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

Abstract

Background 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. Methods A 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. Results The composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV 1 ) ≥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 FEV 1 (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. Conclusions Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials. Trial registration ClinicalTrials.gov NCT00144339 . Graphical abstract

Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD: a Post Hoc Analysis of the TONADO® Trials

“…This post hoc analysis of data from the two TONADO COPD trials further demonstrated that tiotropium/ olodaterol significantly reduces the risk of a CID versus tiotropium alone. The definition of CID assessed here has been described previously, and our findings are in line with recent studies by Singh et al [19], Anzueto et al [18] and Rabe et al [20], all of whom used the same CID composite endpoint. Singh et al [19] demonstrated that the risk of a first CID was reduced with LAMA/LABA (umeclidinium/vilanterol) versus monotherapy with either tiotropium, umeclidinium or vilanterol, or versus placebo in symptomatic patients with COPD.…”

“…Previous studies have demonstrated the suitability of various composite endpoints to predict long-term outcomes in patients with COPD [21][22][23][24], including for CID [18][19][20]. Given that COPD is a progressive disease, the use of CID as a composite endpoint provides a valuable measure to monitor patients who do not respond well to treatment but whose treatments may prevent deterioration or disease worsening-a major treatment goal for patients with COPD [3].…”

“…The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 report recommends LAMA or LABA monotherapy as initial pharmacological therapy for most patients [3]. Dual LAMA/LABA therapy is recommended for patients with COPD who remain symptomatic despite treatment with a single long-acting bronchodilator, or as initial therapy for patients who are highly symptomatic (COPD Assessment Test TM [CAT] [ 20) and classified as being in GOLD group D (at least two moderate exacerbations or at least one leading to hospitalisation, modified British Medical Research Council questionnaire [mMRC] grade C 2 and CAT C 10) or for patients in GOLD group B (at most one moderate exacerbation, mMRC grade C 2 and CAT C 10) with severe breathlessness [3]. The report does, however, acknowledge the lack of high-quality evidence to support initial pharmacological treatment strategies in patients with newly diagnosed COPD [3].…”

“…In COPD, a number of recent studies have explored the use of composite endpoints [18][19][20][21][22][23][24], several of which include components with MCIDs [18][19][20]. Clinically important deterioration (CID) is one such composite measure that has been used to assess COPD worsening.…”

One-year Clinically Important Deterioration and Long-Term Clinical Course in Japanese patients with COPD: A Multicenter Observational Cohort Study

“…A post-hoc analysis of the 3-year TORCH and ECLIPSE studies showed that patients with CID had an increased risk of all-cause mortality compared with patients without CID after a CID assessment at 6 and 12 months, respectively [8]. It was also reported that patients with CID within the rst 6 months of the UPLIFT study had worse outcomes for the remaining 42 months of the study [25]. However, the usefulness of CID in Japanese patients with COPD has not yet been clari ed.…”