Value of Inhaled Treatment With Aztreonam Lysine in Bronchiectasis — VitalBE  

Bronchiectasis Adult Clinical Trial

Official title: A Trial of the Safety, Tolerability and Efficacy of 2 Doses of Cayston (Aztreonam Lysine) Compared to Placebo in Participants With Bronchiectasis

Status Recruiting

Clinical Trial Summary

A randomised controlled trial of the safety, tolerability and effectiveness of 2 doses of Cayston (Aztreonam Lysine) compared to placebo in participants with bronchiectasis.

Bronchiectasis not due to cystic fibrosis is a chronic inflammatory disease characterised by cough, sputum production and frequent respiratory tract infections. There are currently no licensed therapies for bronchiectasis approved by regulators in the United States or Europe. The disease has a high morbidity, particularly in the presence of chronic P. aeruginosa and other chronic Gram-negative infections.

This trial will test the hypothesis that 12 months treatment with Aztreonam lysine for inhalation will be safe and well tolerated, and will result in a significant increase in the time to first pulmonary exacerbation in participants with bronchiectasis and a history of frequent exacerbations.

This is a multi-centre randomised double-blind placebo controlled parallel group trial with four treatment arms. It will enroll 100 bronchiectasis patients with a history of at least 3 exacerbations in the previous year and the presence of chronic Gram-negative infection in sputum at screening. Patients will be treated following a one month on, one month off treatment regimen for 12 months.

The primary objective is to evaluate the safety and tolerability of Aztrenam lysine in these patients by recording adverse events and trial treatment withdrawals.

Clinical Trial Description

Chronic neutrophilic inflammation is a feature of bronchiectasis and the levels of neutrophilic inflammation predict the risk of future exacerbations. Neutrophilic inflammation is highest in participants with P. aeruginosa and other Gram negative pathogens and inflammation can be suppressed by inhaled antibiotic treatment . There is therefore a strong rationale for the effectiveness of inhaled antibiotic treatment in bronchiectasis.

Studies of inhaled antibiotics in bronchiectasis have given mixed results to date. Several open label studies in the late 1980's, testing nebulised β-lactams, demonstrated reduced sputum purulence, sputum volume and improvements in inflammatory markers. In an early phase II double-blind placebo-controlled trial by Barker et al. nebulised tobramycin significantly reduced the primary outcome of P. aeruginosa bacterial load but was poorly tolerated by some participants. Subsequently a single centre randomised controlled trial of nebulised gentamicin for 12 months reported significant benefits but was limited by open label design and small sample size. Haworth et al recruited 144 participants with chronic P. aeruginosa infection and randomized participants to nebulised colistin or placebo. The trial narrowly failed to meet its primary end-point (colistin group 165 days versus placebo 111 days; p=0.11). In the secondary end-points, a large improvement in quality of life using the SGRQ was noted (mean difference -10.5 points; p=0.006).

Aztreonam is an inhaled antibiotic licensed for treatment in cystic fibrosis. Two recent phase III trials in bronchiectasis randomised 266 (AIR-BX1) and 274 (AIR-BX2) participants to Aztreonam 75mg three times daily or placebo over the course of two 28-day treatment cycles (with 28 days off treatment between cycles). The primary outcome was the newly developed Quality of Life Bronchiectasis (QoL-B) questionnaire. Unfortunately the trial failed to meet its primary end-point, with a significant change observed in the QOL-B respiratory symptom score in AIR-BX2 but not in AIR-BX1. Treatment related adverse effects were also increased in the Aztreonam treated participants.

Likely explanations for the difficulties encountered in this previous trial include that the trial population was quite heterogeneous, with many participants having no history of exacerbations and appearing to have relatively mild disease. Many patients did not have a history exacerbations in this trial whereas the ERS bronchiectasis guidelines suggest limiting inhaled antibiotic use to patients with a history of 3 or more exacerbations per year. The characteristics of the included participants included high rates of pulmonary non-tuberculous mycobacterial disease and COPD. Nadig and Flume compared the characteristics of included participants in this trial to their own population of participants with severe bronchiectasis treated with inhaled antibiotics and identified little correlation, suggesting that the trials included a skewed population that was not representative of real-life clinical practice (Nadig and Flume AJRCCM 2016).

In addition, no dose finding studies were performed in bronchiectasis. The dose of 75mg three times daily was chosen based on efficacy and safety in cystic fibrosis. The rates of adverse events appear to be higher in bronchiectasis suggesting that doses selected for CF may not be fully appropriate for participants with non-CF bronchiectasis. Whether lower doses may have efficacy and better safety has not been investigated.

There is a need to determine the safety and efficacy of Aztreonam lysine in participants with bronchiectasis and a history of frequent exacerbations.

The researchers hypothesise that Aztreonam lysine will be safe and well tolerated and will reduce the frequency of exacerbations in participants with bronchiectasis and a history of frequent exacerbations. This trial will test two different doses of Aztreonam lysine compared to placebo. The efficacy and safety of Aztreonam is supported by the evidence for Aztreonam in cystic fibrosis where Aztreonam prolonged the time to first exacerbation by 21 days compared to placebo and improved quality of life. The AIR-BX studies evaluated Aztreonam for inhalation for only 2 treatment cycles. They showed suppression of chronic Gram-negative airway bacterial load but were not designed to evaluate the impact of Aztreonam on the frequency or time to first exacerbation. No attempt to identify the optimal dose was made. The incidence of treatment related adverse effects was increased in AIR-BX1 but was more balanced in AIR-BX2, a trial conducted primarily in European bronchiectasis participants. The reason for this imbalance is unknown.

The researchers hypothesise that 12 months treatment with Aztreonam lysine for inhalation will be safe and well tolerated, and will result in a significant increase in the time to first pulmonary exacerbation in participants with bronchiectasis and a history of frequent exacerbations.

The Vital BE trial will evaluate two doses of aztreonam lysine to determine the optimal dose for testing in future phase 3 trials. ;

Related Conditions & MeSH terms

• Bronchiectasis
• Bronchiectasis Adult

• NCT number: NCT03696290
• Study type: Interventional
• Source: University of Dundee
• Contact: James Chalmers, MBChB, MRCP
• Phone: 01382 386131
• Email: j.chalmers@dundee.ac.uk
• Status: Recruiting
• Phase: Phase 2
• Start date: October 19, 2019
• Completion date: September 30, 2025