Table 1.
Characteristics of main clinical trials on the clinical efficacy of inhaled ciprofloxacin in NCFB patients
| Study design | Patients and treatment | Endpoints | Outcomes | Treatment compliance |
|---|---|---|---|---|
| Phase II, randomized, double- blind, placebo-controlled, multicenter20 | 124 patients with NCFB and positive sputum culture for respiratory pathogens. Randomized to DPI ciprofloxacin (n=60) or placebo (n=64), administered twice daily for 28 days |
Change in sputum predefined potential respiratory pathogens’ bacterial density at Day 28 Time to first pulmonary exacerbation |
Bacterial density at Day 28 in the CFI group −3.62 log10 CFU⋅g−1 vs −0.27 log10 CFU⋅g−1, P<0.001 | >80% compliance was reached in 97% of subjects in the DPI ciprofloxacin group and 94% of subjects in the placebo group |
| ORBIT-2, Phase II, randomized, double-blind, placebo-controlled, multicenter23 | 42 adult bronchiectasis subjects with more than two exacerbations in the prior 12 months, with ciprofloxacin-sensitive P. aeruginosa at screening. Randomized to DPI ciprofloxacin (n=20) group or placebo group (n=22) in three treatment cycles of 28-days on/28-days off | Change in sputum P. aeruginosa bacterial density at Day 28 Time to first pulmonary exacerbation |
P. aeruginosa bacterial density at Day 28 in the CFI group −4.2 log10 CFU⋅g−1 vs −0.08 log10 CFU⋅g−1 in the placebo group, P=0.002. Time to first pulmonary exacerbation in the DPI group at 134 days vs 58 days in the placebo group, P=0.057 |
Compliance 65% in the DPI ciprofloxacin group vs 41% in the placebo group |
| ORBIT-3, Phase III, randomized, double-blind, placebo-controlled trial, multicenter24 Countries that enrolled at least 10% of overall patients were Australia (25.2%), the USA (18.7%), and Great Britain (10.8%) |
278 patients with NCFB and chronic P. aeruginosa lung infections Randomized to CFI group (n=183) or placebo group (n=95), in six treatment cycles of 28-days on/28-days off | Time to first pulmonary exacerbation Frequency of exacerbations by Week 48 | At least one pulmonary exacerbation by 48 weeks, 59% of patients in the CFI vs 57% in the placebo group, with a difference in median times of 78 days (median time to first exacerbation in the CFI group 214 days vs 136 days in the placebo group), HR 0.99, 95% CI 0.71–1.38, P=0.974 A 14.8% reduction in frequency of pulmonary exacerbations in the CFI group compared to the placebo group, 95% CI (−12.3 to 35.3), P>0.05 | Study drug discontinuation in the CFI group 13.1% vs 9.5% in the placebo group |
| ORBIT-4, Phase III, randomized, double-blind, placebo-controlled trial, multicenter24 Countries that enrolled at least 10% of overall patients were UK (14.1%) and the USA (11.8%). Australia enrolled 8.6% of patients |
304 patients with NCFB and chronic P. aeruginosa lung infections Randomized to CFI group (n=206) or placebo group (n=98), in six treatment cycles of 28-days on/28-days off | Time to first pulmonary exacerbation Frequency of exacerbations by Week 48 | At least one pulmonary exacerbation by 48 weeks, 55% of patients in the CFI group vs 65% in the placebo group, with a difference in median times of 72 days (median time to first exacerbation in the CFI group 230 days vs 158 days in the placebo group), HR 0.71, 95% CI 0.52–0.97, P=0.032 A 36.9% reduction in frequency of pulmonary exacerbations in the CFI group compared to the placebo group, 95% CI 17.9–51.5, P<0.001 |
Study drug discontinuation in the CFI group 4.9% vs 7.1% in the placebo group |
