. 2018 Jun 1;31(3):121–138. doi: 10.1089/jamp.2017.1415

Table 3.

Overview of Clinical Trials Investigating Inhaled Antibiotic Therapy for Non-cystic Fibrosis Bronchiectasis

Study	Study design	No. of randomized patients	Intervention	Key outcome measures	Efficacy results	Safety results
Barker et al.⁽²⁰⁾	Two randomized, placebo-controlled, phase 3 trials	AIR-BX1: n = 266	Aztreonam for inhalation	Change in QOL-B respiratory symptom scores to week 4	No difference versus placebo across outcome measures	Treatment-related AEs were more common in the aztreonam group versus placebo
Barker et al.⁽²⁰⁾	Two randomized, placebo-controlled, phase 3 trials	AIR-BX2: n = 274	Aztreonam for inhalation	Change in QOL-B respiratory symptom scores to week 4	No difference versus placebo across outcome measures
Drobnic et al.⁽¹⁴¹⁾	Randomized, placebo-controlled, two-period, crossover trial	n = 30	Inhaled tobramycin BID in two cycles, each for 6 months	Number of exacerbations, number of hospital admissions and number of hospital admission days	No difference in number of exacerbations (p = 0.330); significant reduction in hospital admissions (p = 0.038) and days in hospital (p = 0.047) in treatment group	Inhaled tobramycin was associated with bronchospasm in 10% of patients
Wilson et al.⁽⁵³⁾ (Clinicaltrials.gov identifier: NCT00930982)	Randomized, placebo-controlled, phase 2 trial	n = 124	Ciprofloxacin DPI 32.5 mg or placebo BID 28 days on/28 days off	Effect on total bacterial density of predefined pathogens in sputum on day 28	Ciprofloxacin DPI resulted in a statistically significant reduction in total bacterial load on day 28 (p < 0.001)	No significant differences between the ciprofloxacin DPI and placebo arms; the incidence of bronchospasm was low
RESPIRE-1⁽¹³²⁾ (Clinicaltrials.gov identifier: NCT01764841)	Randomized (2:1), placebo-controlled, phase 3 trial	n = 416	Ciprofloxacin DPI 32.5 mg or placebo BID 28 days on/28 days off or 14 days on/14 days off over 48 weeks	Time to first pulmonary exacerbation versus pooled placebo and frequency of exacerbation versus matched placebo	Ciprofloxacin DPI significantly reduced number of exacerbations (p = 0.0005) and exacerbation frequency (p = 0.0061) versus placebo with the 14-day on/14-day off regimen. No significant changes versus placebo in exacerbations or exacerbation frequency were observed with the 28-day on/28-day off regimen	No difference in serious treatment-emergent AEs with the 14-day regimen (16.9%), the 28-day regimen (19.9%), or placebo (23.4%). Rates of discontinuation because of respiratory AEs were similar
RESPIRE-2⁽¹³³⁾ (Clinicaltrials.gov identifier: NCT02106832)	Randomized (2:1), placebo-controlled, phase 3 trial	n = 521	Ciprofloxacin DPI 32.5 mg BID 28 days on/28 days off or 14 days on/14 days off over 48 weeks	Time to first pulmonary exacerbation versus pooled placebo and frequency of exacerbation versus matched placebo	Ciprofloxacin DPI did not significantly prolong time to first exacerbation or reduce exacerbation frequency to predefined significance thresholds	Ciprofloxacin DPI was well tolerated in both regimens
ORBIT-1^(2,59) (Clinicaltrials.gov identifier: NCT00889967)	Randomized, placebo-controlled, double-blind trial	n = 96	Ciprofloxacin for inhalation (150 or 100 mg once daily) for one cycle of 28 days on and 28 days off	Mean change in Pseudomonas aeruginosa density in sputum (log₁₀) CFU/g of sputum from baseline to day 28	Significant mean decreases from baseline in P. aeruginosa CFU at day 28 after 150 mg dose of 3.5 log₁₀ (p < 0.001) and after 100 mg dose of 4.0 log₁₀ units (p < 0.001)	Treatment was well tolerated, with no statistically significant differences between active treatment and placebo groups in the number of patients experiencing ≥1 respiratory treatment-emergent event
Serisier et al.⁽¹³¹⁾ ORBIT-2	Randomized, placebo-controlled, phase 2 trial	n = 42	Dual-release liposomal ciprofloxacin for inhalation (150 mg) and free ciprofloxacin (60 mg) versus placebo 28 days on/28 days off in three cycles	Mean change in sputum P. aeruginosa density from baseline to day 28 (first treatment cycle)	At day 28, dual-release ciprofloxacin resulted in a reduction from baseline of mean (SD) −4.2 (3.7) log₁₀ CFU/g in sputum P. aeruginosa density versus a change from baseline of −0.08 (3.8) log₁₀ CFU/g in the placebo group (p = 0.002)	Incidence of systemic AEs similar between two arms; there were fewer pulmonary AEs in the ciprofloxacin arm versus Placebo
