Heterogeneity of treatment response in bronchiectasis clinical trials

Introduction Recent randomised clinical trials (RCTs) in Bronchiectasis have failed to reach their primary endpoints, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QOL) and lung function are the most common endpoints evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis.

Methods We evaluated treatment response in 3 RCTs that evaluated mucoactive therapy (inhaled Mannitol), an oral anti-inflammatory/antibiotic (Azithromycin) and an inhaled antibiotic (Aztreonam). Treatment response was defined by absence of exacerbations during follow-up, an improvement of QOL above the minimum clinically important difference (MCID) and an improvement in FEV₁ of ≥100 mL from baseline.

Measurements and main results Cumulatively the three trials included 984 patients. Changes in FEV₁, QOL and exacerbations were heterogeneous in all trials analysed. Improvements in QOL were not correlated to changes in FEV₁ in the azithromycin and aztreonam trials (r=−0.17, p=0.1 and r=0.04, p=0.4) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QOL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV₁ is not a responsive measure in bronchiectasis.

Conclusions Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV₁ is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response suggesting the need to develop biomarkers to identify responders