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Beclometasone for chronic obstructive pulmonary disease

  1. Daan A De Coster1,*,
  2. Melvyn Jones2,
  3. Nikita Thakrar3

Editorial Group: Cochrane Airways Group

Published Online: 9 OCT 2013

Assessed as up-to-date: 6 FEB 2013

DOI: 10.1002/14651858.CD009769.pub2


How to Cite

De Coster DA, Jones M, Thakrar N. Beclometasone for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD009769. DOI: 10.1002/14651858.CD009769.pub2.

Author Information

  1. 1

    University College London, Upper 3rd Floor, UCL Medical School (Royal Free Campus), Department of Primary Care and Population Health, London, UK

  2. 2

    UCL, Department of Primary Care and Population Health, Division of Population Health, Faculty of Population Health Sciences, London, UK

  3. 3

    UCL, Department of Primary Care and Population Health, London, UK

*Daan A De Coster, Department of Primary Care and Population Health, University College London, Upper 3rd Floor, UCL Medical School (Royal Free Campus), Rowland Hill Street, London, NW3 2PF, UK. d.coster@ucl.ac.uk. decosterdaan@googlemail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 9 OCT 2013

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Characteristics of included studies [ordered by study ID]
Calverley 2010

MethodsParallel, double-blind, randomised trial. Duration: 48 weeks and 4 weeks of run-in (52 weeks in total)


Participants1. Total number randomly assigned 476 (BDP/FF 237, FF 239). Additional treatment groups not covered in this review: BUD/FF 242

2. Setting: 76 centres in 8 European countries (Bulgaria, France, Italy, Poland, Russia, Spain, Ukraine, United Kingdom)

3. Diagnostic criteria (according to GOLD or other): claims “GOLD” criteria and this is accurate save for a small detail: The study required a 30-minute postbronchodilator (post-BD) change in FEV1 of < 12% (although GOLD guidelines specify 10 to 15 minutes post-BD). Other inclusion criteria: age ≥ 40; > 2 years diagnosis of symptomatic COPD; post-BD 30% < FEV1 < 50% of the predicted normal; ≥ 0.7 L FEV1; ≥ 1 exacerbation (with oral CS and/or antibiotics and/or visit to emergency department and/or hospitalisation) within 2 to 12 months before screening; clinically stable for 2 months before study

Baseline characteristics of postbronchodilator FEV1 were: BDP/FF 41.9 ± 5.6 % and LABA 42.5 ± 5.9%.

4. Age 63.0 ± 9.0 and 63.7 ± 8.8

5. Comorbidity: no asthma, allergic rhinitis or atopic disease, diurnal symptoms suggesting asthma

6. Smoking status: ≥ 20 pack-years smoking history; smokers and ex-smokers (baseline characteristics: smokers/ex-smokers: BDP/FF 90/142, FF 87/146; number of packs per year (SDs): BDP/FF 37.3 (14.1), FF 39.7 (19.1))


InterventionsRun-in: ipratropium/salbutamol (20/100 µg, 2 puffs TDS)

Total number of intervention groups: 3 (2 relevant)

MDI, DPI or spacer? pMDI for BDP/FF, DPI for FF

Co-pharmacy? All COPD treatments were discontinued after the run-in, except for rescue inhaler (salbutamol PRN)

 

1. Beclometasone/formoterol pMDI 100/6 µg, 2 puffs BD (so daily dose 400/24) (Foster, Chiesi)

2. Formoterol DPI 12 µg, 1 puff BD (so daily dose 24) (Oxis, AstraZeneca)


Outcomes1. Pulmonary function tests (FEV1 of interest), according to ATS/ERS

2. COPD exacerbations (defined as need for treatment with oral corticosteroids and/or antibiotics and/or the need to visit or be admitted to a hospital)

  • Number of participants with at least one exacerbation
  • Mean rate of exacerbations


