Renkema et al7 | Derenne et al10 | Kerstjens 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)-smoker | Age ⩽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 consent | Age 18–60; “symptom-based diagnosis of COPD”; FEV1 <FEV1pred − 1.64SD and >1.2 l; PC20histamine ⩽8 mg/ml |
Exclusion criteria | Age ⩾70; continuous corticosteroid therapy; severe concomitant disease | Other 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/ml | Maintenance treatment with corticosteroids; asthmatic attacks |
Setting | Clinical, one centre | Clinical, multicentre | Clinical, multicentre |
Design | Double blind, placebo controlled, 3 parallel arms | Double blind, placebo controlled, 2 parallel arms | Double blind, placebo controlled, 3 parallel arms |
Duration of study | 24 months | 24 months | 30 months |
Study drugs | Bud 800 μg bd MDI through NebuhalerR + plac 1dd versus bud 800 μg bd + pred 5 mg 1 dd versus plac bd + plac 1 dd | Becl 1500 μg MDI versus plac | Terb 2 mg + becl 800 μg MDI versus terb 2 mg + ipra 160 μg versus terb 2 mg + plac |
Concomitant drugs | Anticholinergics, β2 agonists, theophylline or antihistamines | Anticholinergics, β2 agonists, theophylline, mucolytics, almitrine | Salbutamol 400 μg on demand |
Outcome | FEV1 decline; symptoms; duration of exacerbations | Level of FEV1; level of PEF; duration of corticosteroid course | Drop outs; level of FEV1; FEV1 decline; level of PC20 |
Criteria pulmonary dropout | ⩾3 exacerbations within 3 consecutive months; severe progressive deterioration of lung function level | Insufficient effectiveness | Doctor’s initiative: >2 corticosteroid courses/3 months or >4/year; patient’s initiative: >>symptoms |
Definition exacerbation | Increased complaints of dyspnoea and/or cough and/or sputum with(out) fever | (1) Increase in dyspnoea and/or (2) purulent sputum and fever | Increased symptoms and >4 additional salbutamol/day |
Treatment of exacerbation | 7 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 measurement | Skin tests, serum IgE, eosinophil count | Serum IgE and eosinophil count | Skin tests, serum IgE, eosinophil count |
Compliance check | Weighing canisters; counting tablets | Verbal check | Weighing canisters |
Statistical analysis: | |||
Overall method | Explanatory analysis of variance | Repeated measurement analysis, explanatory analysis | Analysis of variance, explanatory |
Subgroup? | No | No | Yes |
Measurement of FEV1 decline | Linear regression, ⩾3 measurements needed | Repeated measurement | Linear regression from month 3 on, ⩾4 measurements needed |
Financial support | Astra Pharmaceuticals | GlaxoWellcome 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.