Comparison of Two Treatment Regimens to Reduce PA Infection in Children With Cystic Fibrosis (EPIC)

This study has been completed.
Sponsor:
Collaborators:
Cystic Fibrosis Foundation
CF Therapeutics Development Network Coordinating Center
Information provided by (Responsible Party):
Bonnie Ramsey, Seattle Children's Hospital
ClinicalTrials.gov Identifier:
NCT00097773
First received: November 30, 2004
Last updated: January 28, 2014
Last verified: January 2014
  Purpose

Cystic fibrosis (CF) is a chronic disease that significantly affects an individual's lung function. Antibiotic medications have been proven effective at reducing Pseudomonas aeruginosa (PA) infection, which is one of the main causes of death in individuals with CF. The purpose of this study is to compare the effectiveness of treatment based on quarterly culture results versus consistent quarterly antibiotic treatment at reducing PA infection in children with CF.


Condition Intervention Phase
Cystic Fibrosis
Pulmonary Disease, Chronic Obstructive
Drug: Tobramycin solution for inhalation (TOBI)
Drug: Oral placebo
Drug: Oral ciprofloxacin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Effectiveness and Safety of Intermittent Antimicrobial Therapy for the Treatment of New Onset Pseudomonas Aeruginosa Airway Infection in Young Patients With Cystic Fibrosis

Resource links provided by NLM:


Further study details as provided by Seattle Children's Hospital:

Primary Outcome Measures:
  • Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization [ Time Frame: Measured over the 18 month study ] [ Designated as safety issue: No ]

    The primary comparison is between the pooled culture-based group and the pooled cycled group. A secondary comparison is between the pooled ciprofloxacin group vs the pooled placebo group. Descriptive results are provided for the pooled treatment groups.

    Participants are represented once in the cycled and culture-based therapy columns, and once in the cipro and placebo columns.



Secondary Outcome Measures:
  • Proportion of Participants With a Pa Positive Culture [ Time Frame: Week 10 (after initial treatment course for Pa) through Month 18 ] [ Designated as safety issue: No ]

    Proportion of participants with a Pa positive culture compared between (1) the pooled cycled therapy group (n=152) and pooled culture-based therapy group (n=152), and (2) between the pooled oral placebo (n=152)and pooled cipro groups (n=152).

    Participants are included once in the cycled and culture-based columns, and once in the oral cipro and placebo columns


  • Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics [ Time Frame: Measured over the 18 month time period ] [ Designated as safety issue: No ]

    The primary comparison is between the pooled culture-based group and the pooled cycled group. No interactions with ciprofloxacin were identified. A secondary comparison is between the pooled ciprofloxacin group vs the pooled placebo group. Descriptive results are provided for the pooled treatment groups.

    Participants are represented once in the cycled and culture-based therapy columns, and once in the cipro and placebo columns.



Enrollment: 304
Study Start Date: September 2004
Study Completion Date: August 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Cycled TOBI & placebo
Tobramycin inhalation solution and oral placebo for six consecutive quarterly cycles
Drug: Tobramycin solution for inhalation (TOBI)
Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days administered only when quarterly respiratory cultures are found positive for Pa.
Other Name: TOBI, TIS
Drug: Oral placebo
Oral placebo for six consecutive quarterly cycles. For the initial 14 days of the 28-day treatment period, the participants will receive placebo, twice daily.
Other Name: Placebo
Active Comparator: Cycled TOBI & oral ciprofloxacin
Tobramycin solution for inhalation and oral ciprofloxacin for six consecutive quarterly cycles.
Drug: Tobramycin solution for inhalation (TOBI)
Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days administered only when quarterly respiratory cultures are found positive for Pa.
Other Name: TOBI, TIS
Drug: Oral ciprofloxacin
Oral ciprofloxacin for six consecutive quarterly cycles. For the initial 14 days of the 28-day treatment period, the participants will receive oral ciprofloxacin, 15-20 mg/kg/dose, twice daily.
Other Names:
  • Cipro
  • Ciprofloxacin
Placebo Comparator: Culture based TOBI & placebo
Tobramycin solution for inhalation and oral placebo administered only when quarterly respiratory cultures are found positive for Pa.
Drug: Tobramycin solution for inhalation (TOBI)
Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days administered only when quarterly respiratory cultures are found positive for Pa.
Other Name: TOBI, TIS
Drug: Oral placebo
Oral placebo for six consecutive quarterly cycles. For the initial 14 days of the 28-day treatment period, the participants will receive placebo, twice daily.
Other Name: Placebo
Active Comparator: Culture based TOBI & oral cipro
Tobramycin solution for inhalation and oral ciprofloxacin administered only when quarterly respiratory cultures are found positive for Pa.
Drug: Tobramycin solution for inhalation (TOBI)
Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days administered only when quarterly respiratory cultures are found positive for Pa.
Other Name: TOBI, TIS
Drug: Oral ciprofloxacin
Oral ciprofloxacin for six consecutive quarterly cycles. For the initial 14 days of the 28-day treatment period, the participants will receive oral ciprofloxacin, 15-20 mg/kg/dose, twice daily.
Other Names:
  • Cipro
  • Ciprofloxacin