3. Dyspnoea scores (Modified Medical Research Council questionnaire) (Mahler 1988)

High score is bad

4. Quality of life (SGRQ)

High score is bad

5. Exercise capacity (6MWT)

High score is good (longer distance)

6. Body Mass Index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) Index. (Celli 2004)

High score is bad

7. Use of rescue bronchodilator

Unit: inhalations/d

8. Adverse events: I. QTc interval evaluations, ii. Holter monitoring, iii. Serum cortisol, iv. Plasma glucose, v. Pneumonia, vi. Adverse event (AE) statistics

9. Withdrawal (reviewer’s outcome): I. all cause, ii. due to AEs

10. Outcome definition: mortality I) all cause, ii) respiratory


NotesDate of study: December 2006 to August 2008

Funding: Chiesi


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The IXRS assigned the patient to a certain treatment group using a list-based randomisation algorithm"

Comment: IXRS is a computer-based system (see below)

Allocation concealment (selection bias)Low riskQuote: "Patients 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 riskQuote: "Almac Clinical Technologies (UK) was in charge of the IXRS study drug management. The investigators at the sites called the IXRS to screen and randomise patients"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "Study drug was kitted and uniquely numbered and the IXRS was used to assign both initial and subsequent kits in order to have an inventory control and patient dose tracking. The IXRS also maintained quantities, kit numbers, drug types, batch/code numbers, expiration dates and did not dispense after these dates. On each study day, patients took both active medications and matched placebo twice daily, in order to maintain blinding"

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Missing values were accounted for using the last observation carried forward (LOCF) approach"

Comment: The LOCF was deemed by us as an acceptable manner of imputing data in the difficult area of imputing data in ITT analyses

Withdrawal reasons were extensively reported. Two participants seemed missing from randomisation when the Consort Flow Diagram was scrutinised (Both the total N of BDP/FF and the total N of FF are different from the breakdown into N withdrawn and N completed) Calverley PM responded to this query by saying that this was due to the strict reporting rules—Calverley P thinks these were two participants who were randomly assigned but never received study medication. Furthermore, we deemed that two participants missing out of 476 (237 ± 239) is unlikely to affect outcomes

Selective reporting (reporting bias)Low riskAlthough no full protocol was available, a national trial registry entry appeared on clinicaltrials.gov. Review of this entry revealed the following: All protocol outcomes were included. One country (Germany) was not mentioned in the final paper. When the authors Professors Peter M Calverley and Stefano Petruzzelli, Chief Medical Officers of Chiesi, were emailed, they clarified that German centres did not recruit participants, as although the German Regulatory Authority approved the study, some questions related to the comparator arm (formoterol alone) were raised by ethics committees

Other biasLow riskPossible conflict of interest: funding provided by Chiesi. Two of the authors are employed by Chiesi

However, these conflicts of interest were declared. The main author is an expert in the field and has conducted trials for several competing manufacturers

Derenne 1995

MethodsRandomised placebo-controlled multicentre trial. Duration: 2 years


Participants1. Total number: 194 (100 BDP, 94 PL)

2. Setting: 28 outpatient lung clinics in France

3. Diagnostic criteria: ATS 1987 (chronic bronchitis: cough + sputum most days for minimum of 3 consecutive months in 2 consecutive years)

Prebronchodilator FEV1 30% to 60% of predicted (Quanjer 1983)

10 minutes postbronchodilator FEV1 increase < 15% predicted (FEV1)

Further assessment at end of run-in: pre-BD FEV1 not different by > 10% from pretrial FEV1 +  IgE < 200 IU and/or blood eosinophils < 500/mm3 + PaO2 ≥ 55 mm Hg.

Baseline characteristics of postbronchodilator FEV1 were: BDP 51 ± 12% and PL 48 ± 11%.

