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

Summary

Background

In patients with non-cystic fibrosis bronchiectasis, lung infection with Pseudomonas aeruginosa is associated with frequent pulmonary exacerbations and admission to hospital for treatment, reduced quality of life, and increased mortality. Although inhaled antibiotics are conditionally recommended for long-term management of non-cystic fibrosis bronchiectasis with frequent exacerbations, there is no approved therapy. We investigated the safety and efficacy of inhaled liposomal ciprofloxacin (ARD-3150) in two phase 3 trials.

Methods

ORBIT-3 and ORBIT-4 were international, randomised, double-blind, placebo-controlled, phase 3 trials run concurrently in similar geographical regions. Eligible patients had non-cystic fibrosis bronchiectasis, had had at least two pulmonary exacerbations treated with antibiotics in the previous 12 months, and had a history of chronic P aeruginosa lung infection. Patients were randomly assigned (2:1) to receive either ARD-3150 or placebo. ARD-3150 (3 mL liposome encapsulated ciprofloxacin 135 mg and 3 mL free ciprofloxacin 54 mg) or 6 mL placebo (3 mL dilute empty liposomes mixed with 3 mL of saline) was self-administered once daily for six 56-day treatment cycles, for 48 weeks. The primary endpoint was time to first pulmonary exacerbation from the date of randomisation to week 48. We did primary and secondary efficacy, safety, and microbiology analyses on the full analysis population, which comprised all randomised patients who received at least one dose of study drug. ORBIT-3 and ORBIT-4 are registered with ClinicalTrials.gov, numbers NCT01515007 and NCT02104245, respectively.

Findings

Between March 31, 2014, and Aug 19, 2015, we screened 514 patients in ORBIT-3 and 533 patients in ORBIT-4. The full analysis populations consisted of 278 patients in ORBIT-3 (183 patients received at least one dose of ARD-3150 and 95 received placebo) and 304 patients in ORBIT-4 (206 patients received at least one dose of ARD-3150 and 98 received placebo). In ORBIT-4, the median time to first pulmonary exacerbation was 230 days in the ARD-3150 group compared with 158 days in the placebo group, a statistically significant difference of 72 days (hazard ratio [HR] 0·72 [95% CI 0·53–0·97], p=0·032). In ORBIT-3, the median time to first pulmonary exacerbation was 214 days in the ARD-3150 group and 136 days in the placebo group, a non-statistically significant difference of 78 days (HR 0·99 [95% CI 0·71–1·38], p=0·97). In a pooled analysis of data from both ORBIT-3 and ORBIT-4, the median time to first pulmonary exacerbation was 222 days in the ARD-3150 group and 157 days in the placebo group, a non-statistically significant difference of 65 days (0·82 [0·65–1·02], p=0·074). The numbers of adverse events and serious adverse events were similar in both groups in ORBIT-3 and ORBIT-4.

Interpretation

In patients with non-cystic fibrosis bronchiectasis and chronic P aeruginosa lung infection requiring antibiotic therapy in the preceding year, ARD-3150 led to a significantly longer median time to first pulmonary exacerbation compared with placebo in ORBIT-4, but not in ORBIT-3 or the pooled analysis. Inconsistency between the trials suggests further research is needed into the heterogeneity of non-cystic fibrosis bronchiectasis and optimal outcome measures for inhaled antibiotics.

Funding

Aradigm Corporation.

Introduction

Non-cystic fibrosis bronchiectasis is a chronic lung disease characterised by recurrent infection, inflammation, persistent cough, and production of sputum,1, 2 and its prevalence is increasing worldwide.3, 4, 5

Bacteria commonly isolated from the sputum of patients with bronchiectasis include Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and non-tuberculous mycobacteria.2, 6 Chronic P aeruginosa infection in patients with non-cystic fibrosis bronchiectasis is of particular concern because it is associated with more severe disease, characterised by frequent exacerbations, hospital admissions, reduced quality of life, and increased mortality.7, 8