| RESPIRE-1 Phase III, randomized, double- blind, placebo-controlled, multicenter27 | 416 patients with NCFB (idiopathic or post-infectious etiology), with at least two exacerbations in the previous 12 months and a positive sputum culture at screening for at least one of seven pre-specified pathogens (P. aeruginosa, H. influenzae, M. catarrhalis, S. aureus, S. pneumoniae, S. maltophilia. or B. cepacia) Randomized to the 14-day on/off regimen (DPI ciprofloxacin group [n=137] and placebo group [n=68]) and the 28-day on/off regimen (DPI ciprofloxacin group [n=141] and placebo group [n=70]) |
Time to first exacerbation Frequency of exacerbations |
14-days on/off regimen Time to first exacerbation in the DPI ciprofloxacin group >336 days vs 186 days in the placebo group, HR 0.53, 97.5% CI 0.36–0.80, P=0.0005 Reduction of frequency of exacerbations in the DPI ciprofloxacin group by 39% over 48 weeks, compared to the placebo group (incidence rate ratio 0.61, 97.5% CI 0.40–0.91, P=0.0061) 28-day on/off regimen Prolongation of time to first exacerbation and reduction of exacerbation rate in the DPI ciprofloxacin group compared to the placebo group, but not statistically significant (HR 0.73, 97.5% CI 0.50–1.07, P=0.07 and HR 0.98, 97.5% CI 0.64–1.48, P=0.89, respectively) |
14-days on/off regimen • DPI ciprofloxacin group 94.4±8.4 days • Placebo group 91.8±10.3 days 28-days on/off regimen • DPI ciprofloxacin group 94.3±10.1 days • Placebo group 89.9±15.8 days |
| RESPIRE-2 Phase III, randomized, double- blind, placebo-controlled, multicenter31 | Patients with NCFB (idiopathic or post- infectious etiology), with at least two exacerbations in the previous 12 months and a positive sputum culture at screening for at least one of the seven pre-specified pathogens (P. aeruginosa, H. influenzae, M. catarrhalis, S. aureus, S. pneumoniae, S. maltophilia, or B. cepacia) Randomized to the 14-day on/off regimen (DPI ciprofloxacin group [n=176] and placebo group [n=88]) and the 28-day on/off regimen (DPI ciprofloxacin group [n=171] and placebo group [n=86]) |
Time to first exacerbation within 48 weeks after start of treatment (FDA) Frequency of exacerbations during the 48-week study (EMA) |
14-days on/off regimen Time to first exacerbation in the DPI ciprofloxacin vs placebo group, HR 0.87, 95% CI 0.62–1.21, P=0.39 28-days on/off regimen Time to first exacerbation in the DPI ciprofloxacin vs placebo group, HR 0.71, 99.9% CI 0.39–1.27, P=0.05 14-days on/off regimen Reduction of frequency of exacerbations in the DPI ciprofloxacin group by 17% over 48 weeks, (incidence rate ratio [IRR] 0.83, 95.1% CI 0.59–1.17, P=0.2862), (IRR 0.55, 99.9% CI 0.30–1.02, P=0.0014) 28-days on/off regimen Reduction of frequency of exacerbations in the DPI ciprofloxacin group by 45% over 48 weeks (IRR 0.55, 99.9% CI 0.30–1.02, P=0.0014) Number of exacerbations, 0.6±0.8 for ciprofloxacin DPI 14-days on/off compared with 0.7±1.0 in the matching placebo arm and 0.4±0.6 for ciprofloxacin DPI 28-days on/ off vs 0.7±1.1 in the matching placebo arm |
14-days on/off regimen • DPI ciprofloxacin group 96.2±8.2 days • Placebo group 96.2±9.9 days 28-days on/off regimen • DPI ciprofloxacin group 95.8±10.8 days • Placebo group 96.3±8.9 days |
Abbreviations: NCFB, non-cystic fibrosis bronchiectasis; CFI, liposomal, ciproxin for inhalation; CFU, colony forming unit; DPI, dry-powder for inhalation; FDA, US Food and Drug Administration; EMA, European Medicines Agency; P. aeruginosa, Pseudomonas aeruginosa; H. influenza, Haemophilus influenza; M. catarrhalis, Moraxella catarrhalis; S. aureus, Staphylococcus aureus; S. pneumonia, Streptococcus pneumonia; S. maltophilia, Stenotrophomonas maltophilia; B. cepacia, Burkholderia cepacia.