4. Age: < 75 years

5. Comorbidity: exclusion: history of severe exacerbations of COPD past 3 months; lung cancer/bullous emphysema/asthma or history suggestive of asthma in past 10 years; long-term use of ICS; oral corticosteroids in past 15 days; inability to follow protocol, participation in other trial; pregnant/lactating; stomach ulcer without treatment; pulmonary TB; unable to use inhaler

6. Smoking status: both smokers and non-smokers (baseline characteristics: current/former/non-smoker: BDP 27/62/11; PL 28/56/10. Pack-years (SDs): BDP 37 (27); PL 41 (28))


InterventionsRun-in: 2-week period maintaining participants' usual treatments (anticholinergics, beta2-agonists, theophylline, mucolytics, almitrine)

Total number of intervention groups: 1

MDI, DPI or spacer? MDI

Co-pharmacy:

1. Antibiotics (max 15 days): in case of exacerbation

2. Prednisone orally: on investigator’s judgement (e.g. in case of increased dyspnoea)

3. No complete certainty from article or correspondence that participants' usual regimens (anticholinergics, beta2-agonists, theophylline, mucolytics, almitrine) were discontinued after run-in period (baseline characteristics (% of subjects): anticholinergics BDP 19%, PL 22%; beta2-agonists BDP 59%, PL 61%; theophylline BDP 58%, PL 61%; mucolytics BDP 40%, PL 48%; almitrine BDP 10%, PL 17%)

Interventions:

1. Beclometasone dipropionate (Becotide) 1500 μg (3 puffs of 250 μg BD)

2. Placebo


OutcomesOutcomes and time points: I. collected, ii. reported

1. “Reversibility” of lung function tests: post-BD FEV1

I. Every half year, stated elsewhere as “assessed annually”

Outcome definition: FEV1 (as % of FEV1 predicted) 10 minutes after 4 puffs 100 μg salbutamol

Unit of measurement: % of FEV1 predicted

Limits: 0-100%. High score is good

2. Number of exacerbations

I. Every three months (each follow-up visit)

Outcome definition: prescribed courses of antibiotics or oral corticosteroids

NB: Patients were told to come to the clinic to have exacerbation diagnosed if they noticed increased mucopurulent sputum and fever

3. Symptom: dyspnoea

I. At baseline, 3, 6, 12, 18 and 24 months
Outcome definition: 1 = no dyspnoea, 2 = no dyspnoea when walking on flat ground, 3 = no dyspnoea when walking slowly, 4 = dyspnoea even when walking slowly, 5 = dyspnoea while undressing

Unit of measurement: Fletcher Scale (Fletcher 1964)

Limits of scale: 1 to 5. High score is bad

4. Hospitalisation and duration

I. Every three months (each follow-up visit)
Outcome definition: n/a

5. Adverse events

I. At every visit (three months or in between)
Outcome definition: “... at each visit, the subjects were asked if the drug of treatment was well tolerated and if not, the investigator had to fill in a standard (serious) adverse event form”

6. Withdrawal (reviewer’s own outcome)

ii. At end of 24 months

7. Mortality (reviewer’s own outcome) (all-cause and respiratory)

ii. At 24 months


NotesDate of study: 15 May 1989 to 9 February 1990

Funding: GlaxoWellcome Pharmaceutical


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Block randomisation was performed".

Comment: As Chapter 8.9.2.3 states (Higgins 2011), this inadequate level of reporting requires a judgement of "unclear risk"

Allocation concealment (selection bias)High riskQuote: "Each of the investigators was given a set of 8 sealed envelopes containing the assignment codes"

Comment: Although they are described as "sealed" envelopes, no details on opacity or sequential numbering of the envelopes are provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "At each visit, a box with 8 MDI's, sufficient for 3 months, was supplied"

Comment: Other than this quote, no more description provided, leaving unanswered questions such as: Who provided the MDI? Was it an independent body? Who was in charge of labelling with the assignment codes?

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "The code could be broken in the event of a serious adverse event"

Comment: This implies that throughout the study, the assessors could find out who was actually being treated only if they had to go back to break the assignment code.

Quote:"All measurements were taken with the same apparatus, and if possible, with the same technician and at the same time of day."