Research in context

Evidence before this study

We did a literature search using PubMed with no start or end date without limitations, and using the search terms “non-cf bronchiectasis”, “noncystic fibrosis bronchiectasis”, “non cystic fibrosis bronchiectasis”, “dry powder”, “liposome”, “ciprofloxacin”, and “bronchiectasis” to assess all clinical studies that evaluated the use of inhaled antibiotics in the treatment of adult patients with non-cystic fibrosis bronchiectasis before a meeting in February, 2011, with the US Food and Drug Administration to discuss the design of the ORBIT phase 3 trials. We limited our search to studies published in English. Although at that time there were no large, well-controlled trials and no approved therapies of inhaled antibiotics for non-cystic fibrosis bronchiectasis, inhaled antibiotics were anticipated to be effective on the basis of trials in cystic fibrosis. With no established outcome measures, the phase 3 trial design was informed by the results of a phase 2, randomised, double-blind, placebo-controlled trial of once-daily, inhaled antibiotic composed of liposome-encapsulated ciprofloxacin and free ciprofloxacin (ARD-3150) in 42 adults with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa. In this phase 2 study, ARD-3150 significantly reduced P aeruginosa sputum density, significantly delayed time to first pulmonary exacerbation in the population adhering to the protocol, and was well tolerated.

Added value of this study

In patients with non-cystic fibrosis bronchiectasis and chronic lung infection with P aeruginosa who had at least two pulmonary exacerbations requiring antibiotics in the preceding year, ARD-3150 significantly prolonged the time to first exacerbation in ORBIT-4 but there was no difference in time to first exacerbation in the identically designed ORBIT-3 or the pooled analysis. ARD-3150 caused a reduction in the frequency of pulmonary exacerbations over a period of 48 weeks, with pooled data from both studies showing clinically meaningful reductions in all exacerbations, exacerbations requiring antibiotic therapy, and severe exacerbations requiring intravenous antibiotic therapy or admission to hospital for treatment. Both phase 3 trials showed substantial antimicrobial activity of once-daily ARD-3150 against P aeruginosa in airways, with a safety and tolerability profile similar to placebo. The results of ORBIT-3 and ORBIT-4 provide added value to the existing literature by supporting the use of inhaled antibiotics in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with P aeruginosa and frequent exacerbations. Both trials were the first to focus on patients with non-cystic fibrosis bronchiectasis with chronic P aeruginosa infection, which is known to be associated with higher morbidity and mortality, and lower quality of life.

Implications of all the available evidence

Although there is no inhaled antibiotic approved for non-cystic fibrosis bronchiectasis, such drugs are conditionally recommended with a moderate amount of evidence to support safety and efficacy in the recent European Respiratory Society guidelines for the management of adult bronchiectasis for long-term treatment in patients with non-cystic fibrosis bronchiectasis who have at least three pulmonary exacerbations per year and chronic lung infections with P aeruginosa. Our results suggest that patients with frequent pulmonary exacerbations are more likely to benefit from long-term inhaled antibiotic treatment, which has implications for patient selection in clinical practice and for future clinical trials of inhaled antibiotics in non-cystic fibrosis bronchiectasis.

Inhaled antibiotics have the potential to produce higher concentrations in the airways and lower systemic concentrations than with intravenous or oral antibiotics, with potentially fewer systemic adverse effects.2, 6, 9, 10, 11 Several inhaled antibiotics have been approved for the treatment of cystic fibrosis; however, local intolerability (occurrence of respiratory side-effects, such as coughing or bronchospasm, because of irritation of the respiratory tract by the inhaled medication) and safety issues or inadequate clinical benefits have restricted the availability of such medications for non-cystic fibrosis bronchiectasis,12, 13 and there is no inhaled antibiotic approved for this disease. Nevertheless, inhaled antibiotics are conditionally recommended in the 2017 European Respiratory Society guidelines for the management of acute bronchiectasis for off-label use for long-term treatment in patients with non-cystic fibrosis bronchiectasis who have at least three pulmonary exacerbations per year and chronic lung infections with P aeruginosa because of a moderate amount of supportive clinical data.¹⁴

ARD-3150 is a once-daily inhaled antibiotic composed of liposome-encapsulated ciprofloxacin and free ciprofloxacin. This drug was designed to overcome the potential intolerance issues associated with some inhaled antibiotics in non-cystic fibrosis bronchiectasis,12, 13, 15, 16, 17, 18, 19 and to maximise the antipseudomonal activity of ciprofloxacin in the airways by providing a high peak concentration from the free ciprofloxacin component, followed by a slower release of liposomal ciprofloxacin in the airways.²⁰ The use of biocompatible components in the liposomes reduces the potential for local side-effects, thereby limiting airway irritation.20, 21

Thus, the rationale for the development of ARD-3150 was that reduction of the burden of infection with P aeruginosa, achieved with a well-tolerated, potent antipseudomonal therapy, would delay onset and reduce the number of pulmonary exacerbations. We did two identical phase 3 trials in patients with non-cystic fibrosis bronchiectasis and chronic P aeruginosa lung infection to investigate the efficacy and safety of once-daily ARD-3150.