Detailed Description:

CF is an inherited disease that causes mucus to build up in the lungs and digestive tract, which can cause lung infections and digestive problems. It is the most common type of chronic lung disease in children and young adults and may result in early death. There is no cure for this disease. The primary cause of death in individuals with CF is progressive obstructive pulmonary disease associated with chronic Pseudomonas aeruginosa (PA) infection. PA infection can occur early in life and can become highly resistant to antibiotics. Once an individual has been diagnosed with chronic PA infection, it is almost impossible to manage effectively. The need exists for an effective treatment to control and eliminate PA infection. Past research has shown that if PA infection is treated early, there is a greater likelihood that it may be eliminated completely. This study will examine two treatment regimens to compare which is more effective at eliminating PA infection. In the first regimen, participants will receive antibiotic treatment at various times throughout the study, based on findings of PA respiratory cultures obtained on a quarterly basis. In the second regimen, participants will receive antibiotic medications in consistent, quarterly cycles throughout the study. The antibiotic medications used in this study will be ciprofloxacin and inhaled tobramycin, which will be administered with a nebulizer. Both of these medications have been proven effective at treating bacterial lung infections. The overall purpose of this study is to compare the effectiveness of culture-based treatment versus consistent treatment at reducing PA infection in children with CF.

This 18-month study will enroll children with CF. For the first 28 days of the study, all participants will receive inhaled tobramycin. For the initial 14 days of this 28-day period, half of the participants will also receive either ciprofloxacin or placebo. If respiratory cultures after three weeks of treatment confirm the presence of PA, participants will receive tobramycin for an additional 28 days. Participants will then be randomly assigned to one of four treatment options: tobramycin and placebo for six consecutive quarterly cycles; tobramycin and ciprofloxacin for six consecutive quarterly cycles; tobramycin and placebo only when PA is found during quarterly respiratory cultures; or tobramycin and ciprofloxacin only when PA is found during quarterly respiratory cultures.

At the first study visit, participants will undergo a physical examination, a chest x-ray, and a review of their medical history. Lung function will be measured via spirometry (in children greater than four years of age who are able to perform spirometry), and hearing ability will be measured via audiometry (at selected sites). Blood will be drawn for laboratory tests, and a specimen will be obtained for a respiratory culture. Subsequent study visits will take place at Day 21, Weeks 10, 22, 34, 46, 58, and 70. At each visit, participants will undergo a physical examination and a spirometry test (as appropriate), and a respiratory specimen for PA culture and blood will again be collected. Participants will be required to maintain a medication diary throughout the study, and they will be contacted between visits to review medication adherence and test results.

  Eligibility

Ages Eligible for Study:   1 Year to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of CF, as determined by the 1997 CF Consensus Conference criteria: sweat chloride level greater than 60 milliequivalent/liter (mEq/L) by quantitative pilocarpine iontophoresis; or a genotype with two identifiable mutations consistent with CF; or an abnormal nasal transepithelial potential difference and one or more clinical features consistent with CF
  • For participants greater than 15 months of age: documented new onset of positive oropharyngeal, sputum, or lower respiratory tract culture for PA within 6 months of study entry, defined as either: 1) first lifetime documented PA positive culture; or 2) PA recovered after at least a 2-year history of PA negative respiratory cultures (at least one culture per year)
  • For participants 12-15 months of age: at least one documented positive oropharyngeal, sputum, or lower respiratory tract culture for PA since birth or CF diagnosis
  • Clinically stable with no evidence of any significant respiratory symptoms or chest radiograph findings at screening that would require administration of intravenous anti-pseudomonal antibiotics, oxygen supplementation, or hospitalization

Exclusion Criteria:

