Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial

Klaus F. Rabe,Fernando J. Martinez,Florian Voß,David M. G. Halpin,Dave Singh,MeiLan K. Han,Marc Miravitlles,Lars Grönke

doi:10.1186/s12931-020-01431-y

Abstract

BackgroundAssessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting.MethodsA composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2–4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 μg or placebo.ResultsThe composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George’s Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6–81.6%) and SGRQ (72.3–78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment.ConclusionsComposite endpoints provide additional information on COPD progression and treatment effects in clinical trials.Trial registrationClinicalTrials.gov NCT00144339.Graphical abstract

Highlights

Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials
This analysis demonstrated the importance of using confirmed events in clinically important deterioration (CID) analysis and that CID predicts future outcomes. It confirmed that the components of this composite endpoint behaved differently based on the baseline forced expiratory volume in 1 s (FEV1) of the individual patient. These data suggest that sustained decline in trough FEV1, sustained deterioration in St. George’s Respiratory Questionnaire (SGRQ) score of ≥4 units and a moderate/severe exacerbation are appropriate components of a composite endpoint for the assessment of CID in Patients with both confirmed FEV1 decline and confirmed SGRQ deterioration, n (%) On same assessment
Unscheduled visits were excluded for this analysis FEV1 forced expiratory volume in 1 s, GOLD Global Initiative for Chronic Obstructive Lung Disease, SGRQ St

Summary

Introduction

Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting. Chronic obstructive pulmonary disease (COPD) is a chronic, progressive, heterogeneous disease. The manifestation of disease progression varies over time and between patients. Most clinical trials conducted in COPD typically focus on a single primary outcome such. The impact of interventions on disease progression has been measured by the annual rate of decline in FEV1 over several years [1]. Individuals with a slower rate of decline may dilute any observable treatment benefit in rapidly progressing subgroups. Individuals with a rapid decline may discontinue studies early, underestimating the true mean rate of decline in the control arm [2]

Methods

Results

Discussion

Conclusion