), Transition Dyspnoea Index (TDI, exacerbations of COPD, participant‐recorded daily morning PEF rate, supplemental salbutamol use, night‐time awakenings and quality of life (CDRQ)

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised trial (GSK funded, likely to be computerised randomisation schedule)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded trial (presumed participant and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout high but even across groups. The intent‐to‐treat (ITT) population consisted of all randomly assigned participants who received at least 1 dose of study medication. The ITT population was the primary population for all efficacy and safety analyses

Selective reporting (reporting bias)

Low risk

All outcomes were reported in the results summary

Methods

Design: multi‐centre, randomised, double‐blind, double‐dummy, parallel‐group design

6 month treatment period

Conducted at 135 centres in 20 countries (Australia (10), Bulgaria (5), Croatia (1), Czech Republic (8), France (14), Germany (18), Greece (4), Italy (16), Latvia (5), Lithuania (2), Netherlands (12), Philippines (3), Poland (5), Romania (3), Russian Federation (8), Slovakia (4), Slovenia (4), Sweden (4), Thailand (4) and United Kingdom (5))

Participants

Participants: 1050 people were randomly assigned to fluticasone/salmeterol combination (518) and salmeterol alone (532)
Baseline characteristics:

Male %: flut/salm 78.4, salm 77.3

Mean age (SD), years: flut/salm 63.5 (9.4), salm 63.7 (9.0)

Smoking history (mean pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: male or female, 40 to 80 years of age with an established history of GOLD stage II COPD; poor reversibility of airflow obstruction (defined as ≤ 10% increase in FEV₁ as a percentage of normal predicted value); minimum score of ≥ 2 on the Modified Medical Research Council Dyspnoea Scale and a smoking history of at least 10 pack‐years. In addition, participants had to achieve a composite symptom score of ≥ 120 (out of 400 maximum score, measured using visual analogue scales) on at least 4 of the last 7 days of the run‐in period, and to have a Baseline Dyspnoea Index (BDI) score of ≤ 7 units at visit 2
Exclusion criteria: Participants would be excluded if they had asthma or atopic disease, had a lung disease likely to confound the drug response other than COPD, had a recent exacerbation (within 4 weeks of screening or during run‐in); were receiving long‐term oxygen therapy or pulmonary rehabilitation or had taken tiotropium bromide, inhaled corticosteroids or anti‐leukotriene medication within 14 days of visit one

Interventions

Run‐in: run‐in mentioned, unclear duration

Treatments:

1. Salmeterol/fluticasone propionate 50/250 mcg twice daily

2. Salmeterol 50 mcg twice daily

Inhaler device: Diskus accuhaler

Co‐treatment: not reported

Outcomes

Primary: FEV₁, Transitional Dyspnoea Index (TDI)

Secondary: change from baseline in trough FEV₁, change from baseline in trough FVC and FVC/FEV₁ ratio, TDI focal score, change from baseline in postdose FEV₁, FVC and FVC/FEV₁ ratio, change from baseline in mean morning PEF, change from baseline in St George's Respiratory Questionnaire

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Described as randomised (assumed to adhere to usual GSK methodology)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described—only results summary available

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout low and even between groups (11.4% vs 13.9%). The ITT (intent‐to‐treat) population (all participants randomly assigned and confirmed as having received at least one dose of double‐blind study medication) was the primary population for analysis of all efficacy and health outcome variables; the safety population (identical to the ITT population) was used for analysis of all safety variables

Selective reporting (reporting bias)

Low risk

All stated outcomes were reported and no expected outcomes were missing

Methods

Design: multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group study

Three‐month treatment period

Conducted at 11 centres (4 centres in the Russian Federation, 4 centres in the United States, 2 centres in Chile and 1 centre in Estonia)

Participants

Participants: 161 people were randomly assigned to fluticasone (42), placebo (42), fluticasone/salmeterol combination (39) and salmeterol (38)
Baseline characteristics:

Male %: flut 69.0, placebo 76.2, flut/salm 82.1, salm 78.9

Mean age (SD), years: flut 64.2 (11.2), placebo 65.2 (8.6), flut/salm 63.6 (7.8), salm 64.0 (9.3)

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: Males or females of non‐childbearing potential 40 years of age or older were eligible to participate if they had an established clinical history of COPD, evidence of bronchitis as a component of the COPD disease and a current or prior history of at least 10 pack‐years of cigarette smoking. Participants had a measured postalbuterol FEV₁/FVC ≤ 70% at visit 1 (screening) and a measured postalbuterol FEV₁ ≥ 30% and ≤ 70% of predicted normal
Exclusion criteria: no other criteria reported

Interventions

Run‐in: not reported

Treatments:

1. Fluticasone propionate 500 mcg twice daily

2. Placebo twice daily

3. Fluticasone/salmeterol combination 500/50 mcg twice daily

4. Salmeterol 50 mcg twice daily

Inhaler device: not reported

Co‐treatment: not reported

Outcomes

Primary: predose resistance difference between 5 Hz and 15 Hz (R5 to R15) as measured by IOS

Secondary: predose‐ and 2 hours postdose low‐frequency reactance area (AX); 2 hours postdose R5 to R15; postalbuterol computed tomography (CT) parameters of area of airway wall and area of airway lumen

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomly assigned to treatment (assumed to adhere to GSK protocol)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Withdrawal uneven between groups but all less than 20%. ITT analysis used

Selective reporting (reporting bias)

Low risk

All outcomes reported in detail

Methods

Design: multi‐centre, randomised, double‐blind, parallel‐group, placebo‐controlled study

12‐Month treatment period

Conducted at 49 centres in Italy and 7 in Poland

Participants

Participants: 256 people were randomly assigned to fluticasone (131) and placebo (125)
Baseline characteristics:

Male %: flut 83, placebo 80

Mean age (SD), years: flut 64.6 (8.7), placebo 65.7 (9.0)

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: male or female individuals aged > 40 years with an established clinical history of COPD; participants who demonstrated at visit 1 a pre‐bronchodilator baseline FEV₁/VC < 88% for men and < 89% for women of predicted normal values and FEV₁ ≤ 70% of predicted normal value, but > 800 mL; participants who demonstrated at visit 1, poor reversibility of airflow obstruction, defined as an increase in FEV₁ < 10% of the normal predicted FEV₁ value (or < 200 mL from baseline), 30 minutes after inhalation of 400 mcg salbutamol via MDI; current smokers or ex‐smokers with a smoking history of at least 10 pack‐years
Exclusion criteria: as above

Interventions

Run‐in: two‐week run‐in during which all inhaled corticosteroids and long‐acting beta₂‐agonists were discontinued

Treatments:

1. Fluticasone propionate 500 mcg twice daily

2. Placebo twice daily

Inhaler device: metered‐dose inhaler

Co‐treatment: not reported

Outcomes

Primary: time to first moderate or severe exacerbation

Secondary: number and severity of exacerbations, withdrawals due to exacerbations, clinic FEV₁, VC, FEV₁/VC, daily record card symptoms, PEFR, distance walked in the six‐minute walk test (SWT), perceived breathlessness before and after SWT, quality of life (SGRQ), use of relief medication, adverse events, SAEs on therapy

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomly assigned to treatment. No details given but assumed to adhere to GSK methodology

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout high at 26% and 32% for ICS and placebo, respectively. The safety population/Intent‐to‐treat (ITT) population consisted of all randomly assigned participants who took study medication (all of those randomly assigned)

Selective reporting (reporting bias)

Low risk

All outcomes stated in the GSK summary were reported in detail

Methods

Design: randomised, double‐blind, parallel‐group trial

Three‐year treatment period

Conducted at 31 centres in the United States

Participants

Participants: 186 people were randomly assigned to fluticasone/salmeterol combination (92) and salmeterol alone (94)
Baseline characteristics:

