Ciprofloxacin Dry Powder for Inhalation (ciprofloxacin DPI): Technical design and features of an efficient drug-device combination.

Bronchiectasis is a chronic respiratory disease with heterogeneous etiology, characterized by a cycle of bacterial infection and inflammation, resulting in increasing airway damage. Exacerbations are an important cause of morbidity and are strongly associated with disease progression. Many patients with bronchiectasis suffer from two or more exacerbations per year. However, there are no approved therapies to reduce or delay exacerbations in this patient population. Ciprofloxacin DPI is in development as a long-term, intermittent therapy to reduce exacerbations in patients with non-cystic fibrosis (CF) bronchiectasis and evidence of respiratory pathogens. Ciprofloxacin DPI combines drug substance, dry powder manufacturing technology, and an efficient, pocket-sized, dry powder inhaler to deliver an effective antibiotic directly to the site of infection, with minimal systemic exposure and treatment burden. Here we review the drug substance and particle engineering (PulmoSphere™) technology used, and key physical properties of Ciprofloxacin Inhalation Powder, including deposition, delivered dose uniformity, consistency, and stability. Design features of the T-326 Inhaler are described in relation to lung targeting, safety and tolerability of inhalation powders, as well as treatment burden and adherence. If approved, Ciprofloxacin DPI may provide a valuable treatment option for those with frequent exacerbations and respiratory pathogens.

Characterization of the "Frequent Exacerbator Phenotype" in Bronchiectasis.

RATIONALE: Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described. OBJECTIVES: To establish if there is a "frequent exacerbator phenotype" in bronchiectasis and the impact of exacerbations on long-term clinical outcomes. METHODS: We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality. MEASUREMENTS AND MAIN RESULTS: A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype. The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P < 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P < 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P < 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV1, radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during follow-up. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency. CONCLUSIONS: The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up.

RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.

We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and pre-defined bacteria in sputum.In this phase III, double-blind, placebo-controlled trial, patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in two treatment regimens consisting of on/off treatment cycles of 14 or 28 days for 48 weeks. The primary end-points were time to first exacerbation and frequency of exacerbations.A total of 416 patients were randomised to the 14-day on/off regimen (ciprofloxacin DPI (n=137) and placebo (n=68)) or the 28-day on/off regimen (ciprofloxacin DPI (n=141) and placebo (n=70)). Ciprofloxacin DPI 14 days on/off significantly prolonged time to first exacerbation versus pooled placebo (median time >336 versus 186 days; hazard ratio 0.53, 97.5% CI 0.36-0.80; p=0.0005) and reduced the frequency of exacerbations compared with matching placebo by 39% (mean number of exacerbations 0.6 versus 1.0; incidence rate ratio 0.61, 97.5% CI 0.40-0.91; p=0.0061). Outcomes for ciprofloxacin DPI 28 days on/off were not statistically significantly different from placebo. The safety profile of ciprofloxacin DPI was favourable.Ciprofloxacin DPI was well tolerated and has the potential to be an effective treatment option in non-cystic fibrosis bronchiectasis.

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

We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and predefined sputum bacteria.Patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in 14- or 28-day on/off treatment cycles for 48 weeks. Primary end-points were time to first exacerbation and frequency of exacerbations. Enrolling countries and α level split (0.049 and 0.001 for 14- and 28-day cycles, respectively) differed from RESPIRE 1.Patients were randomised to ciprofloxacin DPI (14 days on/off (n=176) or 28 days on/off (n=171)) or placebo (14 days on/off (n=88) or 28 days on/off (n=86)). The exacerbation rate was low across treatment arms (mean±sd 0.6±0.9). Active treatment showed trends to prolonged time to first exacerbation (ciprofloxacin DPI 14 days on/off: hazard ratio 0.87, 95.1% CI 0.62-1.21; p=0.3965; ciprofloxacin DPI 28 days on/off: hazard ratio 0.71, 99.9% CI 0.39-1.27; p=0.0511) and reduced frequency of exacerbations (ciprofloxacin DPI 14 days on/off: incidence rate ratio 0.83, 95.1% CI 0.59-1.17; p=0.2862; ciprofloxacin DPI 28 days on/off: incidence rate ratio 0.55, 99.9% CI 0.30-1.02; p=0.0014), although neither achieved statistical significance. Ciprofloxacin DPI was well tolerated.Trends towards clinical benefit were seen with ciprofloxacin DPI, but primary end-points were not met.

The RESPIRE trials: Two phase III, randomized, multicentre, placebo-controlled trials of Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) in non-cystic fibrosis bronchiectasis.

