Safety, Tolerability and Efficacy of MP-376 Given for 28 Days to Cystic Fibrosis (CF) Patients

Study Overview
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Brief Summary
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Patients with cystic fibrosis (CF) suffer from chronic infections of the lower respiratory tract that can be caused by one or multiple bacteria, including Pseudomonas aeruginosa, which has been particularly problematic to eradicate and been implicated as the major cause of morbidity and mortality in CF patients. Aerosol delivery of antibiotics directly to the lung increases the local concentrations of antibiotic at the site of infection resulting in improved antimicrobial effects compared to systemic administration. Bacterial resistance to current aerosol antibiotic treatments indicate a need for improved therapies to treat CF patients with pulmonary infections caused by multi-drug resistant Pseudomonas aeruginosa and other bacteria. High concentrations of MP-376 delivered directly to the lung are projected to have antimicrobial effects on even the most resistant organisms.

Detailed Description
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This trial will be a double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of levofloxacin administered as MP-376 of three dosage regimens given for 28 days by the aerosol route to CF patients.

Official Title
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Phase II, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety, Tolerability and Efficacy of Three Dosage Regimens of MP-376 Solution for Inhalation Given for 28 Days to Stable CF Patients

Conditions
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Cystic Fibrosis (CF)

Intervention / Treatment
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* Drug: MP-376
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (selected): > 16 years of age Confirmed Diagnosis of Cystic Fibrosis Positive sputum culture for P. aeruginosa within the past 18 months Patients are able to elicit a forced expiratory volume in 1 second (FEV1) >/= 25% but </= 85% of predicted value at screening Have received at least 3 courses of inhaled antimicrobials over the preceding 12 months Clinically stable with no changes in health status within the last 30 days Able to reproducibly produce sputum and perform spirometry Exclusion Criteria (selected): Use of any nebulized or systemic antibiotics within 30 days prior to baseline History of hypersensitivity to fluoroquinolones or intolerance with aerosol medication Evidence of acute upper within 10 days or lower respiratory infections within 30 days prior to dosing Creatine clearance < 50mg/ml, aspartate transaminase (AST), alanine transaminase (ALT) or total bilirubin >/= 3 x upper limit of normal (ULN) at Screening

Ages Eligible for Study
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Minimum Age: 16 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo inhaled either once or twice daily via the PARI eFlow nebulizer for 28 days | Drug: Placebo<br>* same frequency as study drug using the same nebulizer<br>|
| Experimental: MP-376 120 mg QD<br>MP-376 120 mg inhaled Once Daily (QD) via the PARI eFlow nebulizer for 28 days | Drug: MP-376<br>* 3 dose regimens of MP-376 administered twice daily (BID) or once daily (QD) for 28 days<br>* Other names: Aeroquin;|
| Experimental: MP-376 240 mg QD<br>MP-376 240 mg inhaled QD bia the PARI eFlow nebulizer for 28 days | Drug: MP-376<br>* 3 dose regimens of MP-376 administered twice daily (BID) or once daily (QD) for 28 days<br>* Other names: Aeroquin;|
| Experimental: MP-376 240 mg BID<br>MP-376 240 mg inhaled twice daily (BID) via the PARI eFlow nebulizer for 28 days | Drug: MP-376<br>* 3 dose regimens of MP-376 administered twice daily (BID) or once daily (QD) for 28 days<br>* Other names: Aeroquin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in P. Aeruginosa Density | Patients were required to cough deeply and then spit sputum into a sterile container. The bacteria contained in the sputum sample was incubated in a laboratory and the number of P. aeruginosa colony forming units per gram of sputum (CFU/g) was determined. The difference in CFUs/g were then compared from baseline to the conclusion of the 28 day treatment period | from baseline to end of treatment (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Administration of Other Anti-pseudomonal Antimicrobials | Time to administration of other anti-pseudomonal antimicrobials in patients with at least one of the following: decreased exercise tolerance, increased cough, increased sputum/chest congestion, or decreased appetite; 25th percentile data reported | from baseline until final study visit (up to 56 days) | 
| Percent Change in Forced Expiratory Volume in 1 Second (FEV1) | Percent change in the amount of air the patient could exhale in 1 second | from baseline to end of the 28-day treatment period (28 days) | 
| Change in FEV1 Percent Predicted | Change in the predicted percent of air the patient could exhale in one second | from baseline to the end of the treatment 28-day treatment period (28 days) | 
| Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R) | Change in the score from 0 to 100 that a patient reports for their respiratory symptoms in the CFQ-R. An increase in score illustrates an improvement in symptoms. An increase of 4 or more is considered clinically significant | from baseline to the end of the 28-day treatment period (28 days) | 
| Changes in Susceptability Patterns of Isolated Organisms | All isolates of P. aeruginosa cultures grown from patient sputum samples were evaluated to see whether the minimum concentration of levofloxacin needed to inhibit growth of the bacteria (i.e., minimum inhibitory concentration; MIC) had increased; 2. The MIC50 and MIC90 values were calculated as the 50th percentile value and the 90th percentile value, respectively. Note that percentile values between dilution values were rounded up to the nearest dilution value | from baseline until the end of the 28-day treatment period (28 days) |