Abstract
In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow‐up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at‐risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at‐risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at‐risk period used. Our results showed that treatment efficacy is underestimated when the at‐risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at‐risk period, some modest savings in required sample size can be achieved. Using the proposed at‐risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol.
Highlights
Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disorder
We examine the reduction in sample size that can be made by using the more appropriate excluding recovery time (ERT) at‐risk definition over always at risk (AAR)
We further study the properties of the estimated confidence intervals to assess coverage, which is the proportion of simulations for which the true treatment effect lies within the 95% confidence interval from the simulation, and examine the power to show a statistically significant difference, given varying true differences
Summary
Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disorder. The length of the recovery period has previously been defined using a 3‐day moving average of a symptom score[3] or peak flow[4] or a combination of symptom‐free days and peak flow[5] returning to preexacerbation levels, or time until a number of symptom‐ free days have been reached.[6] it has been acknowledged that some recovery definitions can be problematic, with a number of episodes not returning to baseline levels,[7] and a maximum duration cut‐off or degree of expert judgment is sometimes required Within an episode it is entirely possible for symptom or lung function fluctuations to go beyond the threshold used to define the initial exacerbation event (ie, a worsening of symptoms), but these are generally not considered to indicate a new event. All results are discussed in the context of future clinical trial practice
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