Results from the RESPIRE trials fell short of expectations but even so offer hope for bronchiectasis, providing important lessons for future clinical trials and disease management, experts say.

The RESPIRE trials – together the largest clinical trial program ever conducted in bronchiectasis – evaluated 32.5 mg ciprofloxacin dry powder inhalation twice-daily as a treatment for non-cystic fibrosis bronchiectasis, but failed to meet all but one of the primary goals.

RESPIRE 1 included 416 patients from across Europe, North and South America, Australia and Japan and found a significant increase in time to first exacerbation and a reduced frequency of exacerbations in a 14-day on/off drug regimen but not in a 28-day on/off regimen over 48 weeks.

RESPIRE 2 involved 521 patients from Asia and Eastern Europe but did not show any statistically significant improvement in either endpoint.

Bronchiectasis not fully understood

In their editorial published in the European Respiratory Journal Professors Sanjay Chotirmall and James Chalmers say a clear challenge emerging from RESPIRE and other clinical trials in bronchiectasis is the vast ethnic, geographic and endophenotypic heterogeneity of the disease.

“This makes trials in bronchiectasis challenging to perform, analyse and report accurately,” they write.

“RESPIRE 2 is a strong case in point. Patients from different geographic regions behaved differently to what was expected with devastating consequences for the trial.”

Talking to the limbic James Chalmers, Professor of Respiratory Research at the University of Dundee, UK, said: “I think the results of RESPIRE 2 were particularly confusing, with a very low rate of exacerbations and conflicting data. This study was heavily focused in Eastern Europe and Asia where there are few studies on the characteristics, outcomes or treatment of bronchiectasis.

“I think we need to understand more clearly how different or similar patients in those regions are to the patients in Western Europe, Australia and the USA where most existing research into bronchiectasis has been conducted.”

Low exacerbation rate

 Another key limitation of the trials flagged by Professor Chalmers is that patients had fewer exacerbations than expected, even in the placebo arm. Up to 60% of patients in RESPIRE 1 and nearly 70% in RESPIRE 2 did not experience an exacerbation during the 12-month trial.

“This is surprising because patients had to have a history of two or more exacerbations per year coming into the trial,” he said.

“The reasons for this are unclear but could indicate underreporting of exacerbations during the trial or the inclusion of patients that were too ‘mild’. It is very tough to get a positive trial when the endpoint is exacerbations when few patients have exacerbations.”

 Impact on future trials

Professor Chalmers thinks the trials will have a huge impact on future bronchiectasis study design, and suggests future trials may wish to include a more homogenous population with an established standard of care and consider methods to enrich for more severe patients.

In the editorial, he and Professor Chotirmall write: “To avoid making mistakes of the past, we need novel approaches to ensure we identify the right group of patients, at the right time and use the right therapeutic.”

“Future clinical trials for bronchiectasis must consider patient stratification and selection more closely including potential delineation based on airway inflammation and/or specific components of the lung microbiome.”

Also, methods to reduce underreporting of exacerbations such as patient symptom diaries may be helpful.

 Benefit in selected patients

According to Professor Chalmers the RESPIRE trials have proved very helpful in understanding the role of inhaled antibiotics in bronchiectasis, with the main take away message being they work to reduce exacerbations but picking the right patients is essential.

“The inconsistent results suggest what many of us in recognise in clinical practice – that some patients respond really well to inhaled antibiotics but that some patients do not, and it’s hard to identify the responsive patients,” he said.

“The study suggests that in patients with frequent exacerbations who have airway infection it is reasonable to try an inhaled antibiotic because there is some evidence for a reduction in exacerbations, and some arms of the trials also suggested an improvement in health status using the St Georges Respiratory Questionnaire.”

For patients that are relatively mild and are not having frequent exacerbations, then the patients are unlikely to get a benefit from inhaled antibiotics and alternative therapies should be considered, he added.

Professor Chalmers suggests following the European Respiratory Society guidelines to use inhaled antibiotics in patients with airway infection and a history of three or more exacerbations per year.

He also notes that antibiotic resistance developed as result of ciprofloxacin treatment and so cautions that physicians using long term antibiotics need to be aware of this potential problem and use antibiotics judiciously.