Comparison of Two Treatment Regimens to Reduce PA Infection in Children With Cystic Fibrosis - Full Text View

Sponsor:	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators:	Cystic Fibrosis Foundation CF Therapeutics Development Network Coordinating Center
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00097773

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 and oral ciprofloxacin Drug: Tobramycin solution for inhalation and oral placebo	Phase II

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:

Genetics Home Reference related topics: cystic fibrosis

MedlinePlus related topics: Antibiotics COPD (Chronic Obstructive Pulmonary Disease) Cystic Fibrosis

Drug Information available for: Tobramycin Tobramycin sulfate Ciprofloxacin Ciprofloxacin hydrochloride Ciprofloxacin lactate

U.S. FDA Resources

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

Proportion of recurrent PA positive cultures [ Time Frame: Measured at Month 18 ] [ Designated as safety issue: No ]
Time to occurrence of pulmonary exacerbations [ Time Frame: Measured at Month 18 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Safety of antibiotic therapy [ Time Frame: Measured at Month 18 ] [ Designated as safety issue: Yes ]
Clinical variables, including hospitalization, proportion of participants with pulmonary exacerbations, linear growth, weight gain, and forced expiratory volume in one second (FEV1) [ Time Frame: Measured at Month 18 ] [ Designated as safety issue: Yes ]
Microbiology findings of PA isolates [ Time Frame: Measured at Month 18 ] [ Designated as safety issue: No ]
PA serology [ Time Frame: Measured at Month 18 ] [ Designated as safety issue: No ]

Estimated Enrollment:	300
Study Start Date:	September 2004
Estimated Study Completion Date:	August 2009
Estimated Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: 1 TOBI and oral placebo for six consecutive quarterly cycles	Drug: Tobramycin solution for inhalation and oral placebo Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days. For the initial 14 days of this 28-day period, the participants will also receive oral placebo, 15-20 mg/kg/dose, twice daily. Other Names: TOBI Placebo
Active Comparator: 2 TOBI and oral ciprofloxacin for six consecutive quarterly cycles	Drug: Tobramycin solution for inhalation and oral ciprofloxacin Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days. For the initial 14 days of this 28-day period, the participants will also receive oral ciprofloxacin, 15-20 mg/kg/dose, twice daily. Other Names: TOBI Cipro
Placebo Comparator: 3 TOBI and oral placebo administered only when quarterly respiratory cultures are found positive for PA	Drug: Tobramycin solution for inhalation and oral placebo Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days. For the initial 14 days of this 28-day period, the participants will also receive oral placebo, 15-20 mg/kg/dose, twice daily. Other Names: TOBI Placebo
Active Comparator: 4 TOBI and oral ciprofloxacin administered only when quarterly respiratory cultures are found positive for PA	Drug: Tobramycin solution for inhalation and oral ciprofloxacin Tobramycin solution for inhalation, 300 mg, administered twice daily for 28 days. For the initial 14 days of this 28-day period, the participants will also receive oral ciprofloxacin, 15-20 mg/kg/dose, twice daily. Other Names: TOBI Cipro

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 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 ALT and/or 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

Show 54 Study Locations

Sponsors and 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
Principal Investigator:	Miriam Treggiari, MD	University of Washington

More Information

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. Epub 2009 Jan 15.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Bonnie Ramsey, MD, CF Therapeutics Development Network Coordinating Center
ClinicalTrials.gov Identifier:	NCT00097773 History of Changes
Other Study ID Numbers:	169, U01 HL80310
Study First Received:	November 30, 2004
Last Updated:	March 18, 2009
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):

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 February 09, 2012