ORBIT-3/ORBIT-4^(134–136) (Clinicaltrials.gov identifier: NCT01515007, NCT02104245)	Randomized (2:1), placebo-controlled, phase 3 trials	Five hundred eighty-two patients were enrolled (ORBIT-3, n = 278; ORBIT-4, n = 304)	Dual-release ciprofloxacin for inhalation (ARD-3150; liposome-encapsulated ciprofloxacin [150 mg/3 mL] and free ciprofloxacin [60 mg/3 mL]) for 28 days on/28 days off for six cycles	Time to first pulmonary exacerbation, frequency of all and severe pulmonary exacerbations	ARD-3150 was associated with an increased median time to first exacerbation >2 months versus placebo; the result was significant for ORBIT-4, but not for ORBIT-3. Significant reductions in frequency of all and severe exacerbations were observed for ARD-3150 versus placebo in ORBIT-4, but not ORBIT-3. In the pooled analysis of the two trials, ARD-3150 led to a significant increase versus placebo in median time to first exacerbation that required antibiotics and a significant reduction in PE frequency; it also significantly reduced PA sputum density during each on-treatment period	Rates of TEAEs and serious TEAEs were similar in both treatment groups
Murray et al.⁽⁸⁸⁾	Randomized, controlled trial	Sixty-five patients with NCFBE and chronically infected sputum	Nebulized gentamicin 80 mg BID or placebo (0.9% saline) BID for 12 months	Sputum bacterial density reduction of at least 1 log unit, sputum purulence, exacerbation rate, time to first exacerbation	Baseline sputum bacterial density was 8.02 log₁₀ CFU/g. Gentamicin treatment significantly reduced sputum bacterial density to 2.96 log₁₀ CFU/g versus 7.67 log₁₀ CFU/g in the placebo group (p < 0.0001)	Gentamicin was well tolerated, 7 (22%) patients reported bronchospasm but 5 continued treatment with albuterol use as a bronchodilator. Only two patients withdrew owing to poor tolerability, the same as in the placebo arm
Murray et al.⁽⁸⁸⁾	Randomized, controlled trial				Gentamicin treatment reduced purulence, exacerbation rates, and increased time to first exacerbation. However, 3 months post-treatment, there was no difference between treatment and placebo groups in any of these parameters
Barker et al.⁽¹⁴²⁾	Randomized, placebo controlled trial	Randomized 74 patients with chronic P. aeruginosa colonization	Nebulized tobramycin 300 mg BID or placebo (quinine/saline) BID for 28 days	P. aeruginosa density in sputum, medical condition, and emergence of resistance	Tobramycin significantly reduced P. aeruginosa density by 4.54 log₁₀ CFU/g sputum compared with a mean increase of 0.02 log₁₀ CFU/g sputum in placebo patients (p < 0.01) Tobramycin improved medical condition at week 6. No significant increase in tobramycin resistance was observed	Tobramycin was associated with significantly increased dyspnea, chest pain, and wheezing compared with the placebo group
Haworth et al⁽⁷²⁾	Multicenter, randomized, controlled trial	Bronchiectasis patients with chronic P. aeruginosa infection (n = 144)	Nebulized colistimethate sodium 1,000,000 U BID or placebo (0.45% saline) BID for 6 months using an INeb device or until first exacerbation. Patients receiving oral macrolides at the start of the trial were continued on therapy	Time to first exacerbation, emergence of resistant organisms, P. aeruginosa CFUs	No significant difference between treatment and placebo in time to first exacerbation was observed (p = 0.11). Analysis of patients with ≥80% compliance showed that median time to first exacerbation was significantly increased; no emergence of resistant organisms. P. aeruginosa CFUs were reduced at weeks 4 and 12	Bronchoconstriction after the first dose in 7.5% of colistin patients versus 1.4% in patients receiving placebo. No significant difference in AEs (143 in 47 colistin patients versus 108 in 38 placebo patients, p = 0.25)

AE, adverse events; BID, twice a day; CFU, colony-forming units; DPI, dry powder for inhalation; EOT, end of treatment; NCFBE, non-cystic fibrosis bronchiectasis; PE, pulmonary exacerbation; QOL, quality of life; SD, standard deviation; TEAEs, treatment-emergent adverse events.