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

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis (CF)
• Intervention / Treatment: Drug: Placebo; Drug: MP-376

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
  • Essen, Germany
  • Frankfurt, Germany
  • Gerlingen, Germany
  • Gieben, Germany
  • Kiel, Germany
  • Munchen, Germany
  • Tubingen, Germany
• Netherlands
  • Amsterdam, Netherlands
  • Groesbeek, Netherlands
  • Rotterdam, Netherlands
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
  • Arizona
    • Phoenix, Arizona, United States, 85016
    • Tucson, Arizona, United States, 85724
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
  • California
    • Los Angeles, California, United States, 90033
    • Los Angeles, California, United States, 90027
      • Childrens Hospital
    • Oakland, California, United States, 94611
    • Orange, California, United States, 92868
    • Palo Alto, California, United States, 94304
    • Sacramento, California, United States, 95817
    • San Diego, California, United States, 92103
  • Florida
    • Miami, Florida, United States, 33136
    • Orlando, Florida, United States, 32801
  • Illinois
    • Chicago, Illinois, United States, 60025
    • Oak Lawn, Illinois, United States, 60453
    • Park Ridge, Illinois, United States, 60068
  • Iowa
    • Iowa City, Iowa, United States, 52242
  • Kentucky
    • Louisville, Kentucky, United States, 40202
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
    • Kalamazoo, Michigan, United States, 49007
  • Minnesota
    • Minneapolis, Minnesota, United States
  • Nevada
    • Las Vegas, Nevada, United States, 89107
  • New Jersey
    • Morristown, New Jersey, United States, 07962
  • New York
    • Albany, New York, United States, 12208
    • Valhalla, New York, United States, 10595
  • Ohio
    • Cincinnati, Ohio, United States, 45224
    • Columbus, Ohio, United States, 43205
    • Dayton, Ohio, United States, 45404
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma CF Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
    • Pittsburgh, Pennsylvania, United States, 15213
  • South Carolina
    • Charleston, South Carolina, United States, 29425
    • Columbia, South Carolina, United States, 29203
  • Tennessee
    • Memphis, Tennessee, United States, 38105
  • Texas
    • San Antonio, Texas, United States, 78212
    • Tyler, Texas, United States, 75708
  • Utah
    • Salt Lake City, Utah, United States, 84132

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Horizon Pharma USA, Inc.
• Investigators: Principal Investigator: Douglas J Conrad, M.D., UCSD

Publications and helpful links

General Publications

• Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ; Mpex 204 Study Group. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011 Jun 1;183(11):1510-6. doi: 10.1164/rccm.201008-1293OC. Epub 2011 Feb 25.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: May 12, 2008
• First Submitted That Met QC Criteria: May 13, 2008
• First Posted (Estimate): May 14, 2008

Study Record Updates

• Last Update Posted (Actual): January 19, 2018
• Last Update Submitted That Met QC Criteria: January 17, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Levofloxacin
• Other Study ID Numbers: Mpex-204; 2008-001728-30 (EudraCT Number)