Comment: Although this sentence is mainly intended to indicate how the risk of measurement error was reduced, it may also imply that the researchers reduced the risk of treating the placebo and treatment groups differently

However, both these quotes lead to conclusions drawn by implication, as the subject of blinding is not addressed in the study. This would not matter for objective outcome measures (pulmonary function tests, blood gasses, dyspnoea, hospitalisations, consultations) but could have an impact on subjective measures (general well-being [both physician and participant assessed], smoking behaviour, corticosteroid and antibiotic courses)

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "...due to missing values in the multivariate model [of FEV1], which corrected for possible confounding variables, the number of measurements which were to be included was strongly reduced. The better result in terms of postbronchodilator FEV1 compared to pre-bronchodilator FEV1 should therefore be considered with due caution"

Comment: It is odd to see multivariate analysis in an RCT—presumably as the randomisation did not work too well (i.e.the groups were not the same at baseline)

Selective reporting (reporting bias)Low riskComment: A protocol is not available, but another version of the abstract is available in the form of the conference abstract published as a supplement in the American Journal of Respiratory and Critical Care Medicine. Compared with the full text, FEV1 outcomes are reported separately as deviations from baseline in placebo and treatment groups, and the other outcome in the abstract is the peak expiratory flow, which is known to be not helpful in COPD. This abstract may have consisted of preliminary findings

The full text, however, although it also concentrates on outcomes that are not of interest (e.g. pre-bronchodilator FEV1 measures) does not seem to withhold outcomes of interest (e.g. postbronchodilator FEV1 in treatment group vs placebo group)

Other biasLow riskQuote: "This study was originally coordinated by one of the co-authors (J.P. Derenne) in cooperation with GlaxoWellcome France. So far, its results have only been presented in abstract form and have not been published in full. The study was selected for a meta-analysis of published and unpublished studies on the long-term effects of inhaled corticosteroids in COPD. Here, we present the full analysis of the original raw data to avoid publication bias and the restrictions imposed by the meta-analysis"

Comment: funding declared. As this is an original document instead of a peer-reviewed publication, risk of publication bias should be low

Weir 1999

MethodsRandomised placebo-controlled double-blind parallel-group trial

Duration: 2 years


Participants1. Total number: 98 participants randomly assigned, 78 completing at least 12 months of treatment, 59 completing the 2-year study period

2. Setting: Quote: “The patients entered into the study reflect the majority of those presenting to an urban chest clinic with COPD, where the major pathology is smoking-related”

3. Diagnostic criteria: clinical diagnosis of COPD, adult-onset airflow obstruction with FEV1 < 70% predicted and FEV1/FVC < 65%. Excluded if clinically significant BD reversibility; history of acute attacks of breathlessness with recovery between attacks; significant improvement with steroid treatment in the past; if steroid treatment clinically indicated, any form of corticosteroid therapy prescribed for > 3 months in previous year; any steroids prescribed in 4-week run-in.

Baseline characteristics of postbronchodilator FEV1 were reported in Litres as BDP 1.19 ± 0.07L and PL 1.26 ± 0.07. We estimated that this was equivalent to FEV1 42.7% predicted for BDP and 45% for PL.

4. Age: 67.6 (SEM 1.0) and 65.5 (SEM 1.0) years

5. Comorbidity: no clinical diagnosis of asthma

6. Smoking status: smokers and ex-smokers (baseline characteristics: smokers/ex-smokers: BDP 17/31, PL 21/28; number of packs per year (SEMs): BDP 54 (9), PL 56 (8))


InterventionsRun-in: none

Total number of intervention groups: 1

MDI, DPI or spacer: MDI with spacer

Co-pharmacy: rescue inhalers as required. Participants receiving theophylline continued (no change of dose during trial)

Interventions:

  1. 750 μg BD of BDP if weight < 50 kg; 1000 μg BD if > 50 kg
  2. Placebo inhaler; an equivalent number of puffs, as determined by body weight