Male %: flut/salm 59.8, salm 62.8

Mean age (SD), years: flut/salm 65.4 (8.4), salm 65.9 (9.5)

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: male/female participants with an established clinical history of COPD (including a history of exacerbations), a baseline (pre‐bronchodilator) FEV₁ < 70% of the predicted normal value, a baseline (pre‐bronchodilator) FEV₁/FVC ratio of 70%, at least one evaluable native hip and a smoking history of ≥ 10 pack‐years
Exclusion criteria: no information

Interventions

Run‐in: not reported

Treatments:

1. Fluticasone propionate/salmeterol 250/50 mcg twice daily

2. Salmeterol 50 mcg twice daily

Inhaler device: Diskus

Co‐treatment: 'permitted COPD therapy' unclear

Outcomes

Primary: change in bone mineral density at the lumbar spine

Secondary: change in bone mineral density at the hip, adverse events, serious adverse events, fatal SAEs

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomly assigned to treatment (no specific information but assumed to adhere to GSK methods)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Double‐blind (presumed participant and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawal very high in both groups (39% and 41%)

Selective reporting (reporting bias)

Low risk

All outcomes described in the GSK summary were reported

Methods

Design: randomised, double‐blind, multi‐centre, placebo‐controlled study

Six‐month treatment period

Conducted at 76 investigative sites in the United States

Participants

Participants: 723 people were randomly assigned to fluticasone/salmeterol combination (178), fluticasone (183), salmeterol (177) and placebo (185)
Baseline characteristics:

Male %: flut/salm 61, flut 66, salm 58, placebo 68

Mean age (range), years: flut/salm 63 (40 to 87), flut 63 (40 to 84), salm 64 (42 to 87), placebo 65 (40 to 81)

Smoking history (median (range) pack‐years): flut/salm 53 (20 to 220), flut 60 (20 to 162), salm 57 (20 to 224), placebo 56 (20 to 165)

Mean % predicted FEV₁ (SD): flut/salm 41 (11), flut 42 (11), salm 42 (12), placebo 42 (12)

Inclusion criteria: Participants were > 40 years of age, were current or former smokers with a > 20 pack‐year history and had received a diagnosis of COPD, as defined by the American Thoracic Society. Inclusion criteria required a baseline FEV₁/FVC ratio of < 70% and a baseline FEV₁ of < 65% of predicted normal, but > 0.70 L (or if < 0.70 L, then > 40% of predicted normal). Participants were required to have symptoms of chronic bronchitis and moderate dyspnoea
Exclusion criteria: current diagnosis of asthma; use of oral corticosteroids within the past six weeks; abnormal clinically significant ECG; long‐term oxygen therapy; moderate or severe exacerbation during the run‐in period; and any significant medical disorder that would place the individual at risk, interfere with evaluations or influence study participation

Interventions

Run‐in: two‐week, single‐blind run‐in period during which participants received placebo and albuterol and discontinued use of corticosteroids and bronchodilators with the exception of stable regimens of theophylline

Treatments:

1. Fluticasone propionate 250 mcg twice daily

2. Salmeterol 50 mcg twice daily

3. Fluticasone/salmeterol 250/50 mcg twice daily

4. Placebo twice daily

Inhaler device: Diskus

Co‐treatment: Participants were given as‐needed albuterol and were not allowed corticosteroids or bronchodilators, with the exception of stable regimens of theophylline

Outcomes

Primary: predose and 2 hours postdose FEV₁

Secondary: morning PEF, dyspnoea (TDI), supplemental albuterol use, health status (CRDQ), Chronic Bronchitis Symptom Questionnaire, exacerbations, adverse events, ECG, vital signs and clinical laboratory evaluations

Notes

Funding: GSK (ID: SFCA3007)

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was stratified by reversibility (no other info but GSK sponsored—likely to adhere to GSK methods)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind trial (presumed participant and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout relatively high but even across groups. To account for participant withdrawals, endpoint was used as the primary time point and was defined as the last on‐treatment post‐baseline assessment excluding any data from the discontinuation visit

Selective reporting (reporting bias)

Low risk

Compared with GSK result summary and protocol—no evidence of publication bias

Methods

Design: double‐blind, placebo‐controlled study

Three‐month study period

Conducted at the London Chest Hospital

Participants

Participants: 36 people were randomly assigned to fluticasone (17) and placebo (19)
Baseline characteristics:

Male %: flut 81.3, placebo 92.9

Mean age (SD), years: flut 64.7 (6.2), placebo 64.7 (6.5)

Smoking history (mean (SD) pack‐years): flut 64.9 (50.3), placebo 60.3 (46.6)

Mean % predicted FEV₁ (SD): flut 46.2 (13.6), placebo 45.5 (16.1)

Inclusion criteria: male or female, 40 to 75 years of age, current smokers or ex‐smokers with more than 20 pack‐years of smoking, non‐atopic and with an FEV₁ 25% to 80% of predicted, which improved by less than 15% over baseline and 200 mL after 200 mcg inhaled salbutamol
Exclusion criteria: Individuals with severe concurrent medical problems, psychological impairment on immunosuppressive treatment or with a chest infection within 8 weeks were excluded. Participants who were already taking inhaled steroids had the drug withdrawn and had to be stable for at least 8 weeks before the first biopsy

Interventions

Run‐in: After recruitment, participants had a run‐in period of 8 weeks to ensure that they were stable before the first bronchoscopy

Treatments:

1. Fluticasone 500 mcg twice daily

2. Placebo twice daily

Inhaler device: multi‐dose dry powder Accuhaler

Co‐treatment: All reliever medications (inhaled beta₂‐agonist, anticholinergics and theophylline) were continued as before

Outcomes

Primary: bronchoscopy

Secondary: spirometry (FEV₁ and VC), biopsy processing and counts, symptom scores

Notes

Funding: Glaxo‐Wellcome and Departmental Funds

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly assigned to FP or P in a double‐blind manner using a random numbers table

Allocation concealment (selection bias)

Low risk

Randomly assigned in a double‐blind manner

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Seven of the randomly assigned participants did not appear in the analyses (18.9%) but were counted in the adverse event data relevant for this review

Selective reporting (reporting bias)

High risk

Serious adverse events not reported. No reply from study authors at time of publication

Methods

Design: randomised, double‐blind, parallel‐group study

10‐Month study period

Conducted at 95 respiratory centres in Germany

Participants

Participants: 994 people were randomly assigned to fluticasone/salmeterol combination (507) and salmeterol alone (487)
Baseline characteristics:

Male %: flut/salm 74.0, salm 77.6

Mean age (SD), years: flut/salm 63.8 (8.3), salm 64.0 (8.2)

Smoking history (mean pack‐years): flut/salm 36.8, salm 37.0

Mean % predicted FEV₁ (SD): flut/salm 40.4 (8.9), salm 40.3 (8.5)

Inclusion criteria: outpatients with postbronchodilator FEV₁ < 50% predicted, FEV₁/FVC of 70% predicted or less, age 40 years or older, smoking history of 10 or more pack‐years and a documented history of two or more moderate to severe exacerbations during the year before the study
Exclusion criteria: Individuals with COPD exacerbations, hospital admissions or change in COPD therapy during the 4 weeks before visit one or during the 4‐week run‐in period were excluded. Those with asthma, significant lung diseases other than COPD and need for long‐term oxygen therapy or long‐term systemic steroid use were also excluded

Interventions

Run‐in: four weeks

Treatments:

1. Salmeterol/fluticasone 50/500 mcg twice daily

2. Salmeterol 50 mcg twice daily

Inhaler device: Diskus

Co‐treatment: Inhaled salbutamol was used as reliever medication, and regular treatment with short‐acting bronchodilators, antioxidants/mucolytics, short‐acting oral beta₂‐agonists and theophylline was permitted

