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

NCT ID: NCT00097773

Last Updated: 2014-02-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 304 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-09-30
• Study Completion Date: 2009-08-31

Brief 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.

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.

Conditions

Cystic Fibrosis; Pulmonary Disease, Chronic Obstructive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Cycled TOBI & placebo

Tobramycin inhalation solution and oral placebo for six consecutive quarterly cycles

Group Type: PLACEBO_COMPARATOR

Tobramycin solution for inhalation (TOBI)

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Cycled TOBI & oral ciprofloxacin

Tobramycin solution for inhalation and oral ciprofloxacin for six consecutive quarterly cycles.

Group Type: ACTIVE_COMPARATOR

Tobramycin solution for inhalation (TOBI)

Intervention Type: DRUG

Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days administered only when quarterly respiratory cultures are found positive for Pa.

Oral ciprofloxacin

Intervention Type: DRUG

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.

Culture based TOBI & placebo

Tobramycin solution for inhalation and oral placebo administered only when quarterly respiratory cultures are found positive for Pa.

Group Type: PLACEBO_COMPARATOR

Tobramycin solution for inhalation (TOBI)

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Culture based TOBI & oral cipro

Tobramycin solution for inhalation and oral ciprofloxacin administered only when quarterly respiratory cultures are found positive for Pa.

Group Type: ACTIVE_COMPARATOR

Tobramycin solution for inhalation (TOBI)

Intervention Type: DRUG

Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days administered only when quarterly respiratory cultures are found positive for Pa.

Oral ciprofloxacin

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

TOBI, TIS; Placebo; Cipro; Ciprofloxacin

Eligibility 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Cystic Fibrosis Foundation

OTHER

Sponsor Role: collaborator

CF Therapeutics Development Network Coordinating Center

NETWORK

Sponsor Role: collaborator

Seattle Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Bonnie Ramsey

Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bonnie W. Ramsey

Role: PRINCIPAL_INVESTIGATOR

University of Washington

George Retsch-Bogart, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Miriam Treggiari, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Children's Hospital of Los Angeles

Los Angeles, California, United States

Northern California Kaiser Cystic Fibrosis Center

Oakland, California, United States

Stanford University

Palo Alto, California, United States

University of California, San Francisco

San Francisco, California, United States

Children's Hospital Denver

Aurora, Colorado, United States

duPont Hospital for Children

Wilmington, Delaware, United States

Nemours Children's Clinic

Jacksonville, Florida, United States

All Children's Hospital Cystic Fibrosis Center

St. Petersburg, Florida, United States

Emory University Cystic Fibrosis Center

Atlanta, Georgia, United States

Medical College of Georgia

Augusta, Georgia, United States

Children's Memorial Hospital

Chicago, Illinois, United States

Riley Hospital/Indiana University

Indianapolis, Indiana, United States

University of Iowa

Iowa City, Iowa, United States

University of Kentucky

Lexington, Kentucky, United States

Maine Medical Center

Portland, Maine, United States

Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Children's Hospital, Boston

Boston, Massachusetts, United States

University of Massachusetts Memorial Health Care

Worcester, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Children's Hospital of Michigan

Detroit, Michigan, United States

Spectrum Health Hospitals - DeVos Children's

Grand Rapids, Michigan, United States

Children's Hospitals & Clinics

Minneapolis, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Children's Mercy Hospital

Kansas City, Missouri, United States

Cardinal Glennon Children's Hospital

St Louis, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska

Omaha, Nebraska, United States

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Monmouth Medical Center

Long Branch, New Jersey, United States

Albany Medical College

Albany, New York, United States

University of Rochester

Rochester, New York, United States

State University of New York Upstate Medical University

Syracuse, New York, United States

New York Medical College

Valhalla, New York, United States

University of North Carolina, Chapel Hill

Chapel Hill, North Carolina, United States

Children's Hospital Medical Center of Akron

Akron, Ohio, 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

Oregon Health Sciences University

Portland, Oregon, United States

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

St. Christopher's Hospital for Children

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

LeBonheur Children's Medical Center

Memphis, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Texas Children's Hospital

Houston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Vermont Children's Hospital at Fletcher Allen Health Care

Burlington, Vermont, United States

University of Virginia

Charlottesville, Virginia, United States

Children's Hospital & Regional Medical Center

Seattle, Washington, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 19470318 (View on PubMed)

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.

Reference Type: RESULT

PMID: 21893650 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26288390 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25972024 (View on PubMed)

Other Identifiers

U01HL080310

Identifier Type: NIH

Identifier Source: secondary_id

View Link

169

Identifier Type: -

Identifier Source: org_study_id