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

Effectiveness and Safety of Intermittent Antimicrobial Therapy for the Treatment of New Onset Pseudomonas Aeruginosa Airway Infection in Young Patients With Cystic Fibrosis

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive; Cystic Fibrosis
• Intervention / Treatment: Drug: Tobramycin solution for inhalation (TOBI); Drug: Oral placebo; Drug: Oral 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.

• Study Type: Interventional
• Enrollment (Actual): 304
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: 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 Names: 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: Ciprofloxacin; Cipro
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 Names: 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 Names: 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 Names: 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: Ciprofloxacin; Cipro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization	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.	Measured over the 18 month study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With a Pa Positive Culture	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	Week 10 (after initial treatment course for Pa) through Month 18
Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics	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.	Measured over the 18 month time period

Collaborators and Investigators

• Sponsor: Seattle Children's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); 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

Publications and helpful links

General Publications

• Treggiari MM, Rosenfeld M, Mayer-Hamblett N, Retsch-Bogart G, Gibson RL, Williams J, Emerson J, Kronmal RA, Ramsey BW; EPIC Study Group. Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study'. Contemp Clin Trials. 2009 May;30(3):256-68. doi: 10.1016/j.cct.2009.01.003. Epub 2009 Jan 15.
• Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, Williams J, Hiatt P, Gibson RL, Spencer T, Orenstein D, Chatfield BA, Froh DK, Burns JL, Rosenfeld M, Ramsey BW; Early Pseudomonas Infection Control (EPIC) Investigators. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011 Sep;165(9):847-56. doi: 10.1001/archpediatrics.2011.136.
• Sanders DB, Emerson J, Ren CL, Schechter MS, Gibson RL, Morgan W, Rosenfeld M; EPIC Study Group. Early Childhood Risk Factors for Decreased FEV1 at Age Six to Seven Years in Young Children with Cystic Fibrosis. Ann Am Thorac Soc. 2015 Aug;12(8):1170-6. doi: 10.1513/AnnalsATS.201504-198OC.
• Mayer-Hamblett N, Kloster M, Rosenfeld M, Gibson RL, Retsch-Bogart GZ, Emerson J, Thompson V, Ramsey BW. Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis. Clin Infect Dis. 2015 Sep 1;61(5):707-15. doi: 10.1093/cid/civ377. Epub 2015 May 13.

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: November 30, 2004
• First Submitted That Met QC Criteria: November 30, 2004
• First Posted (Estimate): December 1, 2004

Study Record Updates

• Last Update Posted (Estimate): February 28, 2014
• Last Update Submitted That Met QC Criteria: January 28, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Lung Diseases; Chronic Obstructive Pulmonary Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Lung Diseases, Obstructive; Pancreatic Diseases; Fibrosis; Lung Diseases; Pulmonary Disease, Chronic Obstructive; 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; Ciprofloxacin; Tobramycin
• Other Study ID Numbers: 169; U01HL080310 (U.S. NIH Grant/Contract)