Outcomes

Primary: number of exacerbations

Secondary: Time to first exacerbation, pre‐bronchodilator PEF, postbronchodilator FEV₁, SGRQ, symptoms and breathlessness, reliever medication use and use of other COPD medications were recorded on diary cards

Notes

Funding: GSK

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Consecutive numbers assigned to participants determined the blinded treatment based on a centrally generated list with blocks of six

Allocation concealment (selection bias)

Low risk

Randomisation list was centrally generated

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind treatment (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Similar withdrawal rates in each group. ITT included 99.6% of the randomly assigned population (4 participants were excluded as the result of a randomisation error)

Selective reporting (reporting bias)

Unclear risk

Unable to locate prospective trial registration to check that all outcomes were reported. Study author contacted and forwarded request to GSK—no data were provided in time for publication

Methods

Design: randomised, multi‐centre, placebo‐controlled, parallel‐group trial

Six‐month treatment period

Conducted at 221 centres in nine countries (Chile, Estonia, Germany, Japan, Korea, Phillipines, Poland, Russian Federation and the United States)

Participants

Participants: 1030 people were randomly assigned to placebo (207), fluticasone furoate 100 mcg (206), vilanterol 25 mcg (205), fluticasone furoate 50 mcg and vilanterol combination (206) and fluticasone furoate 100 mcg and vilanterol combination (206)
Baseline characteristics:

Male %: placebo 68, flut100 64, vil 68, flut50/vil 66, flut100/vil 67

Mean age (SD), years: placebo 62.1, flut100 62.7, vil 63.4, flut50/vil 62.8, flut100/vil 62.3

Smoking history (mean (SD) pack‐years): placebo 45.6, flut100 46.2, vil 47.6, flut50/vil 44.2, flut100/vil 46.6

Mean % predicted FEV₁ (SD): placebo 42.4, flut10041.5, vil 44.5, flut50/vil 42.5, flut100/vil 42.3

Inclusion criteria: over 40 years of age and have a clinical diagnosis of COPD, a smoking history of 10 pack‐years, a postbronchodilator FEV₁/forced vital capacity (FVC) ratio of less than or equal to 0.70, a postbronchodilator FEV₁ less than or equal to 70% predicted (NHANES III) and a score of greater than or equal to 2 on the Modified Medical Research Council Dyspnoea Scale (mMRC). A history of COPD exacerbations was not required for individuals to be eligible to enter the study. Albuterol reversibility was assessed at the screening visit, and both reversible and non‐reversible individuals were eligible to enter the study
Exclusion criteria: current diagnosis of asthma or other non‐COPD respiratory disorders; lung volume reduction surgery within 12 months of visit one; poorly controlled COPD, defined as acute worsening of COPD requiring patient‐managed therapy with corticosteroids or antibiotics or treatment prescribed by a physician within 6 weeks before visit 1; hospitalisation due to poorly controlled COPD within 12 weeks before visit 1; lower respiratory tract infection that required the use of antibiotics within 6 weeks before visit 1; the need for long‐term oxygen therapy or nocturnal oxygen therapy (greater than or equal to 12 hours/d)

Interventions

Run‐in: 2‐week, single‐blind run‐in period during which participants received placebo once daily in the morning via a dry powder inhaler that contains two strips

Treatments:

1. Fluticasone furoate 100 mcg daily

2. Vilanterol 25 mcg daily

3. Fluticasone 50 mcg/ vilanterol 25 mcg daily

4. Fluticasone 100 mcg/ vilanterol 25 mcg daily

5. Placebo

Inhaler device: dry powder inhaler

Co‐treatment: Albuterol, ipratropium (provided that the person was on a stable dose from the screening visit throughout the study), mucolytics, antibiotics for short‐term treatment, cough suppressants for short‐term treatment, intranasal decongestants and corticosteroids, flu and pneumonia vaccines, MAOIs, medications for other disorders as long as the dose remained constant whenever possible and their use were not expected to affect lung function

Outcomes

Primary: weighted mean FEV₁ (0 to 4 hours postdose) on day 168 to assess bronchodilation by FF/VI and VI (vs placebo) and FF/VI vs FF; and the change from baseline in trough (23 to 24 hours postdose) FEV₁ on day 169 to assess the 24‐hour effect of VI and to determine the contribution of FF to lung function (i.e. FF/VI vs VI)

Secondary: CRQ self administered standardised dyspnoea domain on day 168, various FEV₁ parameters, PEF, symptom measures, adverse events, exacerbations and pneumonia events

Notes

Funding: GSK (ID: HZC112206)

Clinicaltrials.gov ID: NCT01053988

Definition of pneumonia: presumptive diagnosis or radiographically confirmed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central randomisation schedule was generated using a validated computerised system (RandAll; GlaxoSmithKline, London, UK)

Allocation concealment (selection bias)

Low risk

Participants were randomly assigned using the Registration and Medication Ordering System (RAMOS; GlaxoSmithKline, London UK) to register and randomly assign the participant and to receive medication assignment information

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Protocol stated that the study medication was double‐blind for participant and investigator

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated in protocol. Some details in supplementary material about outcome assessors but unclear who was blind

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout was quite high but even across groups (26.7% to 33.3%). ITT population used

Selective reporting (reporting bias)

Low risk

All stated outcomes were available in full in the published report and on clinicaltrials.gov

Methods

Design: double‐blind, parallel, 4‐group, placebo‐controlled, randomised design

2.5‐Year treatment period

Conducted at 2 centres in the Netherlands

Participants

Participants: 55 people were randomly assigned to fluticasone (26) and placebo (29)
Baseline characteristics:

Male %: flut 88.5, placebo 83.3

Mean age (SD), years: flut 62 (8), placebo 59 (8)

Smoking history (mean (range) pack‐years): flut 44 (31 to 55), placebo 42 (34 to 54)

Mean % predicted FEV₁ (SD): flut 57 (9.9), placebo 54 (8.3)

Inclusion criteria: 45 to 75 years of age, were current or former smokers, had smoked for 10 or more pack‐years and had lung function levels compatible with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II and III
Exclusion criteria: asthma and receipt of ICS within 6 months before random assignment. Important co‐morbid conditions

Interventions

Run‐in: not reported

Treatments:

1. Fluticasone 500 mcg twice daily

2. Placebo twice daily

Inhaler device: Diskus dry powder inhaler

Co‐treatment: short‐acting bronchodilators

Outcomes

Primary: inflammatory cell counts in bronchial biopsies and induced sputum

Secondary: postbronchodilator spirometry, hyperresponsiveness to methacholine PC20, dyspnoea score by the MRC scale, health status by the SGRQ and the Clinical COPD Questionnaire

Notes

Funding: Netherlands Asthma Foundation, both centres and GSK

Clinicaltrials.gov ID: NCT00158847

Definition of pneumonia: confirmed by chest x‐ray

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

At entry, an independent randomisation centre provided participant and medication numbers by using a minimisation procedure that balanced treatment groups for centre, sex, smoking status, FEV₁/IVC 60% and methacholine PC20 (the provocative concentration of methacholine that causes a 20% decrease in FEV₁) 2 mg/mL)

Allocation concealment (selection bias)

Low risk

An independent randomisation centre provided participant and medication numbers

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study medications were individually numbered, and we used Diskus dry powder inhalers (GlaxoSmithKline, Zeist, The Netherlands) with 60 doses per inhaler; all active treatment medications and placebo were identical in appearance

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawal rates were very high compared with the numbers of events for the different outcomes. Per‐protocol analysis was used

Selective reporting (reporting bias)

Low risk

Data for several outcomes not available from the published report, but study authors provided data upon request

