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 (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.

Conclusions: Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials.

Trial registration: ClinicalTrials.gov NCT00144339 .

Keywords: Exacerbations; Lung function; Tiotropium.

Conflict of interest statement

K.F.R. reports personal fees from Boehringer Ingelheim, AstraZeneca, Novartis and Chiesi, and grants from Boehringer Ingelheim, AstraZeneca and Takeda, outside the submitted work. D.M.G.H. reports personal fees from AstraZeneca, Chiesi and Pfizer, and grants and personal fees from Boehringer Ingelheim, GlaxoSmithKline and Novartis, outside the submitted work.

M.M. reports speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, and consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols and research grants from GlaxoSmithKline and Grifols.

M.K.H. reports consultancy fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca and Mylan, speaker fees from Boehringer Ingelheim, and research support from Novartis Sunovion, outside the submitted work. F.J.M. reports grants from NHLBI during the conduct of the study, grants from the National Institutes of Health, personal fees from Continuing Education, Forest Laboratories, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon Therapeutics (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, the Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, the National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, the Western Society of Allergy and Immunology, ProterixBio (formerly Bioscale), Unity Biotechnology, Concert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd., WebMD, PeerView Network, the California Society of Allergy and Immunology, Chiesi and the Puerto Rico Thoracic Society, and advisory board participation for Janssen, outside the submitted work. D.S. reports personal fees from Apellis, Cipla, Genentech, Peptinnovate and Skyepharma, and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Theravance and Verona, outside the submitted work. L.G. was an employee of Boehringer Ingelheim at the time of the study and is now employed by CSL Behring. F.V. is an employee of Boehringer Ingelheim.

Figures

Fig. 1

Kaplan–Meier estimates for the time to CID in the overall population and GOLD subgroups. Kaplan–Meier estimates of time to first event, two of three events, or three of three events of the components of the composite endpoint (trough FEV1 decline ≥100 mL, SGRQ score deterioration ≥4 units, or moderate/severe exacerbation) in (a) the overall population, (b) GOLD 2 patients, (c) GOLD 3 patients, and (d) GOLD 4 patients. - indicates either that this value could not be assessed (median was not estimable) or is not applicable (HR only displayed for time to event analysis). CI: confidence interval; FEV1: forced expiratory volume in 1 s; GOLD: Global Initiative for Chronic Obstructive Lung Disease; HR: hazard ratio; SGRQ: St. George’s Respiratory Questionnaire

Fig. 2

Kaplan–Meier estimates of time to first subsequent SGRQ deterioration or first subsequent FEV1 deterioration. Kaplan–Meier estimates of median time from FEV1 decline ≥100 mL to SGRQ score deterioration ≥4 units, and median time from SGRQ score deterioration ≥4 units to FEV1 decline ≥100 mL in the overall population. CI: confidence interval; FEV1: forced expiratory volume in 1 s; NE: not evaluable; SGRQ: St. George’s Respiratory Questionnaire