title: Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial.
abstract: Chronic 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.
  
  
  
  Retrospective 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.
  
  
  
  The 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.
  
  
  
  A 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.
  
  
  
  NCT00144339 .
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, 75 Francis Street, PBB Clinics 3, Boston, MA, 02115, USA. bcelli@partners.org.
authors.forename: Bartolomé R
authors.initials: BR
authors.lastname: Celli
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Decramer
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Liu
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Metzdorf
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
authors.forename: Guus M
authors.initials: GM
authors.lastname: Asijee
authors.affiliation: David Geffen School of Medicine UCLA, Los Angeles, CA, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Tashkin
mesh_terms: D000368:Aged; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018680:Cholinergic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D016017:Odds Ratio; D010352:Patient Dropouts; D061214:Patient Safety; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012307:Risk Factors; D018401:Sample Size; D013997:Time Factors; D000069447:Tiotropium Bromide / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D000069447:Tiotropium Bromide
keywords: COPD; Composite endpoint; Discontinuation; Exacerbation; Mortality; Outcomes; Safety