  • History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycoside
  • History of hypersensitivity or adverse reaction to ciprofloxacin or other fluoroquinolone medications
  • History of persistent, unresolved hearing loss documented by audiometric testing on at least two occasions and not associated with middle ear disease or an abnormal tympanogram
  • Abnormal kidney function at study entry (defined as a serum creatinine level greater than 1.5 times the upper limit of normal for participant's age)
  • Abnormal liver function test results at study entry (defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels greater than two times the upper limit of normal range)
  • Use of any investigational drug within 30 days of study entry
  • Use of loop diuretics, phenytoin, warfarin, theophylline, or other methylxanthines within 30 days of study entry
  • Use of more than one course of intravenous anti-pseudomonal antibiotics (at least 10 continuous days of medication use) or more than one course of inhaled anti-pseudomonal antibiotics (at least 28 continuous days of medication use) within 2 years of study entry; intravenous or inhaled anti-pseudomonal antibiotics must be stopped at least 30 days prior to study entry
  • Chronic macrolide use (more than 90 day duration) in the 3 months prior to study entry
  • Presence of a condition or abnormality that would compromise the participant's safety or the quality of the study data, in the opinion of the investigator
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00097773

  Hide Study Locations
Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, California
Children's Hospital of Los Angeles
Los Angeles, California, United States, 90027
Northern California Kaiser Cystic Fibrosis Center
Oakland, California, United States, 94611
Stanford University
Palo Alto, California, United States, 94304-5786
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Colorado
Children's Hospital Denver
Aurora, Colorado, United States, 80045
United States, Delaware
duPont Hospital for Children
Wilmington, Delaware, United States, 19803
United States, Florida
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207
All Children's Hospital Cystic Fibrosis Center
St. Petersburg, Florida, United States, 33701
United States, Georgia
Emory University Cystic Fibrosis Center
Atlanta, Georgia, United States, 30322
Medical College of Georgia
Augusta, Georgia, United States, 30912
United States, Illinois
Children's Memorial Hospital
Chicago, Illinois, United States, 60614
United States, Indiana
Riley Hospital/Indiana University
Indianapolis, Indiana, United States, 46202
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536-0284
United States, Maine
Maine Medical Center
Portland, Maine, United States, 04102
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Children's Hospital, Boston
Boston, Massachusetts, United States, 02115
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
University of Massachusetts Memorial Health Care
Worcester, Massachusetts, United States, 06155
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109-0212
Children's Hospital of Michigan
Detroit, Michigan, United States, 48201
Spectrum Health Hospitals - DeVos Children's
Grand Rapids, Michigan, United States, 49503
United States, Minnesota
Children's Hospitals & Clinics
Minneapolis, Minnesota, United States, 55102
United States, Mississippi
University of Mississippi Medical Center
Jackson, Mississippi, United States, 39216
United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Cardinal Glennon Children's Hospital
St. Louis, Missouri, United States, 63104
United States, Nebraska
University of Nebraska
Omaha, Nebraska, United States, 68198-5190
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756-0001
United States, New Jersey
Monmouth Medical Center
Long Branch, New Jersey, United States, 07740
United States, New York
Albany Medical College
Albany, New York, United States, 12208
University of Rochester
Rochester, New York, United States, 14642
State University of New York Upstate Medical University
Syracuse, New York, United States, 13210
New York Medical College
Valhalla, New York, United States, 10595
United States, North Carolina
University of North Carolina, Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Children's Hospital Medical Center of Akron
Akron, Ohio, United States, 44308
Rainbow Babies & Children's Hospital
Cleveland, Ohio, United States, 44106
Children's Hospital
Columbus, Ohio, United States, 43205
Children's Medical Center
Dayton, Ohio, United States, 45404
United States, Oregon
Oregon Health Sciences University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
St. Christopher's Hospital for Children
Philadelphia, Pennsylvania, United States, 19134-1095
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
LeBonheur Children's Medical Center
Memphis, Tennessee, United States, 38105
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232-9500
United States, Texas
Cook Children's Medical Center
Ft. Worth, Texas, United States, 76104
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84106
United States, Vermont
Vermont Children's Hospital at Fletcher Allen Health Care
Burlington, Vermont, United States, 05401
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
United States, Washington
Children's Hospital & Regional Medical Center
Seattle, Washington, United States, 98105
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Seattle Children's Hospital
Cystic Fibrosis Foundation
CF Therapeutics Development Network Coordinating Center
Investigators
Principal Investigator: Bonnie W. Ramsey University of Washington
Principal Investigator: George Retsch-Bogart, MD University of North Carolina, Chapel Hill
Principal Investigator: Miriam Treggiari, MD University of Washington
  More Information

Publications:
Responsible Party: Bonnie Ramsey, Professor of Pediatrics, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT00097773     History of Changes
Other Study ID Numbers: 169, U01HL080310
Study First Received: November 30, 2004
Results First Received: June 11, 2013
Last Updated: January 28, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Seattle Children's Hospital:
Lung Diseases
Chronic Obstructive Pulmonary Disease

Additional relevant MeSH terms:
Chronic Disease
Cystic Fibrosis
Fibrosis
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases, Obstructive
Tobramycin
Ciprofloxacin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 20, 2014