Methods

Design: randomised, double‐blind, parallel‐group study

Six‐month treatment period

Participants

Participants: 49 people were randomly assigned to budesonide (25) and placebo (24)
Baseline characteristics: none reported—abstract only

Inclusion criteria: individuals between 40 and 65 years of age, FEV₁ 40% to 60% of predicted normal, FEV₁/VC < 55%, bronchodilator reversibility < 15%
Exclusion criteria: not reported

Interventions

Run‐in: not reported

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo

Inhaler device: not reported

Co‐treatment: All participants received anticholinergic drug and methylxanthine or short‐acting beta₂ agent

Outcomes

Number and severity of exacerbations, FEV₁, FVC, diary card symptoms, PEFR

Notes

Abstract only

Funding: not reported

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised, not described

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No details provided

Selective reporting (reporting bias)

High risk

Only abstract available. Outcomes could not be used. Could not find contact information for study authors

Methods

Design: randomised, double‐blind, placebo‐controlled, parallel‐group, multi‐centre trial

6 ‐month treatment period

Conducted at 65 centres

Participants

Participants: 674 people were randomly assigned to fluticasone (168), placebo (181), fluticasone/salmeterol combination (165) and salmeterol alone (160)
Baseline characteristics:

Male %: flut 61, placebo 75, flut/salm 62, salm 64

Mean age (range), years: flut 64.4 (42 to 82), placebo 64 (44 to 90), flut/salm 61.9 (40 to 86), salm 63.5 (40 to 84)

Smoking history (median (range) pack‐years): flut 54 (20 to 200), placebo 60 (20 to 165), flut/salm 55 (15 to 150), salm 52.5 (20 to 193)

Mean % predicted FEV₁ (no SD reported): flut 41, placebo 41, flut/salm 41, salm 40

Inclusion criteria: baseline FEV₁/FVC of 70% or less and baseline FEV₁ of less than 65% of predicted but more than 0.70 L. Participants were required to have daily cough productive of sputum for 3 months of the year for 2 consecutive years and dyspnoea
Exclusion criteria: Specific exclusion criteria were current diagnosis of asthma, oral corticosteroid use within the past 6 weeks, abnormal clinically significant electrocardiogram, long‐term oxygen therapy, moderate or severe exacerbation during the run‐in and any clinically significant medical disorder

Interventions

Run‐in: 2‐week, single‐blind, run‐in period during which participants received placebo via Diskus on an as‐needed basis and discontinued use of corticosteroids and bronchodilators, with the exception of stable regimens of theophylline

Treatments:

1. Fluticasone 500 mcg twice daily

2. Placebo twice daily

3. Fluticasone/Salmeterol combination 500/50 mcg twice daily

4. Salmeterol 50 mcg twice daily

Inhaler device: Diskus

Co‐treatment: as needed albuterol and stable regimens of theophylline

Outcomes

Primary: change in predose FEV₁ values and change in 2‐hour postdose FEV₁ values

Secondary: morning and evening PEF, supplemental albuterol use, dyspnoea as assessed by the TDI, Chronic Bronchitis Symptom Questionnaire, exacerbations defined by treatment, health status on the Chronic Respiratory Disease Questionnaire, adverse events, 24‐hour Holter monitoring and vital signs

Notes

Funding: GSK (protocol number SFCA3006)

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was stratified by reversibility and investigative site to ensure balance between treatment groups at each site and in terms of the number of reversible participants (no other details, industry‐sponsored)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participant and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

17 participants at one investigative site were not evaluable because of poor study practices, and of the remaining 674 participants, 645 had an evaluable baseline assessment. A total of 234 participants were discontinued from the study (between 28% and 40% across groups)

Selective reporting (reporting bias)

Low risk

All outcomes stated in the protocol were reported in detail. Only one secondary outcome was not available

Methods

Design: multi‐centre, randomised, stratified (by smoking status), placebo‐controlled, double‐blind, parallel‐group study

6 month treatment period

Conducted at 145 study centres in 8 countries (Czech Republic, Germany, Japan, Poland, Romania, Russian Federation, Ukraine and the United States)

Participants

Participants: 1224 people were randomly assigned to fluticasone furoate 100 mcg (204), fluticasone furoate 200 mcg (203), placebo (205), fluticasone furoate 100 mcg and vilanterol combination (204), fluticasone furoate 100 mcg and vilanterol combination (205) and vilanterol (203)
Baseline characteristics:

Male %: flut100 74, flut200 74, placebo 74, flut100/vil 71, flut200/vil 67, vil 74

Mean age (SD), years: flut100 61.8 (8.3), flut200 61.8 (9.0), placebo 61.9 (8.1), flut100/vil 61.9 (8.8), flut200/vil 61.1 (8.6), vil 61.2 (8.6)

Smoking history (mean (SD) pack‐years): flut100 39.8 (21.3), flut200 43.5 (22.5), placebo 45.7 (25.8), flut100/vil 42.8 (23.9), flut200/vil 41.5 (23.4), vil 42.0 (23.3)

Mean % predicted FEV₁ (SD): flut100 48.4 (12.2), flut200 47.1 (12.0), placebo 48.3 (12.7), flut100/vil 48.1 (12.9), flut200/vil 47.1 (12.8), vil 48.5 (12.9)

Inclusion criteria: clinical diagnosis of COPD, 40 years of age or older, smoking history of 10 or more pack‐years, postbronchodilator FEV₁/ forced vital capacity (FVC) ratio of 0.70 or less, postbronchodilator FEV₁ 70% predicted or less (NHANES III) and score of 2 or higher on the Modified Medical Research Council Dyspnoea Scale (mMRC). No prior history of COPD exacerbations was required for individuals to be eligible to enter the study. Reversibility to albuterol was assessed at the screening visit; both reversible and non‐reversible individuals were eligible to enter the study
Exclusion criteria: any respiratory disorder other than COPD; lung volume reduction surgery within 12 months of screening; acute worsening (participant‐managed corticosteroid or antibiotic treatment or physician prescription) of COPD within six weeks of screening, hospitalisation for COPD over 12 weeks or lower respiratory tract infection that required the use of antibiotics in the 6 weeks before screening; the need for long‐term oxygen therapy or nocturnal oxygen therapy (12 or more hours/d)

Interventions

Run‐in: 2‐week, single‐blind run‐in period during which participants received placebo once daily in the morning via a dry powder inhaler (DPI) that contained two strips

Treatments:

1. Fluticasone furoate 100 mcg daily

2. Fluticasone furoate 200 mcg daily

3. Placebo

4. Fluticasone furoate 100 mcg/vilanterol 25 mcg daily

5. Fluticasone furoate 200 mcg/vilanterol 25 mcg daily

6. Vilanterol 25 mcg

Inhaler device: dry powder inhaler

Co‐treatment: albuterol, ipratropium (provided that the person was on a stable dose from the screening visit throughout the study), mucolytics, antibiotics for short‐term treatment, cough suppressants for short‐term treatment, intranasal decongestants and corticosteroids, flu and pneumonia vaccines, MAOIs, medications for other disorders as long as the dose remained constant whenever possible and when their use was not expected to affect lung function

Outcomes

Primary: weighted mean FEV₁ (zero to four hours postdose) on day 168 to assess bronchodilation by FF/VI and VI (vs placebo) and FF/VI versus FF; change from baseline in trough (23 to 24 hours postdose) FEV₁ on day 169 to assess the 24‐hour effect of VI and to determine the contribution of FF to lung function (i.e. FF/VI vs VI)

Secondary: CRQ self administered standardised dyspnoea domain on day 168, various FEV parameters, PEF, symptom measures, adverse events, exacerbations and pneumonia events

Notes

Funding: GSK (ID: HZC112207)