Outcomes1. Change in post-BD FEV1

2. Rate of exacerbations (exacerbation not defined)

Unit: number/y

3. Change in BDI (Baseline Dyspnoea Index) (Mahler 1988)

4. Chronic Respiratory Disease Questionnaire (Guyatt 1987) (subgroup of participants) (data declared as not reported in this publication)

5. Withdrawal (reviewer’s own outcome)


NotesNo ITT analysis (Quote: “Only patients with data points for at least 12 months were included in the final analysis”)

Funding: undeclared in the publication. "The study was unfunded, except that GlaxoWellcome provided the drugs and placebo and did the randomisation" (P.S. Burge, 20/12/12, communication by email) "...the analysis of the CRF/lung function" (CRF: Clinical Record Folder (the source data)) "was done by Dr RK Sharma International Clinical Research manager of Glaxo" (P.S. Burge, 26/2/13, communication by email)

Correspondence required: number of participants for each arm used in the analysis (i.e. lasted > 12 mo). Details on random allocation. Details on methods for Cochrane bias tool. Details on matching. Original data if possible for an ITT analysis. Details on what constitutes an exacerbation. Details of conflicts of interest


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The study was a randomised placebo-controlled double-blind parallel group comparison..."

Comment: insufficient information on sequence generation. Furthermore, when the author P.S. Burge was emailed, he could not give further details on which method of random sequence generation was used

Allocation concealment (selection bias)Low riskComment: no detail in the study. However, as emailed by author P.S. Burge, "I cannot find out how randomisation was done within blocks, this was done by GSK, we entered patients serially having already received the inhalers which all looked identical but were numbered, the study was double blind." So, evidence of central allocation and sequentially numbered drug inhalers of identical appearance

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "The study was a randomised placebo-controlled double-blind parallel group comparison..."

Quote: "...each patient having all measurements on the same machine throughout the study"

Comment: Participants were treated in the same way. As above, as emailed by P.S. Burge, inhalers looked the same, received from a central body. So neither participant nor investigator could know which was which

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "All lung function measurements were made on regularly calibrated dry bellows spirometers at the same time of the day, each patient having all measurements on the same machine throughout the study"

Comment: As above quotes illustrate, measurement was the same for both groups

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "Only patients with data points for at least 12 months were included in the final analysis"

Comment: This is not an intention-to-treat analysis, and therefore it is at high risk of introducing bias

Quote: "The 39 patients withdrawn from the study had significantly worse airflow obstruction than the 59 patients completing the study [mean (SEM) baseline FEV1 (litres): withdrawn group 0.93 (0.07), completers 1.21 (0.06), P < 0.01]. Only three patients in the active treatment group and six in the placebo were withdrawn because they experienced two exacerbations in a 3-month period. There were no significant differences in total withdrawal rates for any reason between the two treatment groups"

Comment: As is the problem with many COPD steroid studies, participants withdrew because of lack of effective treatment in both placebo and treatment groups. As withdrawn participants had significantly worse lung function, this could introduce risk of bias in the outcome measurements

The last sentence was clarified with the authors to mean that no significance was found in the total withdrawal rates for any given reason, as well as no significant difference for all-reason withdrawal. As withdrawal is balanced across both groups, risk of bias is minimised. Furthermore, six placebo participants—more than three beclometasone participants—would be likely to underestimate treatment effect of beclometasone, thereby decreasing the risk of bias

Selective reporting (reporting bias)Unclear riskQuote: "A subgroup of patients also answered the Chronic Respiratory Disease Questionnaire of Guyatt et al. [7], although these data are not reported here"

Comment: P.S. Burge informed us (26/2/13) that "The reason that the Guyatt questionnaire was not used on all is due to lack of staff for a period, i.e. selection was by date of clinics rather than anything medical. (...) The Guyatt data was to be analysed by our clinical nurse specialist, Geraldine Bale. There are several published abstracts of this" Despite corresponding with Geraldine Bale (now Geraldine Burge), we were unable to identify any abstracts with numerical reporting of questionnaire results in the text