The primary goals of long-term disease management in non-cystic fibrosis bronchiectasis (NCFB) are to reduce the number of exacerbations, and improve quality of life. However, currently no therapies are licensed for this. Ciprofloxacin Dry Powder for Inhalation (Ciprofloxacin DPI) has potential to be the first long-term intermittent therapy approved to reduce exacerbations in NCFB patients. The RESPIRE programme consists of two international phase III prospective, parallel-group, randomized, double-blinded, multicentre, placebo-controlled trials of the same design. Adult patients with idiopathic or post-infectious NCFB, a history of ≥2 exacerbations in the previous 12months, and positive sputum culture for one of seven pre-specified pathogens, undergo stratified randomization 2:1 to receive twice-daily Ciprofloxacin DPI 32.5mg or placebo using a pocket-sized inhaler in one of two regimens: 28days on/off treatment or 14days on/off treatment. The treatment period is 48weeks plus an 8-week follow-up after the last dose. The primary efficacy endpoints are time to first exacerbation after treatment initiation and frequency of exacerbations using a stringent definition of exacerbation. Secondary endpoints, including frequency of events using different exacerbation definitions, microbiology, quality of life and lung function will also be evaluated. The RESPIRE trials will determine the efficacy and safety of Ciprofloxacin DPI. The strict entry criteria and stratified randomization, the inclusion of two treatment regimens and a stringent definition of exacerbation should clarify the patient population best positioned to benefit from long-term inhaled antibiotic therapy. Additionally RESPIRE will increase understanding of NCFB treatment and could lead to an important new therapy for sufferers. TRIAL REGISTRATION: The RESPIRE trials are registered in ClinicalTrials.gov, ID number NCT01764841 (RESPIRE 1; date of registration January 8, 2013) and NCT02106832 (RESPIRE 2; date of registration April 4, 2014).

Ciprofloxacin DPI: a randomised, placebo-controlled, phase IIb efficacy and safety study on cystic fibrosis.

BACKGROUND: Treatment of infective bronchitis involving Pseudomonas aeruginosa is a cornerstone of care in patients with cystic fibrosis (CF). This phase IIb, randomised, double-blind, placebo-controlled study assessed the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in this population. METHODS: Patients with CF, ≥12 years of age (N=286), were randomised to ciprofloxacin DPI (32.5 mg (n=93) or 48.75 mg (n=93)), or corresponding placebo (32.5 mg, n=65; 48.75 mg, n=35) twice daily for 28 days. The primary objective was the change in forced expiratory volume in 1 s (FEV1) from baseline (day 0) to end of treatment (day 29) in the intent-to-treat population for ciprofloxacin DPI compared with the corresponding placebo group. RESULTS: The primary effectiveness objective was not met; there were no significant differences in change in FEV1 between ciprofloxacin DPI and the corresponding placebo group for either dose (p=0.154). However, in pooled analyses, FEV1 decline from baseline to treatment end was significantly lower with ciprofloxacin DPI than with placebo (pooled data; p=0.02). Ciprofloxacin DPI showed positive effects on sputum bacterial load and quality of life, but these effects were not maintained at the 4-week follow-up. Ciprofloxacin DPI was well tolerated and there were no significant differences in type/incidence of treatment-emergent adverse events by treatment group (p=0.115). CONCLUSIONS: Further investigations are needed to determine the full scope of the beneficial effects of ciprofloxacin DPI for patients with CF. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00645788; EudraCT 2008-008314-40.

Economic burden of non-cystic fibrosis bronchiectasis in the first year after diagnosis from a US health plan perspective.

BACKGROUND: Recent estimates suggest the prevalence of non-cystic fibrosis bronchiectasis (NCFB) may be increasing in the US. The objective of this study was to determine the current economic burden of NCFB compared with non-NCFB controls in the first year after diagnosis within a commercially enrolled US population. METHODS: A retrospective matched cross-sectional case control (1:3) study design was used. Data were derived from MarketScan(®) Commercial Claims and Encounters Database, which captures all patient-level demographic data and all medical and pharmacy claims during the period 1 January 2005 to 31 December 2009. NCFB patients were identified using ICD-9 codes 494.0 and 494.1. Individuals with medical claims for cystic fibrosis or chronic obstructive pulmonary disease were excluded. Incremental burden of NCFB was estimated for overall and respiratory-related expenditures using multivariate regression models which adjusted for baseline characteristics and healthcare resource utilization. All demographic characteristics and economic outcomes were ascertained in 12 months before (baseline period) and 12 months after (follow-up) index event, which was defined as the first bronchiectasis-related medical event. Non-parametric bootstrap technique was used to calculate the 95 % confidence limits for the adjusted estimate. All costs are inflation-adjusted to a baseline year of 2009 using the consumer price index. All statistical tests were conducted using SAS 9.2 and STATA 12.0. RESULTS: The study sample used for healthcare burden analyses had 9,146 cases and 27,438 matched controls. The majority of the sample was between the ages of 45-64 years old and 64 % were female. A greater proportion of cases than controls had an increase from baseline to follow-up in both total (49 vs 40 %) and respiratory-related costs (57 vs 25 %). The average increase in overall and respiratory-related costs compared with controls after adjusting for differences in baseline characteristics was US$2,319 (95 % CI 1,872-2,765) and US$1,607 (95 % CI 1,406-1,809), respectively. The primary driver for this increment was increase in outpatient visits of approximately 2 overall and 1.6 respiratory-related visits per patient per year, which translated to US$1,730 (95 % CI 1,332-2,127) and US$1,253 (95 % CI 1,097-1,408), respectively. CONCLUSION: This study found that the cost of managing NCFB in the first year within a commercially enrolled population may be burdensome. Compared with previously published estimates in the literature, the burden of NCFB may be also increasing.