A Comparison of Study Designs of Inhaled Agents in Non-Cystic Fibrosis Bronchiectasis (NCFB): Key Differences in the Phase 3 RESPIRE Trials of Ciprofloxacin Dry Powder for Inhalation (DPI)

Abstract

SESSION TITLE: Asthma - Bronchiectasis Posters SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: Ciprofloxacin DPI is in development to reduce the frequency of acute exacerbations in patients with NCFB. We compared the study design of the two Ciprofloxacin DPI Phase 3 RESPIRE trials with other Phase 3 study designs from recent or ongoing NCFB trials of inhaled agents. METHODS: Study designs for the Phase 3 RESPIRE trials were obtained from Bayer internal protocols. Comparative Phase 3 study design elements for aztreonam for inhalation (Barker et al., Lancet Respir Med 2014), dual-release ciprofloxacin for inhalation (Clinicaltrials.gov and clinicaltrialsregister.eu), colistin (Haworth et al. AJRCC 2014), and mannitol (Bilton et al. Chest 2013; Bilton et al. Thorax 2014) were extracted from the published literature or online sources. RESULTS: NCFB trials of inhaled agents evaluate the common objective of reducing exacerbations, but study designs show substantial variations. In addition to differences in the agents and formulations/mode of delivery, there are key differences in study design elements among these trials, including entry criteria, pre-defined pathogens, and requirements for protocol-defined exacerbations. The RESPIRE entry criteria require a patient history of ≥2 prior exacerbations/yr and specific baseline pathogens (Pseudomonas aeruginosa or 6 other Gram-positive or Gram-negative respiratory pathogens). Protocol-defined exacerbations in RESPIRE require both initiation of systemic antibiotic therapy and a symptom duration of at least 2 days. Treatment regimens vary widely among NCFB studies, and treatment durations range from 12 to 52 weeks. RESPIRE is the first Phase 3 NCFB development program to test two different treatment cycles: 14 days on/14 days off therapy and 28 days on/28 days off over 48 weeks of treatment. Further, subjects in RESPIRE will be stratified by positive P. aeruginosa culture and chronic macrolide use. CONCLUSIONS: Key study design elements differ among Phase 3 clinical trials of inhaled agents in patients with NCFB. The RESPIRE trials features unique elements that will advance our understanding of NCFB treatment, including a rigorous definition of exacerbation, both 14- and 28-day treatment cycles, inclusion of patients with P. aeruginosa or other relevant pathogens, and stratification for chronic macrolide therapy. CLINICAL IMPLICATIONS: Comparing study design elements will lead to a better understanding of optimal NCFB trial design and improve identification of patients most likely to benefit from inhaled therapies. DISCLOSURE: Anthony De Soyza: Consultant fee, speaker bureau, advisory committee, etc.: Fees from Almirall, AstraZeneca, Bayer, Chiesi, Forest Laboratories, GSK, and Novartis, Grant monies (from industry related sources): AstraZeneca, Gilead, Bayer, Forest Laboratories, and Novartis Elisabeth Operschall: Employee: Nothing else to disclose Tiemo-Joerg Bandel: Employee: Nothing else to disclose Robert Wilson: Consultant fee, speaker bureau, advisory committee, etc.: Bayer for lectures and advisory board memberships The following authors have nothing to disclose: Timothy Aksamit Presentation will involve study designs of inhaled agents for non-cystic fibrosis bronchiectasis. Some of studies have already been published, some are unpublished and ongoing.