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Efficacy and Safety of Inhaled Colistimethate Sodium in Patients With Bronchiectasis and Pseudomonas aeruginosa Infection
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb.
METHODS
Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed.
FINDINGS
377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment.
INTERPRETATION
The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated.
FUNDING
Zambon.
Additional Info
Disclosure statements are available on the authors' profiles:
Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months
Lancet Respir Med 2024 Sep 06;[EPub Ahead of Print], CS Haworth, M Shteinberg, K Winthrop, A Barker, F Blasi, K Dimakou, LC Morgan, AE O'Donnell, FC Ringshausen, O Sibila, RM Thomson, KJ Carroll, F Pontenani, P Castellani, JD ChalmersFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Patients with bronchiectasis are prone to developing chronic airways infections, which can commonly include infections with Haemophilus influenzae, Pseudomonas aeruginosa, and non-tuberculous mycobacteria (NTM). P aeruginosa has been linked to increased airway inflammation, decreased lung function, increased exacerbation frequency, decreased quality of life, and increased mortality in patients with bronchiectasis.1,2 Given that such chronic airway infections are associated with progressive disease and changes in quality of life, the current international guidelines have a strong focus on exacerbation prevention in bronchiectasis management.
To assist in preventing exacerbations, bronchiectasis management has focused decreasing airway inflammation through modalities, including airway clearance, macrolide therapies (in patients without NTM infections), and inhaled antibiotics.2 Several studies have focused on the use of inhaled antibiotics given their ability to achieve high concentrations of the antibiotics with hopes of limiting systemic side effects and antibiotic resistance, with prior studies including nebulized tobramycin and ciprofloxacin.3,4 The PROMIS-I and PROMIS-II trials assessed the use of inhaled colistimethate sodium in affecting the mean frequency of bronchiectasis exacerbations.
The PROMIS-I trial was able to demonstrate an annual exacerbation rate ratio of 0.58 in the colistimethate sodium group versus that of 0.95 in the placebo group. Additional clinically significant secondary endpoints in PROMIS-I included improved quality of life, decreased P aeruginosa density, and increased time to first exacerbation among patients in the intervention group. Although PROMIS-II was not able to replicate the same primary endpoint result and noted concerns for closure during the COVID-19 pandemic, it was able to show similar trends in P aeruginosa density and time to first exacerbation.
Overall, the results of these trials provide hopeful information regarding the use of nebulized colistimethate sodium in preventing bronchiectasis exacerbations in patients with chronic P aeruginosa and bronchiectasis.
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