Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: A post-hoc analysis of randomized clinical trials

Agnieszka Król, Robert Palmér, Virginie Rondeau, Stephen Rennard, Ulf G. Eriksson, Alexandra Jauhiainen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned. Methods: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data. Results: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms. Conclusions: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Original languageEnglish (US)
Article number158
JournalRespiratory Research
Volume21
Issue number1
DOIs
StatePublished - Jun 22 2020

Keywords

  • COPD
  • Dropouts
  • Early treatment discontinuations
  • Exacerbations
  • Joint frailty model
  • Recurrent events
  • Survival analysis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Fingerprint

Dive into the research topics of 'Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: A post-hoc analysis of randomized clinical trials'. Together they form a unique fingerprint.

Cite this