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

Cystic Fibrosis Clinical Trial

— EPIC  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00097773
• Other study ID #: 169
• Secondary ID: U01HL080310
• Status: Completed
• Phase: Phase 2
• First received: November 30, 2004
• Last updated: January 28, 2014
• Start date: September 2004
• Est. completion date: August 2009

Study information

• Verified date: January 2014
• Source: Seattle Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 304
• Est. completion date: August 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 12 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Chronic Disease
• Cystic Fibrosis
• Fibrosis
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical College	Albany	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University Cystic Fibrosis Center	Atlanta	Georgia
United States	Medical College of Georgia	Augusta	Georgia
United States	Children's Hospital Denver	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Children's Hospital, Boston	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Vermont Children's Hospital at Fletcher Allen Health Care	Burlington	Vermont
United States	University of North Carolina, Chapel Hill	Chapel Hill	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Rainbow Babies & Children's Hospital	Cleveland	Ohio
United States	Children's Hospital	Columbus	Ohio
United States	Children's Medical Center	Dayton	Ohio
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Cook Children's Medical Center	Ft. Worth	Texas
United States	Spectrum Health Hospitals - DeVos Children's	Grand Rapids	Michigan
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital/Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky	Lexington	Kentucky
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	LeBonheur Children's Medical Center	Memphis	Tennessee
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals & Clinics	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Northern California Kaiser Cystic Fibrosis Center	Oakland	California
United States	University of Nebraska	Omaha	Nebraska
United States	Stanford University	Palo Alto	California
United States	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health Sciences University	Portland	Oregon
United States	University of Rochester	Rochester	New York
United States	University of Utah	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California
United States	Children's Hospital & Regional Medical Center	Seattle	Washington
United States	Cardinal Glennon Children's Hospital	St. Louis	Missouri
United States	Washington University School of Medicine	St. Louis	Missouri
United States	All Children's Hospital Cystic Fibrosis Center	St. Petersburg	Florida
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	New York Medical College	Valhalla	New York
United States	duPont Hospital for Children	Wilmington	Delaware
United States	University of Massachusetts Memorial Health Care	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Seattle Children's Hospital	CF Therapeutics Development Network Coordinating Center, Cystic Fibrosis Foundation Therapeutics, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. Compar — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No