Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

Abstract

Objectives: To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease.

Design: Double blind, placebo controlled study.

Setting: Eighteen UK hospitals.

Participants: 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal.

Interventions: Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo.

Main outcome measures: Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events.

Results: There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034).

Conclusions: Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.

Figure 1

Profile of number of patients at each phase of study

Figure 2

Mean FEV₁ (litres) after bronchodilator by time from start of double blind treatment. Numbers reflect patients with valid readings at each time point. Measurements within four weeks of exacerbation are excluded. Direct comparisons of FEV₁ means at each time point are not possible because fewer patients remained in the study as it progressed

Figure 3

Effect of treatment on decline in health indicated by increasing total scores on respiratory questionnaire (means (95% confidence intervals) calculated from analyses of covariance). Numbers at each assessment indicate number of patients for whom measurements of health status were available at that visit. Direct comparisons of respiratory questionnaire scores at each time point are not possible because fewer patients remained in the study as it progressed

Figure 4

Weighted regressions from random coefficients (mixed) model (see text) to account for the effect of differences in the number of observations between patients, with adjustment for baseline covariates (baseline questionnaire score, age at entry, sex, centre, and smoking during the study)