Findings from the phase 3 ORBIT-4 trial show that inhaled liposomal ciprofloxacin (ARD-3150) is associated with a longer median time to first pulmonary exacerbation vs placebo in patients with non-cystic fibrosis bronchiectasis and chronic P aeruginosa lung infection requiring antibiotic therapy. Despite this finding, ARD-3150 had no such effect in the ORBIT-3 trial or in the pooled analysis of the ORBIT-3 and ORBIT-4 trials, according to a report published in Lancet Respiratory Medicine.
The ORBIT-3 (ClinicalTrials.gov Identifier: NCT01515007) and ORBIT-4 (ClinicalTrials.gov Identifier: NCT02104245) phase 3 trials were double-blind, placebo-controlled trials that ran concurrently. Patients included in each study had non-cystic fibrosis bronchiectasis, ≥2 pulmonary exacerbations managed with antibiotics in 12 months before enrollment, and a clinical history of chronic P aeruginosa lung infection. In ORBIT-3, 183 patients were randomly assigned to ARD-3150 and 95 were randomly assigned to placebo, and in ORBIT-4, 206 patients were allocated to ARD-3150 and 98 to placebo.
A pooled analysis of the 2 studies was performed, which included 389 patients in the ARD-3150 group and 193 patients in the placebo group. ARD-3150 consisted of 3 mL liposome encapsulated ciprofloxacin at 135 mg and 3 mL free ciprofloxacin at 54 mg vs placebo, which consisted of 3 mL dilute empty liposomes mixed with 3 mL saline. Treatment and placebo were self-administered once per day for six 56-day treatment cycles totaling 48 weeks. Time to first pulmonary exacerbation from randomization to the 48-week follow-up was the primary end point.
The median time to first pulmonary exacerbation in ORBIT-4 was significantly longer in the ARD-3150 group vs the placebo group (230 days and 158 days, respectively; difference, 72 days; hazard ratio [HR], 0.72; 95% CI, 0.53-0.97; P =.032). No significant difference was found between the ARD-3150 and placebo groups in the ORBIT-3 trial in terms of the median time to first pulmonary exacerbation (214 days vs 136 days, respectively; difference, 78 days; HR, 0.99; 95% CI, 0.71-1.38; P =.97). In addition, the pooled analysis of both trials found no difference between the study treatment and placebo in the median time to first pulmonary exacerbation (222 days vs 157 days; difference, 65 days; HR, 0.82; 95% CI, 0.65-1.02; P =.074).
The hypothesis-generating nature of the findings, as well as the inclusion of a relatively small number of participants in the final cohorts of each study, represent limitations of the overall analysis.
“Recognition that patients with frequent pulmonary exacerbations are more likely to benefit from long-term inhaled antibiotic treatment suggests that only evaluating the time to the first pulmonary exacerbation might not reveal the benefit of therapy in patients with frequent exacerbations,” the researchers wrote.
Disclosures: Multiple authors report financial relationships with pharmaceutical companies. For a full list of disclosures, please visit the reference.
Haworth CS, Bilton D, Chalmers JD, et al. Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials [published online January 15, 2019]. Lancet Respir Med. doi:10.1016/S2213-2600(18)30427-2