RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Discussion

The RESPIRE 2 trial constitutes the second trial in the RESPIRE programme. RESPIRE 1 demonstrated a significant treatment effect for the ciprofloxacin DPI 14-day on/off treatment regimen and a trend towards improved outcomes in the ciprofloxacin DPI 28-day on/off arm [8]. In RESPIRE 2, end-points favoured ciprofloxacin DPI over placebo, but the positive efficacy signals did not translate into statistical significance for either active treatment arm. The observed positive trends in RESPIRE 2 were generally more pronounced in the ciprofloxacin DPI 28-day on/off arm than in the 14-day on/off arm. However, due to the pre-specified significance level of 0.001 for the ciprofloxacin DPI 28-day on/off arm, differences from placebo did not achieve statistical significance.

Exacerbation rates in RESPIRE 2 were much lower than expected and lower than those observed in RESPIRE 1. In RESPIRE 2, 62.2% of patients did not experience an exacerbation according to the primary definition (defined by three signs or symptoms), which was notably higher than the 52% of patients in RESPIRE 1 with no exacerbations [8]. As the study entry criteria were chosen to enrich the population of “frequent exacerbators”, requiring two or more documented exacerbations in the previous year, the low exacerbation rates that occurred during the trial were unexpected. For both trials, a stringent definition of exacerbation was used for primary end-point evaluations [9]. This definition was not, however, applied for the entry criteria. As each patient experiences their disease differently [10] and as patients are often educated to take antibiotic treatment when symptoms increase, it is likely that the prior exacerbations did not meet the stringent definition used during the trial. A proposed standardised definition of an exacerbation has recently been published [11]; this may be of benefit in future clinical trials to reduce heterogeneity.

Understanding the low exacerbation rates observed in both active and placebo arms of RESPIRE 2, and the differences in exacerbation rates between RESPIRE 1 and 2, requires examination of a number of factors, including patient characteristics and geography. Baseline demographics varied somewhat between RESPIRE 1 and RESPIRE 2, despite their identical inclusion and exclusion criteria. As patient phenotype is known to affect prognosis [10], it is possible that the differing patient profiles led to different clinical outcomes. Patients in RESPIRE 2 were generally younger (mean age 60.1 versus 64.7 years) and more likely to have had only two exacerbations in the last year (78% versus 55%) than patients in RESPIRE 1 [8]; two episodes was the minimum frequency of exacerbations required to enter the study. RESPIRE 2 patients had poorer lung function as indicated by the proportion of patients with FEV₁ % pred <50% (41.8% versus 30.0%) and more respiratory symptoms as assessed by the St George's Respiratory Questionnaire symptoms component score (mean 61.0 versus 56.8) [8].

Although a primary diagnosis of COPD was an exclusion criterion, 28% of patients in RESPIRE 2 had a history of COPD versus 16% in RESPIRE 1, suggesting that more patients in RESPIRE 2 had an overlapping diagnosis of bronchiectasis/COPD. This is supported by the greater theophylline use in RESPIRE 2 (8.1%) versus RESPIRE 1 (2.2%). The precise nature of the relationship between COPD and bronchiectasis remains to be established. Optimal treatment of these patients is poorly understood and may differ from therapies recommended for either condition alone [12]. Excluding patients with an overlapping bronchiectasis/COPD diagnosis may result in more homogeneous NCFB patient populations in clinical trials. Patients in RESPIRE 2 had indicators of more severe airflow obstruction, but bronchiectasis severity could not be fully evaluated because computed tomography scans were not assessed at baseline. Not all parameters included in bronchiectasis severity indices were collected at baseline, as details for these had not been published when the RESPIRE studies were being designed [7, 13].

RESPIRE 1 and 2 also differed in the geographical regions that were represented, with RESPIRE 2 enrolling more patients from Asia and Eastern Europe. The variability in clinical practice could have potentially impacted the determination of exacerbations and treatment prior to enrolment. Specialist care for individuals with bronchiectasis is well developed, and research interest is relatively intense in Western Europe, the USA and Australia, which has led to the development of treatment guidelines and national standards [14–16]. European guidelines have only recently been published [17] and similar initiatives have been less common in other areas of the world [1]. This may have led to different disease management practices prior to enrolment. For example, patients in RESPIRE 2 were less likely to be treated with standard respiratory medications (67.9% versus 80.5%) or long-term macrolide treatment (7.7% versus 15.9%) than those in RESPIRE 1 [8]. This might reflect individual country practices or could be explained by different patient phenotypes. Reducing the heterogeneity of patient populations, in terms of phenotypic differences and standards of care prior to enrolment, is an important consideration for future trials.

Any comparison of the outcomes of RESPIRE 1 and 2 should take into consideration the change in extrapolation method and significance levels. Based on experience gained in RESPIRE 1, significance levels were amended by the sponsor with agreement from regulatory authorities to maximise the likelihood of achieving a significant result in the ciprofloxacin DPI 14-day on/off arm. If the α adjustment applied in RESPIRE 1 (p=0.025) had been used in RESPIRE 2, the ciprofloxacin DPI 28-day on/off arm would have met the primary end-point for the EMA/others analysis of frequency of exacerbations (IRR 0.55, 99.9% CI 0.30–1.02; p=0.0014). The FDA primary end-point, however, would not have been statistically significant nor would results in the ciprofloxacin DPI 14-day on/off arm have been affected.

As observed in RESPIRE 1, ciprofloxacin DPI was well tolerated. The number of study-drug-related treatment-emergent adverse events was markedly lower in RESPIRE 2 than RESPIRE 1 (13.7% versus 25.1%) [8]. Differences were largely due to lower numbers of respiratory treatment-emergent adverse events; contributory factors may include a lower rate of exacerbations in RESPIRE 2 or a higher threshold for diagnosis of these adverse events in centres involved in RESPIRE 2 versus RESPIRE 1. Trial discontinuation rates were low (5% due to treatment-emergent adverse events) and comparable across treatment arms. Together with data from RESPIRE 1, these findings support a favourable safety profile for ciprofloxacin DPI.

The limitations of the RESPIRE programme study design have been discussed previously [8]. RESPIRE 2 additionally highlighted the impact of low exacerbation rates on efficacy outcomes. Future NCFB trials should consider using a more stringent definition for prior exacerbations as an inclusion criterion and collecting data needed to calculate bronchiectasis severity based on published severity assessment tools [7, 13].

In conclusion, despite efficacy signals showing trends towards clinical benefits and excellent tolerability in the RESPIRE 2 study, neither the 14- or 28-day on/off ciprofloxacin DPI arms met the primary end-points of increasing time to first exacerbation or reducing frequency of exacerbations. The RESPIRE clinical trial programme thus encapsulates both the promise and difficulties of documenting a statistically significant impact on exacerbations in NCFB patients, and substantially contributes to the body of knowledge on the optimal design of clinical trials.