Comment: No information was provided on how many participants were in each arm of the analysis, rendering data unusable for entry into a meta-analysis

Other biasHigh riskNo information declared on sponsorship, yet correspondence with P.S. Burge revealed involvement of GSK in the block randomisation process, provision of the study drugs and analysis, so GSK is likely funder

No information on conflicts of interest. For these two reasons alone, this study has been deemed at high risk for "other bias"

Quote: "Patients taking oral theophyllines maintained a constant dose throughout the study period"

Comment: Co-pharmacy was present in the study for recruited participants who were taking theophylline before the start of the trial. Theophylline is a recognised treatment in COPD (GOLD 2010) and has been shown to significantly improve FEV1 and FVC (Ram 2002). It was not specified for how many participants this was the case, nor how many were in each treatment arm, leading to an assessment of unclear risk of further performance bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Boothman-Burrell 1997Primary reason: inadequate inclusion criteria. Inclusion criterion of < 25% reversibility to bronchodilator too broad to exclude asthmatic patients. Secondary reasons: 1 month washout period too short to use the first treatment period as a parallel study, further made impossible by the ten days of prednisone administered after the first treatment period

Dinc 2001Not a randomised trial. Observational study

John 2005No data available beyond the published data. Because our expert opinion was that the washout period of 4 weeks was to short (i.e. < 6 weeks), this cross-over study was to be treated as a parallel study. However, the authors communicated with us that data for the first treatment period only could not be supplied

Miravitlles 2002Not a randomised trial. Observational study

Ouyang 1998Not double-blinded. Single-blind

Shmelev 2006Not double-blinded. No blinding at all

Struijs 1997Not a randomised trial. No randomisation into placebo

Thompson 1992Treatment less than 12 weeks. 6 weeks only

Tzani 2011Not correct research question. Comparison of beclometasone with fluticasone, not with placebo

van Schayck 1995Not a randomised controlled trial

Weir 1990Treatment less than 12 weeks. 2 weeks only

Weir 1993Treatment less than 12 weeks. 3 weeks only

 
Characteristics of studies awaiting assessment [ordered by study ID]
Vengerov 1998

MethodsRandomised prospective trial. Duration: 5 years (blinding not stated in abstract)

Participants1. Total number: 89 men (45 BDP, 44 control)

2. Setting: metal workers in Ukraine (industrial pollutants with extremely irritating activity)

3. Diagnostic criteria: COPD, males, non-smokers, initial FEV1 46% to 70% predicted

4. Age: mean age 43.6 years

5. Comorbidity: not stated in abstract

Interventions1. 750 to 1250 μg beclometasone dipropionate (Becotide/Becloforte) daily

2. Observation as control group

Outcomes1. Change in FEV1

2. Number of exacerbations ("relapses") and length of stay in hospital

3. Symptom score

4. Bronchofibroscopic degree of inflammation

NotesAbstract only. Awaiting full text

 
Characteristics of ongoing studies [ordered by study ID]
Wedzicha (FORWARD) 2013

Trial name or title48-Week, Double Blind, Randomized, Multinational, Multicentre, "Fixed Combination" Beclomethasone Dipropionate Plus Formoterol Fumarate Versus Formoterol in Patients With Severe Chronic Obstructive Pulmonary Disease

MethodsRandomised, double-blind, parallel-group trial

Duration: 48 weeks

Participants1. Total number: 1119 participants enrolled

2. Setting: multinational, multicentre (Germany, Austria, Ireland, UK, Czech Republic)

3. Inclusion criteria:

  • Severe COPD
  • At least one COPD exacerbation in previous year


Exclusion criteria:

  • Asthma, allergic rhinitis or other atopic disease
  • Unstable concurrent disease
  • Evidence of heart failure


4. Age. > 40 years

InterventionsRun-in. Information not available (N/A)

Total number of intervention groups: 2

MDI, DPI or spacer? MDI

Co-pharmacy? N/A

Interventions:

  1. Beclometasone dipropionate 100 µg plus formoterol fumarate 6 µg per metered dose combination inhaler (Foster, Fostair)
  2. Formoterol fumarate 12 µg per metered dose (Atimos)

OutcomesPrimary

  1. Exacerbation rate
  2. Change in predose FEV1


Secondary

  1. Pulmonary function parameters (FEV1/FVC)
  2. Saint George’s Respiratory Questionnaire
  3. Use of rescue medication

Starting dateOctober 2009

Contact informationJadwiga A Wedzicha, MD, Prof, UCL Medical School

NotesFunded by Chiesi

Estimated study publishing date: August 2013

 
Comparison 1. Beclometasone versus placebo

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

 1 Change in FEV11Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 At 1 year
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 At 2 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Mortality (dichotomous Peto method)1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    2.1 All-cause
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Respiratory
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Exacerbations: mean rate (rate ratio)1Rate Ratio (Fixed, 95% CI)Totals not selected

 4 Symptoms: change in dyspnoea scale (Fletcher Scale)1Mean Difference (IV, Random, 95% CI)Totals not selected

 5 Adverse events1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    5.1 Candidiasis
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Dysphonia
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.3 Bone fractures
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Withdrawal2Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    6.1 All-cause
2292Peto Odds Ratio (Peto, Fixed, 95% CI)1.33 [0.83, 2.14]

    6.2 Due to adverse events
1194Peto Odds Ratio (Peto, Fixed, 95% CI)1.06 [0.52, 2.19]

    6.3 Due to ineffectiveness of treatment
2292Peto Odds Ratio (Peto, Fixed, 95% CI)1.55 [0.60, 4.04]

 
Comparison 2. Beclometasone/formoterol versus formoterol

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

 1 Change in FEV11Mean Difference (IV, Fixed, 95% CI)Totals not selected

 2 Mortality (all-cause) (dichotomous Peto method)1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    2.1 All-cause
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Respiratory
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Pneumonia: participants with at least one (dichotomous Peto odds ratios)1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

 4 Change in exercise capacity: 6MWT1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Exacerbations: participants with at least one (dichotomous)1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Exacerbations (hospitalisations): participants with at least one (dichotomous)1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 Exacerbations (hospitalisations): mean rate (rate ratio)1Rate Ratio (Fixed, 95% CI)Totals not selected

 8 Number of hospitalisations (rate ratio)1Rate Ratio (Fixed, 95% CI)Totals not selected

 9 Change in Quality of Life: SGRQ1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 10 Symptoms: change in dyspnoea scale (modified Medical Research Council questionnaire)1Mean Difference (IV, Random, 95% CI)Totals not selected

 11 Symptoms: change in BODE index1Mean Difference (IV, Random, 95% CI)Totals not selected

 12 Use of rescue bronchodilators: self-reported days without1Mean Difference (IV, Random, 95% CI)Totals not selected

 13 Adverse events1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    13.1 Candidiasis
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.2 Dysphonia
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.3 Bone fractures
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Withdrawal1Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected

    14.1 All-cause
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.2 Due to adverse events
1Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Beclometasone/LABA compared with LABA for COPD

Beclometasone/LABA compared with LABA for COPD

Patient or population: participants with stable stage 3 COPD, smokers and ex-smokers with a minimum pack-year history of 20
Settings: 76 centres in 8 European countries (Bulgaria, France, Italy, Poland, Russia, Spain, Ukraine, United Kingdom)
Intervention: beclometasone/formoterol
Comparison: formoterol

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

Assumed riskCorresponding risk

FormoterolBeclometasone/Formoterol

Change in FEV1
Follow-up: 48 weeks
Mean change in FEV1 in the intervention groups was
0.05 higher
(0 to 0.1 higher)
465
(1 study)
⊕⊕⊕⊕
high

Mortality (all-cause) (dichotomous Peto method)
Follow-up: 48 weeks
0 per 10000 per 1000
(0 to 0)
OR 7.48
(0.47 to 120)
474
(1 study)
⊕⊝⊝⊝
very low1,2,3