Clinicaltrials.gov ID: NCT01054885

Definition of pneumonia: presumptive diagnosis or radiographically confirmed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central randomisation schedule was generated using a validated computerised system (RandAll; GlaxoSmithKline, London, UK)

Allocation concealment (selection bias)

Low risk

Participants were randomly assigned using the Registration and Medication Ordering System (RAMOS; GlaxoSmithKline, London, UK) to register and randomly assign the participant and to receive medication assignment information

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Protocol stated that the study medication was double‐blind for participant and investigator

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated in protocol. Some details in supplementary material about outcome assessors but unclear who was blind

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Dropout in all groups was less than 30% (range 20.1% to 29.4%) and an ITT analysis was used

Selective reporting (reporting bias)

Low risk

All stated outcomes were available in full in the published report and in supplementary tables

Methods

Design: randomised, placebo‐controlled, double‐blind, parallel‐group study

Three‐month treatment period

Conducted at a single centre in Turkey

Participants

Participants: 50 people were randomly assigned to budesonide (25) and placebo (25)
Baseline characteristics:

Male %: bud 70, placebo 80

Mean age (SD), years: bud 51.8 (9.5), placebo 54.5 (10.3)

Smoking history (mean (SD) pack‐years): bud 21.7 (12.5), placebo 31.3 (19.1)

Mean % predicted FEV₁ (SD): bud 64.1 (6.5), placebo 59.9 (8.2)

Inclusion criteria: FEV₁ < 70%, FEV₁ reversibility after inhalation of terbutaline from a Turbuhaler of less than 15% of pre‐bronchodilator FEV₁. All participants were smokers who refused or failed a programme to quit smoking
Exclusion criteria: long‐term treatment with oral or inhaled corticosteroids within 6 months of study entry, respiratory tract infection in the previous 3 months, pregnancy or lactation and the presence of other serious systemic disease

Interventions

Run‐in: not reported

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo twice daily

Inhaler device: Turbuhaler

Co‐treatment: Beta₂‐agonists of all kinds, theophylline and mucolytics were allowed. Inhaled corticosteroids other than study medication and oral or parenteral corticosteroids were not allowed

Outcomes

Spirometry and sputum cell analysis

Notes

Funding: unclear

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation sequence was computer‐generated at the Research Centre of the Faculty of Medicine

Allocation concealment (selection bias)

Low risk

Randomisation was masked and case numbers were allocated in consecutive order

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind. All inhalers had the same appearance and did not have drug labels

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All spirometric indices and sputum cell analyses were performed at baseline and after treatment, blind to the clinical details

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Equal and fairly low dropout per group, values not imputed

Selective reporting (reporting bias)

High risk

Key expected outcomes were not reported (mortality and adverse events). Named outcomes were well reported. No reply from authors at the time of publication

Methods

Design: randomised, double‐blind, placebo‐controlled design

Six‐month treatment period

Conducted at a single centre in Turkey

Participants

Participants: 26 people were randomly assigned to budesonide (13) and placebo (13)
Baseline characteristics:

Male %: bud 84.6, placebo 53.8

Mean age (SD), years: bud 64.9 (6.1), placebo 65.9 (8.1)

Smoking history (mean (SD) pack‐years): bud 45.6 (22.2), placebo 44.4 (23.0)

Mean % predicted FEV₁ (SD): bud 61.1 (9.7), placebo 57.3 (11.2)

Inclusion criteria: (1) FEV₁/FVC <70% and FEV₁ 50% of predicted value, (2) reversibility with inhaled beta₂‐agonists (400 mg salbutamol) of less than 200 mL or less than 12% of predicted FEV₁, (3) stable COPD defined as no acute exacerbation within preceding 3 months, (4) no history of systemic disease or other pulmonary disease, (5) no therapy with inhaled or systemic corticosteroids within 3 months before entry into the study and (6) no history of asthma or atopy
Exclusion criteria: no additional information

Interventions

Run‐in: not reported

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo twice daily

Inhaler device: dry powder inhaler

Co‐treatment: All participants were receiving therapy with inhaled salbutamol and ipratropium bromide. For 9 participants, sustained‐released theophyline was also given

Outcomes

Primary: unclear

Secondary: FVC, FEV₁, diary card data, inflammatory measures

Notes

Funding: unclear

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly assigned by a computer‐generated, blinded randomisation list

Allocation concealment (selection bias)

Low risk

‘Blinded’ randomisation list

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Cells were counted by our pathologist, who was also blinded. Not clear for other outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

‘The results presented are an analysis of 22 subjects (12 budesonide‐treated subjects and 10 placebo‐treated subjects) who completed the study’. Both dropout rates were low but uneven between groups (two were excluded from the placebo group and one from the budesonide group. One extra, presumed to have been randomly assigned to placebo (assuming equal group size at randomisation) was excluded for failure to take the medication consistently)

Selective reporting (reporting bias)

High risk

Key expected outcomes missing (mortality, serious adverse events). No reply from study authors by time of publication

Methods

Design: multi‐centre, randomised, placebo‐controlled trial

Six‐month treatment period

Conducted in 13 European countries, New Zealand and South Africa

Participants

Participants: 281 people were randomly assigned to fluticasone (142) and placebo (139)
Baseline characteristics:

Male %: flut 70, placebo 78

Mean age (no SD reported), years: flut 62, placebo 64

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): flut 59 (18), placebo 55 (17)

Inclusion criteria: current or ex‐smokers, 50 to 75 years of age with a history of smoking equivalent to at least 10 pack‐years and chronic bronchitis (a cough with excess sputum production for at least 3 months in at least 2 consecutive years with no other pathology). Participants also had to have a history of at least one exacerbation per year for the previous 3 years that required a visit to their doctor or hospital; high expectation, according to the investigator, of experiencing an exacerbation during the 6‐month treatment period; regular productive cough; predicted FEV₁ of 35% to 90%, ratio of FEV₁ to forced vital capacity of 70% or less and reversibility in FEV₁ of less than 15% after inhalation of 400 mcg or 800 mcg salbutamol via a metered‐dose inhaler or Diskhaler
Exclusion criteria: Individuals with abnormal chest radiographs or who had received oral or depot steroids, inhaled steroids of more than 500 mcg daily or antibiotic therapy; had been admitted to hospital in the 4 weeks before the study; or were currently taking fluticasone propionate were excluded

Interventions

Run‐in: 2 week run‐in period during which usual inhaled steroids were stopped and participants received salbutamol as required

Treatments:

1. Fluticasone propionate 500 mcg twice daily

2. Placebo twice daily

Inhaler device: metered‐dose inhalers, with a spacer if desired

Co‐treatment: Participants could take short‐acting beta₂‐agonists for relief of symptoms as required throughout the study. Other COPD medications, such as anticholinergics and xanthine derivatives, could be continued throughout the study without dose changes

Outcomes

Primary: COPD exacerbations

Secondary: FEV₁, morning PEF, FVC, 6‐minute walk test, Borg score, diary card symptom scores, daily sputum volume, total adverse events, serum cortisol concentration

Notes

Funding: unclear (‘code was held by the sponsor company’s statisticians’)

Definition of pneumonia:Not provided

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random numbers were computer‐generated on PACT (version 2.7)

Allocation concealment (selection bias)

Low risk

All investigators were given a set of four or more sealed envelopes containing assignment codes, from which they assigned treatment, starting with the lowest number

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participant and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

'We did analysis by intention to treat of all patients who took at least one dose of study medication’

‘Only available data was analysed’. Dropout uneven

Selective reporting (reporting bias)

High risk

Key expected outcomes not reported (mortality and serious adverse events). No reply from study authors by time of publication

Methods

Design: parallel‐group, double‐blind, placebo‐controlled, randomised, multi‐centre study

3 year treatment period

Conducted at 39 study centres in nine European countries (Belgium, Denmark, Finland, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom)

