Table 1

The three placebo controlled trials on the long term effects of inhaled corticosteroids in COPD: inclusion and exclusion criteria, method, and analysis

Renkema et al7Derenne et al10Kerstjens et al9 (subgroup)
Inclusion criteria Clinical diagnosis of COPD based on history (persistent dyspnoea without sudden attacks of dyspnoea; FEV1 <80% pred; RV >100% pred; specific compliance(Csp) >100%pred after bronchodilation; no signs of allergy (negative skin test results), total serum IgE <200 IU/ml, eosinophils in peripheral blood <250 ×103/ml; stable phase of disease; α1-antitrypsin within normal range; (ex)-smokerAge ⩽75; “chronic bronchitis”; FEV1 30–60%pred; revFEV1<10% pred; Pao 2 >55 mm Hg; usual treatment without corticosteroid; no exacerbation in the last three months; written informed consentAge 18–60; “symptom-based diagnosis of COPD”; FEV1 <FEV1pred − 1.64SD and >1.2 l; PC20histamine ⩽8 mg/ml
Exclusion criteriaAge ⩾70; continuous corticosteroid therapy; severe concomitant diseaseOther pulmonary diseases; corticosteroids past 15 days; unable to follow protocol; pregnant or lactating women; stomach ulcer without treatment, pulmonary tuberculosis; IgE >200IU/ml and eosinophils >500 × 103/mlMaintenance treatment with corticosteroids; asthmatic attacks
SettingClinical, one centreClinical, multicentreClinical, multicentre
DesignDouble blind, placebo controlled, 3 parallel armsDouble blind, placebo controlled, 2 parallel armsDouble blind, placebo controlled, 3 parallel arms
Duration of study24 months24 months30 months
Study drugsBud 800 μg bd MDI through NebuhalerR + plac 1dd versus bud 800 μg bd + pred 5 mg 1 dd versus plac bd + plac 1 ddBecl 1500 μg MDI versus placTerb 2 mg + becl 800 μg MDI versus terb 2 mg + ipra 160 μg versus terb 2 mg + plac
Concomitant drugsAnticholinergics, β2 agonists, theophylline or antihistaminesAnticholinergics, β2 agonists, theophylline, mucolytics, almitrineSalbutamol 400 μg on demand
OutcomeFEV1 decline; symptoms; duration of exacerbationsLevel of FEV1; level of PEF; duration of corticosteroid courseDrop outs; level of FEV1; FEV1 decline; level of PC20
Criteria pulmonary dropout⩾3 exacerbations within 3 consecutive months; severe progressive deterioration of lung function levelInsufficient effectivenessDoctor’s initiative: >2 corticosteroid courses/3 months or >4/year; patient’s initiative: >>symptoms
Definition exacerbationIncreased complaints of dyspnoea and/or cough and/or sputum with(out) fever(1) Increase in dyspnoea and/or (2) purulent sputum and feverIncreased symptoms and >4 additional salbutamol/day
Treatment of exacerbation7 days pred (35-30-25 mg etc), and a course of antibiotics if necessary(1) Course of pred and/or (2) course of antibiotics ⩽15 days 12 days pred (30-30-25 -25 mg etc)
Method of allergy measurementSkin tests, serum IgE, eosinophil countSerum IgE and eosinophil countSkin tests, serum IgE, eosinophil count
Compliance checkWeighing canisters; counting tabletsVerbal checkWeighing canisters
Statistical analysis:
 Overall methodExplanatory analysis of varianceRepeated measurement analysis, explanatory analysisAnalysis of variance, explanatory
 Subgroup?NoNoYes
 Measurement of FEV1 declineLinear regression, ⩾3 measurements neededRepeated measurementLinear regression from month 3 on, ⩾4 measurements needed
 Financial supportAstra PharmaceuticalsGlaxoWellcome Inc. Netherlands Health Research Promotion Program (SGO); Pharmaceutical companies: Astra Pharmaceuticals, Boehringer Ingelheim, Glaxo
  • bud = budesonide; plac = placebo; pred = prednisone; becl = beclomethasone; terb = terbutaline; ipra = ipratropium.