Pharmacokinetic Evaluation of an 8 -Week Treatment With Inhaled Tobramycin

Study Overview
=================
Brief Summary
-----------------
This study is designed to provide data about the pharmacokinetics (PK), safety and tolerability of two continuous treatment regimes of tobramycin nebulized solution delivered via a 'soft mist' nebulizer in Cystic Fibrosis (CF) subjects. Each treatment period will last 8 weeks. Additionally the PK of patients with a normal forced expiratory flow in 1 second (FEV1) (FEV1≥80% predicted) will be compared to patients with an abnormal FEV1 (FEV1<80% predicted).

Official Title
-----------------
A Multicenter, Open Label, 2 Period Cross-over Study to Evaluate the PK of a 8 Week Continuous Treatment With 1x300mg/d and 2x300mg/d Tobramycin Inhaled With a 'Soft Mist' Nebulizer in Cystic Fibrosis (CF) Subjects

Conditions
-----------------
Pseudomonas Infections

Intervention / Treatment
-----------------
* Drug: tobramycin
* Drug: tobramycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects aged ≥6 years at the time of screening, with an Informed Consent Form signed by patient and if appropriate by parent/legal guardians, prior to any study-related procedure. Confirmed diagnosis of CF by the presence of one or more clinical features of CF in addition to a quantitative pilocarpine iontophoresis sweat chloride test of >60 mEq/L; or identification of well-characterized disease-causing mutations in each CFTR gene; or an abnormal nasal transepithelial potential difference characteristic of CF. P aeruginosa must be present in sputum or deep throat swab (or bronchoalveolar lavage [BAL]) at the screening visit and within 6 months prior to screening. Exclusion Criteria: History of sputum (or BAL) culture yielding Burkholderia cepacia (B cepacia) within 2 years prior to screening and/or sputum culture yielding B cepacia at screening. FEV1 <25% of normal predicted values for age, sex, and height based on Knudson criteria at screening. Hemoptysis of more than 60 cc at any time within 30 days prior to study drug administration. Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics. GFR<60ml/min/1.73m2 calculated with the Formula by Schwartz, BUN 40 mg/dl or more, or an abnormal urinalysis defined as 2+ or greater proteinuria. History of tinnitus or pathologic audiometry diagnosis of Allergic bronchopulmonary aspergillosis (ABPA) at screening Initiation of treatment with macrolide antibiotics within 28 days prior to study drug administration (subjects may be taking macrolide antibiotics at the time of enrollment, but they must have initiated treatment at least 28 days prior to study drug administration). Use of loop diuretics within 7 days prior to study drug administration. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: tobramycin<br>* 1x300mg/d inhaled<br>|
| Experimental: 2<br> | Drug: tobramycin<br>* 2x300mg/d inhaled<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the serum pharmacokinetics (PK) of inhaled tobramycin (AUC 0-90') of continuous daily dosing regimens with 2x300mg/d Tobramycin Nebuliser Solution (=TNS) inhaled with the PARI eFlow® rapid in Cystic Fibrosis (CF) subjects |  | 8 wks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum PK of inhaled tobramycin (AUC 0-90') of continuous daily dosing regimens with 1 x 300mg/d tobramycin nebulized solution (= TNS) inhaled with the PARI eFlow rapid in cystic fibrosis subjects. |  | 8 wks | 
| Compare serum PK of inhaled tobramycin (trough-/peak-level)of both dosing regimens in CF-subjects with a FEV1≥80% vs. CF-Subjects with a FEV1<80%. |  | 8 weeks | 
| Change of MIC of P. aeruginosa during a continuous treatment with 1 x 300 mg/d and 2 x 300 mg/d TNS. |  | 8 weeks | 
| Assess safety of a continuous daily dosing regimen with 1 x 300 mg/d and 2 x 300 mg/d TNS over 8 weeks, compared to historic safety data of the 4 week on/off dosing regimen with 2 x 300 mg/d. |  | 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic infection with P. aeruginosa in Cystic Fibrosis subjects