RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Discussion

RESPIRE is the largest placebo-controlled, double-blind phase III trial programme in NCFB and the first to show a significant benefit for long-term intermittent inhaled antibiotics in patients with NCFB. RESPIRE 1 is also the first to investigate the efficacy of both 14- and 28-day treatment cycles. Cycles of 28 days are conventionally used in CF treatment [10] and have previously been studied in NCFB, with limited success [11, 12]. The choice of 14 days on/off as a treatment regimen in the RESPIRE programme was guided by data from the phase II trial [8].

The ciprofloxacin DPI 14-day on/off arm resulted in statistically significant improvements in time to first exacerbation and frequency of exacerbations over 48 weeks. Subgroup analyses suggest that this regimen was effective in patients with a range of different baseline characteristics, including patients with or without a positive baseline P. aeruginosa culture and those with or without chronic concomitant macrolide use. However, it should be noted that subgroup analyses were exploratory in nature and the small size of subgroups limits definitive conclusions. Post hoc calculations of the number needed to treat determined that 4.5 patients would need to be treated with ciprofloxacin DPI 14 days on/off to prevent one exacerbation over 336 days. Several secondary end-points (EMA/others analysis) were also statistically significant for the 14-day on/off arm, including a significant improvement in respiratory symptoms as measured by the SGRQ symptoms component score, which is noteworthy given the high symptom burden in bronchiectasis [13].

The results observed for ciprofloxacin DPI 28 days on/off were supportive of the efficacy seen in the ciprofloxacin DPI 14-day on/off arm, but did not reach the pre-defined significance level.

The patient enrolment criteria were designed to minimise variability in outcomes due to disease aetiology (e.g. excluding those with immune-deficiency disorders, active or actively treated nontuberculous mycobacterial lung infection, or active allergic bronchopulmonary aspergillosis) and to enrich the population with patients who were most likely to experience bacterial exacerbations. However, the mean number of exacerbations during the study was lower than the number of exacerbations in the previous year (as reported for study enrolment). Participation in a clinical trial is known to influence participant behaviour [14], and perhaps patients became more adherent to physiotherapy and ancillary treatments, thereby reducing fluctuations in baseline symptoms and potentially the number of exacerbations during the study. Data on ancillary treatments and adherence to such therapies were not, however, collected during the study and so we are unable to confirm this hypothesis.

Ciprofloxacin DPI had a good safety profile and was well tolerated; >70% of patients completed treatment. Overall, treatment-emergent adverse event rates, including respiratory events, were generally low and comparable across treatment groups. No increased risk of serious systemic fluoroquinolone-associated events was observed. Potential systemic side-effects, such as nausea or headache, were infrequently reported (total 5.3% nausea and 7.0% headache) during this 48-week study, probably reflecting the low systemic concentrations associated with ciprofloxacin DPI treatment [15].

As increases in MICs are a potential drawback of any antibiotic therapy, changes in the MICs of the seven pre-defined pathogens were studied. Use of a long-term inhaled antibiotic in chronic infection is expected to increase antimicrobial resistance by selecting for bacteria with resistance genes. The use of systemic breakpoints with inhaled therapies is, however, problematic and they are unlikely to accurately apply to this treatment scenario as concentrations achieved in sputum greatly exceed calculated MICs [15, 16]. Nonetheless, based on systemic breakpoints, >20% of patients in each group had elevated MICs to ciprofloxacin at baseline, possibly reflecting the heavy burden of prior antibiotic use associated with frequent exacerbations in this patient population [17]. Subgroup analyses did not indicate reduced efficacy in patients who had baseline pathogens with MICs elevated above systemic breakpoints. Although >50% of ciprofloxacin DPI-treated patients had at least one isolate with an elevated MIC at any time-point during the study, this rate fell to <10% at EOS in patients who had susceptible pathogens at baseline (versus 2% in the placebo arm), which is similar to the resistance rate reported in a meta-analysis of inhaled antibiotic trials in patients with NCFB [18]. Increases in MIC may be offset by a net reduction in bacterial load and overall clinical benefits, including reduced exacerbations and therefore antibiotics. Additional studies will be required to monitor ciprofloxacin resistance during long-term use of ciprofloxacin DPI and to define relevant breakpoints for resistance to inhaled therapy.

We acknowledge the study has limitations. Varying definitions of exacerbation in clinical practice, a topic recently addressed by an expert panel [19], may have influenced patients’ eligibility for this trial. There is currently considerable heterogeneity in how exacerbations are defined [19] and so it is likely that determination of exacerbations in the previous year varied among centres. Related to this, the definition of exacerbation used to ascertain eligibility for the trial relied on clinical judgement rather than specific criteria and was therefore less rigorous than that used for the primary end-points. Taken together, these factors may all have contributed to the lower-than-expected number of on-trial exacerbations. On the basis of this experience, we encourage investigators of future trials to utilise a rigorous definition for exacerbations qualifying as entry criteria. The potential drawback of this approach, however, is a further reduction in trial enrolment in an already limited population.

An additional methodological limitation was that computed tomography scans were not centrally validated and variation among centres may have affected assessment of disease severity or led to overestimation of radiological findings versus inclusion criteria. Validated prognostic indices for evaluating NCFB severity had not been published when the study was designed [2, 20] and the data collected in this trial did not encompass the complete information required to calculate severity scores, including radiological severity. Accordingly, the impact of therapy across disease severity groups could not be determined. Future studies may benefit from targeting patient populations with higher risks of exacerbation. The role of severity assessment tools has yet to be defined in clinical trials. The most appropriate method to measure change in health-related quality of life, particularly in clinical trials with investigational drugs, is also uncertain. Although RESPIRE 1 included both the SGRQ and Quality of Life-Bronchiectasis measures, these are based on different recall periods and the optimal time-point(s) for data collection with long-term cyclical therapy is unclear.

Finally, the 2:1 randomisation of active:placebo, while attractive to patients due to its higher probability of active treatment, meant that the smaller placebo arms were more susceptible to variances, which could potentially influence the outcomes of analyses between ciprofloxacin DPI and matching placebo groups.

In conclusion, the RESPIRE 1 trial has shown that therapy with ciprofloxacin DPI reduces exacerbations in patients with NCFB with frequent exacerbations and pathogens present in sputum. Statistically significant improvements were seen with 14 days on/off treatment, while trends toward improvement were seen with 28 days on/off treatment. Treatment was well tolerated. Consistent with other studies of long-term antibiotic therapy, increased MICs were seen. Our findings suggest that long-term intermittent inhaled antibiotic therapy with ciprofloxacin DPI may provide therapeutic benefit in selected patients with NCFB.