Participants

Participants: 1277 people were randomly assigned to budesonide (634) and placebo (643)
Baseline characteristics:

Male %: bud 73.5, placebo 72.2

Mean age (SD), years: bud 52.5 (7.5), placebo 52.4 (7.7)

Smoking history (mean (SD) pack‐years): bud 39.4 (20.1), placebo 39.2 (20.2)

Mean % predicted FEV₁ (SD): bud 76.8 (12.4), placebo 76.9 (13.2)

Inclusion criteria: Persons 30 to 65 years of age were eligible if they were currently smoking at least five cigarettes per day and had smoked cigarettes for at least 10 years or had a smoking history of at least 5 pack‐years. FEV₁ after use of a bronchodilator had to be between 50% and 100% of predicted normal value, and ratio of pre‐bronchodilator FEV₁ to slow vital capacity had to be less than 70%. Increase in FEV₁ after inhalation of 1 mg of terbutaline from a dry powder inhaler had to be less than 10% of predicted normal value. Change in FEV₁ between the end of the first three‐month period of the run‐in phase and the end of the second had to be less than 15%
Exclusion criteria: Participants with history of asthma, allergic rhinitis or allergic eczema and those who had used oral glucocorticoids for longer than four weeks during the preceding six months were excluded. Use of inhaled glucocorticoids other than the study medication, beta‐blockers, cromones or long‐acting inhaled beta₂‐adrenergic agonists was not allowed

Interventions

Run‐in: three‐month smoking cessation programme. For participants who did not stop smoking, this phase was followed by a three‐month period during which compliance with inhaled medication was assessed with the use of a placebo containing dry powder inhaler with a hidden mechanical counter. Participants who continued smoking and were at least 75% compliant with the recommended treatment regimen were randomly assigned

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo twice daily

Inhaler device: 1, Pulmicort; 2, dry powder turbuhaler

Co‐treatment: Use of inhaled glucocorticoids other than the study medication, beta‐blockers, cromones or long‐acting inhaled beta₂‐adrenergic agonists was not allowed

Outcomes

Primary: change over time in postdose FEV₁

Secondary: serious adverse events, mortality, glucocorticoid‐related adverse effects, bone density, non‐serious adverse events

Notes

Funding: funded by a grant from Astra Draco, Lund, Sweden

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

‘Randomly assigned’. No specific details given but industry‐sponsored

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participant and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Central evaluator who was unaware of the treatment received and was analysed according to a standardised computerised protocol

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data on randomly assigned participants were analysed on an intention‐to‐treat basis. Withdrawal rates under 30% and even in both groups

Selective reporting (reporting bias)

High risk

Several missing outcomes. Could not locate protocol to check that all prospectively registered outcomes were reported. Contacted second study author; no reply by time of publication

Methods

Design: parallel‐group, double‐blind, randomised, placebo‐controlled study

2‐year study period

Conducted at a single centre in the Netherlands

Participants

Participants: 39 people were randomly assigned to budesonide (21) and placebo (18)
Baseline characteristics:

Male %: bud 100, placebo 100

Mean age (SD), years: bud 56 (8), placebo 54 (10)

Smoking history, cigarettes/year (SD): bud 635 (530), placebo 729 (495)

Mean % predicted FEV₁ (SD): bud 67 (15), placebo 60 (18)

Inclusion criteria: clinical diagnosis of COPD based on history (persistent dyspnoea, mainly on exertion, without sudden attacks of dyspnoea); FEV₁ less than 80% of predicted value; residual volume (RV) greater than 100% of predicted value; specific compliance expressed as percentage of predicted value greater than 100% after bronchodilation; when, however, air trapping (calculated as thoracic gas volume measured by body plethysmography minus functional residual capacity measured with an indicator gas) was greater than 1.5 L Csp was allowed to be less than 100% of predicted; no signs of allergy (negative skin test results, total serum IgE < 200 IU/mL, eosinophils in peripheral blood < 250 × l0³/mL); and stable phase of the disease
Exclusion criteria: Excluded were participants older than 70 years at entry, participants receiving continuous corticosteroid therapy and participants with severe concomitant disease, likely to interfere with the purpose of the study. All participants had alpha‐1 antitrypsin serum levels within the normal range. All participants were smokers or ex‐smokers. Smoking history was expressed as cigarette‐years

Interventions

Run‐in: three months with no corticosteroid medication

Treatments:

1. Budesonide 800 mcg twice daily (plus placebo tablet once daily)

2. Placebo twice daily (plus placebo tablet once daily)

Inhaler device: metered‐dose inhaler (MDI) through a 750‐mL spacer (Nebuhaler; ASTRA, Ryswylc, The Netherlands)

Co‐treatment: Throughout the study, participants were maintained on regimens of their usual bronchodilator medication, consisting of anticholinergics. beta‐agonists, theophylline or a combination of these drugs

Outcomes

Primary: FEV₁

Secondary: compliance, symptom scores, fasting morning plasma cortisol levels

Notes

Funding: grants from the Netherlands Asthma Foundation, ASTRA BV Holland and AB DRACO Sweden

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

By computerised randomisation, stratified for smoking

Allocation concealment (selection bias)

Low risk

Allocated blindly

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Uneven withdrawal rates, no description of imputation to account for dropout

Selective reporting (reporting bias)

High risk

Key expected outcomes not reported (mortality and adverse events). No reply from study authors by time of publication

Methods

Design: Randomised, double‐blind, double‐dummy, parallel‐group, active‐ and placebo‐controlled, multi‐centre study

12‐Month treatment period

237 sites in the US, Europe and Mexico

Participants

Participants: 1483 people were randomly assigned to budesonide/formoterol at high (494) and low dose (494), and to formoterol alone (495)
Baseline characteristics:

Male %: bud/form high 62.3, bud/form low 62.8, form 65.3

Mean age (SD), years: bud/form high 63.2 (8.9), bud/form low 63.6 (9.2), form 62.9 (9.1)

Smoking history (median pack‐years): bud/form high 40, bud/form low 40, form 40

Mean % predicted FEV₁ (SD): bud/form high 38.6 (11.4), bud/form low 39.6 (10.9), form 39.3 (11.9)

Inclusion criteria: current smokers or ex‐smokers aged > 40 years with clinical diagnosis of COPD and symptoms for > 2 years were eligible for this study. Participants were required to have a history of at least one COPD exacerbation treated with a course of oral corticosteroids and/or antibacterials, with 1 to 12 months before screening and documented use of an inhaled short‐acting bronchodilator as rescue medication. Prebronchodilator FEV₁ of < 50% of predicted normal and pre‐bronchodilator FEV₁/FVC of < 70% were required at screening. Smoking history of at least 10 pack‐years, score ≥ 2 on the Modified Medical Research Council dyspnoea scale at the time of screening and breathlessness, cough and sputum scale score ≥ 2 per day for at least half of the 2‐week run‐in period
Exclusion criteria: Individuals were excluded if they had any of the following conditions: history of asthma, history of allergic rhinitis before 40 years of age, significant/unstable CV disorder, clinically significant respiratory tract disorder other than COPD and homozygous alpha₁‐antitrypsin deficiency or any other clinically significant co‐morbidities. Individuals were also excluded if they needed additions or alterations to their usual COPD maintenance therapy or an increment in rescue therapy because of worsening symptoms within 30 days before screening. Oral or ophthalmic non‐cardioselective beta‐adrenoceptor antagonists, oral corticosteroids, pregnancy and breast‐feeding also were exclusionary

Interventions

Run‐in: 2 weeks during which previous inhaled corticosteroids were discontinued

Treatments:

1. Budesonide/formoterol 320/9 mcg twice daily

2. Budesonide/formoterol 160/9 mcg twice daily

3. Formoterol 9 mcg twice daily

Inhaler device: 1 and 2, pressurised metered‐dose inhaler. 3, dry powder inhaler

Co‐treatment: salbutamol allowed as reliever medication

Outcomes

Primary: predose FEV₁ and one hour postdose FEV₁

Secondary: morning and evening PEF, COPD exacerbations, quality of life (SGRQ), symptom scores, percentage of awakening‐free nights, any adverse event (AE), pneumonia‐related AEs, serious AEs, mortality, vital signs and cortisol levels

Notes

Funding: AstraZeneca

Clinicaltrials.gov ID: NCT00206167

Definition of pneumonia: reported by physicians based on the Medical Dictionary for Regulatory Activities (version 10.0)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Not described. Industry sponsored, presumed to follow usual AZ methods

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Described as double‐blind [presumed participants and personnel/investigators]

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Safety was assessed by adverse event (AE) reporting. Pneumonia events were reported by physicians based on the Medical Dictionary for Regulatory Activities (version 10.0) pneumonia‐related preferred terms (pneumonia, bronchopneumonia, lobar pneumonia or pneumonia staphylococcal).

