Targeted AntiBiotics for Chronic Pulmonary Diseases

Study Overview
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Brief Summary
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This is a prospective, randomized multi-center trial investigating the impact of lower airway infection with P. aeruginosa in COPD patients. The aim of the study is to evaluate if targeted antibiotic therapy against P. aeruginosa can improve the prognosis in patients with COPD. non-CF bronchiectasis (BE) and asthma.

Detailed Description
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P. aeruginosa represents a potentially significant cause of acute exacerbation of chronic pulmonary diseases and is possibly associated with significant morbidity and mortality. Despite this, the role of P. aeruginosa in the course of COPD, non-CF BE and asthma is less well characterized, and evidence based guidelines for management and treatment of the bacteria are lacking. P. aeruginosa is more likely to be isolated from patients with more advanced disease and severely impaired lung function. It is, however, difficult to draw definitive conclusions regarding the extent to which the bacteria contributes to adverse clinical outcomes since severely reduced lung function by itself is a strong predictor of mortality in patients with chronic pulmonary disease. Infection with P. aeruginosa might therefore be secondary to damaged lung tissue and decreased lung function, and thereby have no independent impact on the prognosis So far, and to the investigators best knowledge, no randomized controlled trial has been conducted to investigate whether specific antibiotic treatment of P. aeruginosa can reduce the risk of new exacerbations and improve the long-term prognosis in patients with COPD, non-CF BE and asthma. In Denmark, the first choice of treatment for P. aeruginosa is usually a 10-14 day therapy of intravenous combination treatment of P. aeruginosa active antibiotics (piperacillin/tazobactam and ciprofloxacin). The aim of the study is to investigate whether the intervention with targeted pseudomonas active antibiotics can reduce the loss of lung function, reduce the frequency of exacerbations and mortality.

Official Title
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Targeted AntiBiotics for Chronic Pulmonary Disease: Can Targeted Antibiotic Therapy Improve the Prognosis of Pseudomonas Aeruginosa Infected Patients With Chronic Pulmonary Obstructive Disease, Non-cystic Fibrosis Bronchiectasis and Asthma? A Multicenter, Randomized, Controlled, Open-label Trial.

Conditions
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Asthma, COPD, Respiratory Tract Infections, Pseudomonas Aeruginosa, Bronchiectasis

Intervention / Treatment
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* Drug: Piperacillin/tazobactam
* Drug: Ciprofloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: P. aeruginosa-positive lower respiratory tract sample. COPD, non-CF bronchiectasis, or asthma verified by a respiratory specialist based on clinical assessment and additional tests: COPD: spirometry; Asthma: reversibility; Non-CF bronchiectasis: high-resolution computed tomography scan. Minimum of two previous exacerbations, or one previous hospitalization-requiring or emergency room-demanding exacerbation, with the treatment of systemic prednisolone and/or antibiotics within the last 12 months. Written informed consent Exclusion Criteria: Immune-modulating therapy (except ≤ 10 mg prednisolone/day) Men < 40 years Women <= 55 years Non- menopausal women > 55 years Life expectancy < 90 days Severe mental illness Severe language difficulties or inability to provide informed consent Known drug allergy to 1) Fluoroquinolones and 2) both Piperacillin/tazobactam, Cephalosporins and Carbapenems Attempted eradication of P. aeruginosa x 2 within the last 12months, or completed eradication therapy within the last 14 days The investigator 's opinion is that the participant requires antibiotic treatment. This exclusion criterion must be discussed with the coordinating investigator before the final decision on exclusion is taken.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard antibiotic treatment<br>Intravenous Piperacillin/tazobactam + oral Ciprofloxacin for 14 days | Drug: Piperacillin/tazobactam<br>* Intravenous Piperacillin/tazobactam four times daily<br>Drug: Ciprofloxacin<br>* Oral Ciprofloxacin twice daily<br>|
| No Intervention: Antibiotic-free treatment<br>No antibiotic treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to prednisolone and/or antibiotic requiring exacerbation or death, in primary or secondary health care sectors from day 20 to day 365 from randomization. | Time alive and without exacerbation between day 20-365 from the date of recruitment. | day 20-365 | 
| Days alive and without hospitalisation from day 20 to day 365 from randomization. | Days alive and out of hospital between day 20-365 from the date of recruitment. | day 20-365 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of re-admissions with pulmonary exacerbation within 365 days from randomization. | Number of re-admissions with pulmonary exacerbation within 365 days from randomization. | 365 days | 
| Death within 365 days from randomization. | Death within 365 days from randomization. | 365 days | 
| Microbiological cure | Microbiological cure = P. aeruginosa-negative sputum culture until day 90. Non-microbiological cure = positive sputum culture with same P.aeruginosa clone as baseline clone ≤ day 90. Re-infection = positive sputum culture with different P. aeruginosa clone compare to baseline clone ≤ day 90. | 90 days | 
| Clinical cure | Resolution or improvement of clinical symptoms related to P. aeruginosa within day 14. Clinical failure = persistent of worsened clinical symptoms related to P. aeruginosa within day 14. | 14 days | 
| Number of days with non-invasive ventilation or invasive ventilation within 90 days from randomization. | Number of days with non-invasive ventilation or invasive ventilation within 90 days from randomization. | 90 days | 
| Change in forced expiratory volume in the first second (FEV1) from randomization to day 90. | Change in forced expiratory volume in the first second (FEV1) from randomization to day 90. | 90 days | 
| Decrease of ≥ 200 ml in FEV1 from randomization to day 365. | Decrease of ≥ 200 ml in FEV1 from randomization to day 365. | 365 days | 
| Change in COPD Assessment Test (CAT) from randomization to day 90. | Change in COPD Assessment Test (CAT) from randomization to day 90. | 90 days | 
| Change in body mass index (BMI) from randomization to day 90. | Change in body mass index (BMI) from randomization to day 90. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic pulmonary disease, Pseudomonas Aeruginosa