Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients

Study Overview
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Brief Summary
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To assess whether the inhalative combination of Tobramycin/Colistin is more effective in reducing Pseudomonas colony forming units (CFUs) and improvement of lung function than Colistin in mono-therapy.

Detailed Description
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Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator molecule (CFTR) and affects approximately 40.000 patients in Europe. The majority of CF patients develop chronic pulmonary infections with Pseudomonas aeruginosa. These are normally treated with single antibiotics, administered orally, intravenously or inhalatively. Once the infection becomes chronic, eradication of the pathogen is not any more possible due to biofilm formation of the pathogen and increasing resistance. However, inhalative antibiotic combination therapy might be more efficient than single antibiotic therapy in chronically infected CF patients. This notion is supported by previous in vitro and animal studies using Tobramycin/Colistin combination therapy. Importantly, a pilot study in five CF patients who inhaled consecutively Colistin and Tobramycin solutions for 4 week, revealed a decrease of log10 2.52 ± 2.5 cfu of P. aeruginosa in sputum specimens during the course of the treatment compared to baseline values (p=0.027). The treatment was shown to be safe and well tolerated. However, forced expiratory volume in 1 sec (FEV1) did not differ significantly. Taking advantage of the new development of dry powder inhalation (DPI) antibiotics, specifically TOBI© Podhaler, a larger randomised trial has been performed in which the combined TOBI© Podhaler and Colistin treatment is compared to the monotherapy with Colistin.

Official Title
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Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients

Conditions
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Cystic Fibrosis With Pulmonary Manifestations

Intervention / Treatment
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* Drug: Tobramycin Powder
* Drug: Colistin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cystic Fibrosis is verified; Patient is 12 years or older; FEV1 is higher than 25% and lower than 100%; The patients' lung is colonised with P. aeruginosa chronically (≥6 months); P. aeruginosa must be sensitive for Tobramycin or Colistin; Pretreated with Colistin >2 months; Last i.v. antibiotic treatment ≥2 weeks; Informed consent is given by patients/legal representatives Exclusion Criteria: Clinical deterioration is present (exacerbation symptoms); Last Tobramycin inhalation treatment ≤ 2 weeks; Renal dysfunction (creatinine <1.5 fold of normal, glomerular filtration rate (GFR) <80%) at baseline auditoria or vestibular dysfunction, hearing loss Intolerances against Tobramycin, Colistin or Polymyxin B Myasthenia gravis Porphyria Pregnancy and nursing

Ages Eligible for Study
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Minimum Age: 12 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, open label clinical study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tobramycin powder / Colistin<br>TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off); and Colistin solution 2 x daily 1 Mega continuously for 112 days | Drug: Tobramycin Powder<br>* TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off);<br>* Other names: TOBI®Podhaler;Drug: Colistin<br>* Colistin solution 2 x daily 1 Mega continuously<br>* Other names: Colistin solution;|
| Active Comparator: Colistin<br>Colistin solution 2 x daily 1 Mega continuously for at least 30 days | Drug: Colistin<br>* Colistin solution 2 x daily 1 Mega continuously<br>* Other names: Colistin solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of P. aeruginosa in sputum | The primary endpoint will be the difference of P. aeruginosa cfu/ml in sputum with combined therapy with Tobramycin/Colistin compared to colistin mono-therapy. The analysis will be adjusted for baseline values of each cycle and parametric (paired t-Test) or non-parametric (sign test) methods will be used as appropriate. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Course of P.aeruginosa amount in sputum | Course of P. aeruginosa in sputum measured as cfu/ml during the study | 112 days | 
| Course of forced vital capacity (FVC) absolute amount | Course of FVC absolute in litres during the study | 112 days | 
| Course of FVC relative amount | Course of FVC relative (percent of expected amount for given body height and gender) during the study | 112 days | 
| Course of FEV1 absolute amount | Course of FEV1 absolute in litres during the study | 112 days | 
| Course of FEV1 relative amount | Course of FEV1 relative (percent of expected amount for given body height and gender) during the study | 112 days | 
| Course of MEF25-75 absolute amount | Course of MEF25-75 absolute in litres during the study | 112 days | 
| Course of MEF25-75 relative amount | Course of MEF25-75 relative (percent of expected amount for given body height and gender) during the study | 112 days | 
| Course of proinflammatory cytokine IL1ß amount | Course of proinflammatory cytokine IL1ß amount in sputum [pg/ml] during the study | 112 days | 
| Course of proinflammatory cytokine IL6 amount | Course of proinflammatory cytokine IL6 amount in sputum [pg/ml] during the study | 112 days | 
| Course of proinflammatory cytokine IL8 amount | Course of proinflammatory cytokine IL8 amount in sputum [pg/ml] during the study | 112 days | 
| Course of antiinflammatory cytokine IL10 amount | Course of antiinflammatory cytokine IL10 amount in sputum [pg/ml] during the study | 112 days | 
| Course of proinflammatory cytokine TNFa amount | Course of proinflammatory cytokine TNFa amount in sputum [pg/ml] during the study | 112 days | 
| Course of proinflammatory cytokine GM-CSF amount | Course of proinflammatory cytokine GM-CSF amount in sputum [pg/ml] during the study | 112 days | 
| Course of DNA amount in sputum | Course of DNA amount {pg/ml] in sputum during the study | 112 days | 
| Course of leukocyte amount in sputum | Course of leukocyte amount [pg/ml] in sputum during the study | 112 days | 
| Exacerbation | Number of exacerbations during the study | 112 days | 
| Antibiotics | Use of antibiotics during the study | 112 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic pulmonary infection