Incomplete outcome data (attrition bias)
All outcomes

High risk

The withdrawal rates were very high compared to the number of events for the different outcomes

Selective reporting (reporting bias)

Low risk

All outcomes reported [checked against protocol]. Only one secondary outcome not reported.

Methods

Design: randomised, double‐blind, double‐dummy, placebo‐controlled phase IV trial

Three‐year treatment period

Conducted at 44 general practices in the Netherlands

Participants

Participants: 190 people were randomly assigned to fluticasone (94) and placebo (96)
Baseline characteristics:

Male %: flut 73, placebo 68

Mean age (SD), years: flut 58.4 (9.9), placebo 59.6 (10.1)

Smoking history (mean (SD) pack‐years): flut 30.2 (18.2), placebo 26.5 (16.7)

Mean % predicted FEV₁ (SD): flut 63.2 (17.1), placebo 65.7 (17.7)

Inclusion criteria: age 35 to 75 years; current or former smoker; chronic dyspnoea, sputum production and cough for at least three consecutive months per year during the previous two years; postbronchodilator forced expiratory volume in one second (FEV₁) < 90% of predicted value and/or postbronchodilator FEV₁/FVC (forced vital capacity) of predicted value < 88% for men and < 89% for women
Exclusion criteria: postbronchodilator FEV₁ < 40% of predicted and/or a history of asthma, allergic rhinitis or allergic eczema

Interventions

Run‐in: Trial was preceded by the following (in chronological order): an optional smoking cessation attempt supported by the GP in trial candidates who were current smokers; a three‐month washout phase to eliminate possible carry‐over effects of a successful smoking cessation attempt or withdrawal of prior treatment with N‐acetylcysteine and/or inhaled corticosteroids; and a 14‐day pretreatment phase (30 mg oral prednisolone) to attain the highest possible baseline condition

Treatments:

1. Fluticasone propionate 500 mcg twice daily

2. Placebo twice daily

Inhaler device: Diskus dry powder inhaler. Unclear from trial report whether placebo was administered to match the fluticasone inhaler or the other active treatment, which was delivered as effervescent tablets dissolved in a glass of tap

Co‐treatment: not reported

Outcomes

Primary: rate of exacerbation and quality of life as measured by the interviewer‐administered version of the Chronic Respiratory Questionnaire (CRQ)

Notes

Funding: Dutch Council for Health Insurances, with complementary funding by the Netherlands Asthma Foundation (authors had received various GSK and other pharma research grants)

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

An independent statistician generated a randomisation list based on a block size of three for treatment allocation to balance the three treatment arms by study centre.

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Neither investigators nor patients were aware of the group assignment. Placebo described as ‘matching’

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Neither investigators nor patients were aware of the group assignment [presuming the investigators were those doing the outcome assessments]

Incomplete outcome data (attrition bias)
All outcomes

High risk

Dropout was high in both groups. The primary analyses were done on an intention‐to‐treat basis. Additional per protocol analyses were done on patients with a trial medication compliance rate >80%. Unclear how data were imputed or who was included in the ITT population

Selective reporting (reporting bias)

High risk

All outcomes stated in the protocol were reported but some key expected outcomes were missing (serious adverse events and pneumonia). No reply from author by time of publication.

Methods

Design: placebo‐controlled, randomised, double‐blind, multi‐centre trial

Six‐month treatment period

Five centres in Denmark

Participants

Participants: unclear how many people were randomly assigned. 26 were evaluable in the budesonide (14) and placebo (12) groups
Baseline characteristics:

Male %: bud 57, placebo 50

Median age (range), years: bud 58.5 (51 to 74), placebo 62.5 (57 to 74)

Smoking history (mean (SD) pack‐years): not reported

Mean % predicted FEV₁ (SD): not reported

Inclusion criteria: outpatients 18 to 75 years of age with stable COPD were included. FEV₁, forced vital capacity (FVC) < 0.7, postbronchodilator FEV₁ < 70% of predicted, FEV₁ > 40% of predicted and increase in FEV₁ < 15% after inhalation of 0 to 5 mg terbutaline
Exclusion criteria: clinical evidence of asthma (e.g. pollen season–related symptoms, exercise‐induced symptoms only and significantly elevated levels of eosinophils and IgE), history of atopy (hay fever and/or atopic dermatitis), treatment with inhaled corticosteroids within the past 6 months, treatment with oral corticosteroids, cromoglycate or nedocromil within the past 4 weeks, other systemic disease making compliance and participation in the study difficult, pregnancy and breast‐feeding and an increase in FEV₁ > 30% of baseline after 2 weeks of prednisolone treatment

Interventions

Run‐in: All participants received 2 weeks of treatment with oral prednisolone 37.5 mg daily. Reversible participants with 15% < AFEV1 < 30% of baseline and irreversible participants with AFEV1 < 15% were separately randomly assigned to inhaled budesonide 400 pg bid or placebo

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo twice daily

Inhaler device: Spirocort Turbuhaler

Co‐treatment: not reported

Outcomes

Primary: FEV₁

Secondary: exacerbations, adverse events and symptom scores

Notes

Funding: not reported

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Reversible participants with 15% < AFEV1 < 30% of baseline and irreversible participants with AFEV1 < 15% were separately randomly assigned

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigators)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

26 of 37 were evaluable (12 in placebo group, 14 in active group—30% dropout overall). Number randomly assigned and number of dropouts not provided for each group. ITT not adopted

Selective reporting (reporting bias)

High risk

Several key expected outcomes not reported (mortality, adverse events, withdrawal per group). Study author contacted but not able to provide data

Methods

Design: randomised, double‐blinded, placebo‐controlled, parallel‐group, single‐centre study

Two‐ to four‐year treatment period

Conducted at a single centre in Denmark

Participants

Participants: 254 people were randomly assigned to budesonide (127) and placebo (127)
Baseline characteristics:

Male %: bud 62.2, placebo 54.3

Mean age (SD), years: bud 63.6 (7.5), placebo (63.6 (7.2)

Smoking history (mean (SD) pack‐years): bud 56 (23), placebo 56 (24)

Mean % predicted FEV₁ (SD): bud 51 (11), placebo 53 (11)

Inclusion criteria: Individuals 50 to 80 years of age were eligible if they were current smokers with a clinical diagnosis of COPD for not less than 2 years. All participants should have a significant smoking history of at least 10 cigarettes per day during the past 6 months and a previous history of at least 20 pack‐years. Ex‐smokers were excluded. Baseline lung function criteria were as follows: FEV₁ between 35% and 70% of predicted (pre‐bronchodilator), and FEV₁/forced vital capacity (FEV₁/FVC) ≤ 60%
Exclusion criteria: Reversibility of ≥ 12% and 200 mL in FEV₁ from baseline values, 15 minutes after inhalation of 1 mg terbutaline or ≥ 15% and 300 mL after 2 weeks on oral prednisolone (25 mg), was an exclusion criterion. Individuals were also excluded if they had any severe concomitant disease; had an exacerbation within 30 days before the first visit; received oral steroids for longer than four weeks within six months of the first visit; or were on long‐term oxygen therapy

