Trial Duration, Disease Severity Impact Discontinuation and COPD Exacerbation

An analysis of discontinuation in randomized controlled trials for chronic obstructive pulmonary disease (COPD) has determined the main factors causing patients to drop out of clinical trials. The results were published in the International Journal of COPD.

Researchers analyzed more than 2300 patients in 3 trials of 6- and 12-month duration comparing budesonide/formoterol and formoterol in moderate, severe, and very severe COPD. Typically, there is a high rate of discontinuation in randomized controlled trials for COPD, especially for patients with more severe disease.

“A particular problem arises when differential dropout between study arms occurs on top of evenly distributed random discontinuations,” the authors explained. “The net effect can lead to potential bias in favor of a weaker treatment, if the sicker people in that arm are lost during follow-up.”

They not only investigated the impact of disease severity and study duration on COPD exacerbations, but also sought to better understand the impact of premature discontinuations. One trial had been conducted in 237 sites in the United States, Europe, and Mexico. The second trial was conducted in 180 sites in the United States, Central and South America, and South Africa. The third trial was conducted at 194 sites in the United States, Czech Republic, the Netherlands, Poland, and South Africa.

The analysis found that exacerbation rates were higher with longer study duration and with formoterol more so than with budesonide/formoterol. With shorter study durations, there was a 40% to 47% reduction in the risk of first exacerbations between treatments.

Disease severity also influenced exacerbation outcomes. The severity of COPD had less of an impact in studies with shorter duration, but there was a significant difference in studies longer than 5 months. Treatment effect decreased from 41%-51% for shorter durations to just 29% for severe COPD and 22% for very severe COPD in studies that were 12 months long. Treatment difference in patients with moderate COPD was unaffected regardless of duration.

“Future studies of new agents designed to modify exacerbation outcomes in COPD may benefit from adopting a shorter focused design, which minimizes the effect of differential dropout, an approach already shown to be effective in clinical trials of COPD,” the authors concluded.