Aztreonam for Inhalation Solution (AZLI) for the Treatment of Exacerbations of Cystic Fibrosis

Study Overview
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Brief Summary
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This study evaluates the role of AZLI in the treatment of acute pulmonary exacerbations of CF. For consecutive exacerbations patients will receive AZLI + IV Colistin, or two IV anti-pseudomonals.

Detailed Description
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AZLI, marketed as Cayston, is an inhaled beta-lactam antibiotic. It has a license for the chronic suppression of Pseudomonas aeruginosa (PA). Current standard practice dictates the use of two IV antipseudomonal antibiotics for the treatment of acute pulmonary exacerbations. The increasing survival, and hence population, in CF means that newer antimicrobial strategies are required in order to manage antimicrobial resistance, minimise adverse systemic effects of heavy antimicrobial exposure and also make effective use of resources. Inhaled antibiotics are commonly used in the chronic suppression of PA yet their use has not been thoroughly investigated in acute pulmonary exacerbation. Inhaled antibiotics deliver their drugs directly to the target-site with minimal systemic absorbance, making them an attractive candidate for treatment of acute exacerbations. Recently, it has become apparent that the bacterial community is much more complex than initially thought. The microbiome, a term used to describe the polymicrobial community in the lungs, has become apparent due to the use of modern culture-independent methods to detect bacteria. The microbiome changes in composition and structure around the time of exacerbations and in response to treatment, although these changes have not been prospectively characterised. We have designed an open-label randomised, controlled cross-over trial to investigate the clinical effectiveness of of AZLI in the treatment of acute pulmonary exacerbation, whilst simultaneously comparing the effect inhaled and intravenous antibiotics have on the microbiome.

Official Title
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Aztreonam for Inhalation Solution (AZLI) for the Treatment of Exacerbations of Cystic Fibrosis. An Randomised, Crossover Pilot Study of AZLI Plus Intravenous Colistin® Versus Standard Dual Intravenous Therapy

Conditions
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Cystic Fibrosis, Infection, Pseudomonas

Intervention / Treatment
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* Drug: Aztreonam
* Drug: Standard Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CF Patients aged 18 - 65 years of age who can give informed consent FEV1 >25% or <75% predicted (in keeping with Cayston® license) Admitted to the Liverpool Heart & Chest Hospital with an exacerbation of CF pulmonary disease Presence of PA in lower respiratory tract cultures in the 6 months prior Exclusion Criteria: Documented allergy to beta-lactam antibiotics or IV Colistin Growth of Burkholderia Cepacia Complex (BCC) within 2 years Pregnancy Previous organ transplant Receiving other clinical trial medication Already prescribed regular Cayston®

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZLI then Standard Care<br>Upon first exacerbation this arm will receive AZLI, on their second they will receive standard care | Drug: Aztreonam<br>* 14 days of AZLI: 75mg TDS PLUS IV Colistin<br>* Other names: AZLI;Drug: Standard Care<br>* 14 days of IV Colistin plus one of Tazocin/Ceftazidime/Meropenem/Aztreonam/Fosfomycin<br>|
| Active Comparator: Standard Care then AZLI<br>Upon first exacerbation this arm will receive standard care, on the second exacerbation this arm will receive AZLI | Drug: Aztreonam<br>* 14 days of AZLI: 75mg TDS PLUS IV Colistin<br>* Other names: AZLI;Drug: Standard Care<br>* 14 days of IV Colistin plus one of Tazocin/Ceftazidime/Meropenem/Aztreonam/Fosfomycin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average actual change in percent predicted forced expiratory volume at 1 second (FEV1) from Day 1 to Day 14 | The actual change in FEV1 (%predicted) from Day 1 of admission to Day 7 & Day 14 | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first pulmonary exacerbation | Time from discharge to next pulmonary exacerbation | 12 months | 
| Average change from baseline in the Cystic Fibrosis Quality of Life Questionnaire (CFQ-R) | Average change from baseline (Day 1) in the CFQ-R Respiratory Symptom Score (RSS) at the end (Day 14) of each arm of the study | 14 days | 
| Microbiome changes | Changes in the structure and composition of the microbiome at the beginning and end of each treatment arm | 14 days | 
| PA sputum counts | Changes in sputum PA counts from the beginning to end of each treatment arm. | 14 days | 
| Antimicrobial resistance | Prevalence of resistance to antibiotics at the beginning and end of each treatment arm. | 14 days |