Pneumonia: participants with at least one (dichotomous Peto odds ratios)
Follow-up: 48 weeks
4 per 100016 per 1000
(3 to 76)
OR 3.88
(0.78 to 19.39)
474
(1 study)
⊕⊕⊝⊝
low2,3

Exacerbations: participants with at least one (dichotomous)
Follow-up: 48 weeks
283 per 1000275 per 1000
(202 to 364)
OR 0.96
(0.64 to 1.45)
465
(1 study)
⊕⊕⊕⊝
moderate2

Change in quality of life: SGRQ
Scale: 0 to 100
Follow-up: 48 weeks
Mean change in quality of life: SGRQ in the intervention groups was
0.85 lower
(3.32 lower to 1.62 higher)
465
(1 study)
⊕⊕⊕⊝
moderate2

Adverse events: candidiasis
Follow-up: 48 weeks
Not estimable474
(1 study)
⊕⊕⊕⊝
moderate1

Withdrawal (all-cause)
Follow-up: 48 weeks
143 per 1000132 per 1000
(83 to 203)
OR 0.91
(0.54 to 1.53)
474
(1 study)
⊕⊕⊕⊝
moderate2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Indirectness of outcome. Unlikely to have been powered for this outcome. May be more appropriate to measure this outcome with e.g. a cohort study.
2Wide confidence intervals.
3Few events.
 
Summary of findings 2. Beclometasone compared with placebo for COPD

Beclometasone compared with placebo for COPD

Patient or population: participants with stable stage 2 and 3 COPD (mainly FEV1 49 ± 12% predicted), ex-smokers (majority), smokers and non-smokers
Settings: outpatient lung clinics in France (and additionally, for "withdrawals", the UK)
Intervention: beclometasone
Comparison: placebo

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

Assumed riskCorresponding risk

PlaceboBeclometasone

Change in FEV1at 2 years
Follow-up: 2 years
Mean change in FEV1—at 2 years in the intervention groups was
0.03 higher
(0.25 lower to 0.31 higher)
194
(1 study)
⊕⊝⊝⊝
very low1,2,3

Mortality (all-cause) (dichotomous Peto method)
Follow-up: 2 years
53 per 100050 per 1000
(14 to 157)
OR 0.94
(0.26 to 3.34)
194
(1 study)
⊕⊝⊝⊝
very low2,3,4,5

Pneumonia: participants with at least one (dichotomous Peto odds ratios)Not estimable0
(0)

Exacerbations: participants with at least one (dichotomous)Not estimable0
(0)

Symptoms: change in dyspnoea scale (Fletcher Scale)
Fletcher dyspnoea scale (1 to 5)
Follow-up: 2 years
Mean symptoms: Change in dyspnoea scale (Fletcher Scale) in the intervention groups was
0.05 higher
(0.06 lower to 0.15 higher)
194
(1 study)
⊕⊕⊕⊝
moderate3

Adverse events: candidiasis
Follow-up: 2 years
21 per 100029 per 1000
(5 to 151)
OR 1.41
(0.24 to 8.31)
194
(1 study)
⊕⊝⊝⊝
very low2,3,5

Withdrawal (all-cause)
Follow-up: 2 years
336 per 1000402 per 1000
(295 to 520)
OR 1.33
(0.83 to 2.14)
292
(2 studies)
⊕⊕⊝⊝
low2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1The Derenne 1995 study was assessed as at high risk of incomplete outcome data for FEV1 (see the Derenne 1995 'Risk of bias' table).
2Wide confidence intervals (includes null effect).
3For the beclometasone versus placebo studies, we strongly suspected publication bias (see section "Potential biases in the review process").
4All-cause mortality is a very objective outcome measure, and no significant difference was noted in participants lost to follow-up through withdrawal.
5Indirectness of outcome, as the Derenne study was unlikely to be powered for comparing this outcome. A cohort study may be more appropriate.