Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial

Abstract

BackgroundChronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials.MethodsRetrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments.ResultsThe CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies.ConclusionsA composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo.Trial registrationNCT00144339.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0361-4) contains supplementary material, which is available to authorized users.

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

“…Composite endpoints have only recently been introduced in post hoc analyses of COPD clinical trials [ 3 – 6 , 16 ]. Here, we conducted a post hoc analysis of the UPLIFT study.…”

The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD

“…They hypothesized that this composite endpoint would be better able to predict COPD-related hospitalization and mortality than its individual components or the customary endpoint of FEV 1 measurements alone 16. Since then, several other COPD indices have been described, which predict not only survival but disease-related hospitalization or exacerbations, disease severity, and even positive outcomes in clinical trials 17–19. What distinguishes the composite endpoint of CID from these indices is that it can be used to compare different active treatments since it measures the relative deterioration in disease following an intervention, and as such could have utility in clinical trials as a means of monitoring disease worsening.…”

Prediction of severe exacerbations and mortality in COPD: the role of exacerbation history and inspiratory capacity/total lung capacity ratio

“…If only the GOLD D group (half of patients in the sample) was analyzed, FEV 1 was the only predictor of cumulative 5-year combined risk of hospital admission or death. The suggestion that these patients can be extremely important in the management of COPD is somehow implicit in the recent GOLD 2017 revision (even though FEV 1 is no longer included in the classification), 5 in a recent proposal of the CERO index by Celli et al 38 (a composite index of major outcomes using admissions and mortality, to use in clinical studies, as was our case), and also in the recent Spanish GesEPOC guidelines, 2017 revision 39 that considers that these patients, GOLD D, are high risk patients. It is our opinion that the lack of prediction of exacerbations and IC/TLC in the separate multivariate analysis of the GOLD D group may be related to the small number of patients.…”