Interventions

Run‐in: two‐week run‐in period on oral prednisolone

Treatments:

1. Budesonide 400 mcg twice daily

2. Placebo twice daily

Inhaler device: Pulmicort Turbuhaler

Co‐treatment: Bronchodilators, mucolytics and short courses of oral corticosteroids (maximum 3 courses of 4 weeks' duration per year) and antibiotics were allowed during the study

Outcomes

Primary: 15th percentile density (PD15)

Secondary: change over time in the relative area of emphysema at a threshold of –910 Hounsfield units (RA‐910), FEV₁ and diffusion capacity (DLCO) and in number of exacerbations, which was defined as a combination of 2 of the 3 following criteria: increased dyspnoea, increased sputum production and change in sputum colour

Notes

Funding: AstraZeneca

Definition of pneumonia: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were allocated to either group in a proportion of 1:1 by block randomisation using a random sequence generated by a computer programme at AstraZeneca

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind. To maintain blinding, all Turbuhalers were of identical appearance

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

High proportion of dropouts in both groups (43% intervention and 49% placebo)

Selective reporting (reporting bias)

Low risk

Could not locate protocol to check that all prospectively registered outcomes were reported, but study authors provided all relevant outcomes upon request

Methods

Design: randomised, double‐blind, double‐dummy, parallel‐group, multi‐centre study

12‐Month treatment period

Conducted at 180 study sites in the United States (106 sites), Central and South America (53 sites) and South Africa (21 sites)

Participants

Participants: 1219 people were randomly assigned to high‐dose budesonide/formoterol (407), low‐dose budesonide/formoterol (408) and formoterol alone (404)
Baseline characteristics:

Male %: bud/form high 64.4, bud/form low 64.7, form 56.8

Mean age (SD), years: bud/form high 63.8 (9.4), bud/form low 62.8 (9.2), form 62.5 (9.4)

Smoking history (mean pack‐years): bud/form high 46, bud/form low 44, form 43

Mean % predicted FEV₁ (SD): bud/form high 37.9 (11.8), bud/form low 37.6 (11.6), form 37.5 (12.4)

Inclusion criteria: Individuals were current smokers or ex‐smokers with a smoking history of 10 pack‐years, 40 years of age, with a clinical diagnosis of COPD with symptoms for >2 years. Participants were required to have a history of 1 COPD exacerbation requiring treatment with a course of systemic corticosteroids, antibiotics or both, within one to 12 months before screening (visit 1) and documented use of an inhaled short‐acting bronchodilator as rescue medication. At screening, a pre‐bronchodilator forced expiratory volume in one second (FEV₁) of 50% of predicted normal and a pre‐bronchodilator FEV₁/forced vital capacity (FVC) of < 70% also were required
Exclusion criteria: Exclusion criteria included current, previous (within past 60 days) or planned enrolment in a COPD pulmonary rehabilitation programme, treatment with oral corticosteroids and incidence of a COPD exacerbation or any other significant medical diagnosis between screening and randomisation visits

Interventions

Run‐in: 2‐week run‐in period

Treatments:

1. Budesonide/formoterol 320/9 mcg twice daily

2. Budesonide/formoterol 160/9 mcg twice daily

3. Formoterol DPI 9 mcg twice daily

Inhaler device: 1 and 2, pressurised metered‐dose inhaler. 3, dry powder inhaler

Co‐treatment: Rescue medication (albuterol pMDI 90 mg 2 inhalations) was provided for as needed use during screening and run‐in, and throughout the study

Outcomes

Primary: COPD exacerbations

Secondary: FEV₁, FVC, morning and evening PEF, diary card symptoms, rescue medication use, BODE index, exercise capacity, health‐related quality of life (SGRQ), adverse events. Unclear which was primary

Notes

Funding: AstraZeneca ID: D589CC00003

Clinicaltrials.gov ID: NCT00419744

Definition of pneumonia: based on clinical judgement, not on radiological or microbial assessments

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Assignments were made sequentially by interactive voice response system in a a computer generated allocation schedule produced in advance.

Allocation concealment (selection bias)

Low risk

Assignments were made sequentially by interactive voice response system following a computer generated allocation schedule produced in advance.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

To maintain patient and investigator blinding, all active treatments were provided in blinded treatment kits. Patients in the budesonide/formoterol pMDI groups received a placebo DPI and those in the formoterol DPI group received a placebo pMDI.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

The withdrawal rates were relatively even but high, especially compared to the low event rates for the outcomes of interest

Selective reporting (reporting bias)

Low risk

All outcomes stated in the protocol were reported in detail

Methods

Design: Randomised, double‐blind, placebo‐controlled, parallel‐group, multi‐centre study

12 month treatment period

Conducted in 89 centres from 11 countries

Participants

Participants: 812 people were randomly assigned to budesonide (198), placebo (205), budesonide/formoterol (208) and formoterol (201)
Baseline characteristics:

Male %: bud 80, placebo 83, bud/form 76, form 76

Mean age (range), years: bud 64 (40 to 90), placebo 65 (47 to 92), bud/form 64 (41 to 82), form 63 (40 to 90)

Smoking history (mean pack‐years (SD not reported)): bud 44, placebo 45, bud/form 44, form 45

Mean % predicted FEV₁ (SD not reported): bud 37, placebo 36, bud/form 36, form 36

Inclusion criteria: Adults with moderate to severe asthma were included and were selected according to the following criteria: outpatients aged 0 to 40 years; COPD symptoms for 2 years; > 10 pack‐year smoking history; FEV₁/FVC 70%; FEV₁ 50% predicted normal (stages IIB and III according to the GOLD classification); total symptom score of two per day during at least 7 days of the run‐in period; documented use of short‐acting inhaled bronchodilators for reliever medication; > 1 severe COPD exacerbation within 2 to 12 months before the first clinic visit
Exclusion criteria: History of asthma and/or seasonal allergic rhinitis before the age of 40; any relevant cardiovascular disorders as judged by the investigator; using beta‐blocking agents; current respiratory tract disorders other than COPD or any other significant diseases or disorders that may have put them at risk or that may have influenced the results of the study; requirement for regular use of oxygen therapy or an exacerbation during run‐in. Individuals for whom it would have been considered unethical to withdraw inhaled steroids were also excluded

Interventions

Run‐in: 2‐week run‐in period

Treatments:

1. Budesonide 400 mcg twice daily (Pulmicort)

2. Placebo twice daily

3. Budesonide/formoterol 320/9 mcg twice daily (Symbicort)

4. Formoterol 9 mcg twice daily (Oxis)

Inhaler device: as above

Co‐treatment: Only study medication was allowed during the treatment period, plus terbutaline 0.5 mg when needed as reliever medication

Outcomes

Primary: severe exacerbations and FEV₁

Secondary: VC and PEF, health‐related quality of life, diary card data, reliever medication use, mild exacerbations, adverse events and clinical chemistry

Notes

Funding: AstraZeneca

Definition of pneumonia: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Total of 812 participants were randomly assigned (no other details, industry‐sponsored)

Allocation concealment (selection bias)

Unclear risk

Not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blind (presumed participants and personnel/investigator)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawal high and uneven between groups (formoterol 31.8%, placebo 43.9%, 31% ICS and 28% LABA/ICS). An intention‐to‐treat analysis was used, but imputation methods were unclear for some outcomes