Cystic Fibrosis, Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Lung Diseases, Chronic Obstructive Pulmonary Disease
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.
Interventions
DRUGTobramycin 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.
DRUGOral 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.
DRUGOral 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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Cystic Fibrosis Foundation
CF Therapeutics Development Network Coordinating Center
Seattle Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to 12 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization | Measured over the 18 month study | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With a Pa Positive Culture | Week 10 (after initial treatment course for Pa) through Month 18 | 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 | Measured over the 18 month time period | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment was conducted from December 2004 to June 2009 from 55 Cystic Fibrosis Foundation accredited clinical centers throughout the US
Participants by arm
| Arm | Count |
|---|---|
| Cycled TIS w/Placebo TOBI and oral placebo for six consecutive quarterly cycles | 76 |
| Cycled TIS w/Cipro TOBI and oral ciprofloxacin for six consecutive quarterly cycles | 76 |
| Culture-Based TIS w/Placebo TOBI and oral placebo administered only when quarterly respiratory cultures are found positive for Pseudomonas aeruginosa (Pa) | 76 |
| Culture-Based TIS w/Cipro TOBI and oral ciprofloxacin administered only when quarterly respiratory cultures are found positive for Pseudomonas aeruginosa (Pa) | 76 |
| Total | 304 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 0 | 1 |
| Overall Study | Other | 1 | 0 | 2 | 0 |
| Overall Study | Physician Decision | 2 | 2 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 3 | 1 |
Baseline characteristics
| Characteristic | Cycled TIS w/Cipro | Culture-Based TIS w/Placebo | Cycled TIS w/Placebo | Culture-Based TIS w/Cipro | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 76 Participants | 76 Participants | 76 Participants | 76 Participants | 304 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 5.9 years STANDARD_DEVIATION 3.28 | 6.0 years STANDARD_DEVIATION 3.74 | 5.8 years STANDARD_DEVIATION 3.43 | 5.0 years STANDARD_DEVIATION 3.58 | 5.7 years STANDARD_DEVIATION 3.51 |
| Region of Enrollment United States | 76 participants | 76 participants | 76 participants | 76 participants | 304 participants |
| Sex: Female, Male Female | 32 Participants | 40 Participants | 45 Participants | 37 Participants | 154 Participants |
| Sex: Female, Male Male | 44 Participants | 36 Participants | 31 Participants | 39 Participants | 150 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 65 / 76 | 67 / 76 | 65 / 76 | 73 / 76 |
| serious Total, serious adverse events | 18 / 76 | 21 / 76 | 17 / 76 | 27 / 76 |
Outcome results
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.
Time frame: Measured over the 18 month study
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cycled TIS | Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization | 24 number of participants |
| Culture-Based TIS | Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization | 26 number of participants |
| Oral Ciprofloxacin | Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization | 29 number of participants |
| Oral Placebo | Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization | 21 number of participants |
Comparison: The primary analysis compared the pooled Cycled Therapy group (n=152) vs. the Pooled culture-based therapy group (n=152). The null hypothesis was no difference between groups in the risk of pulmonary exacerbation requiring IV antibiotics or hospitalization. Assuming a total sample size of 300 (150 per group), the study provided 80% power to detect at least a 40% reduction in the risk of exacerbation in the cycled group as compared to the culture-based group at the two-sided alpha level of 5%.p-value: 0.8695% CI: [0.54, 1.66]Regression, Cox
Comparison: A secondary comparison was between the pooled oral cipro (n=152)and pooled placebo groups (n=152. Null hypothesis was no difference between groups.p-value: 0.295% CI: [0.82, 2.54]Regression, Cox
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.
Time frame: Measured over the 18 month time period
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cycled TIS | Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics | 70 participants |
| Culture-Based TIS | Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics | 81 participants |
| Oral Ciprofloxacin | Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics | 83 participants |
| Oral Placebo | Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics | 68 participants |
Comparison: The analysis compared the pooled Cycled Therapy group (n=152) vs. the Pooled culture-based therapy group (n=152). The null hypothesis was no difference between groups in the risk of pulmonary exacerbation.p-value: 0.1895% CI: [0.58, 1.11]Regression, Cox
Comparison: This analysis was between the pooled oral cipro (n=152)and pooled placebo groups (n=152. Null hypothesis was no difference between groups.p-value: 0.1295% CI: [0.94, 1.78]Regression, Cox
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
Time frame: Week 10 (after initial treatment course for Pa) through Month 18
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cycled TIS | Proportion of Participants With a Pa Positive Culture | 2 Pa positive cultures | 9 Participants |
| Cycled TIS | Proportion of Participants With a Pa Positive Culture | 3 or more Pa positive cultures | 13 Participants |
| Cycled TIS | Proportion of Participants With a Pa Positive Culture | 1 Pa positive culture | 17 Participants |
| Cycled TIS | Proportion of Participants With a Pa Positive Culture | No Pa positive cultures | 109 Participants |
| Cycled TIS | Proportion of Participants With a Pa Positive Culture | Missing | 4 Participants |
| Culture-Based TIS | Proportion of Participants With a Pa Positive Culture | No Pa positive cultures | 85 Participants |
| Culture-Based TIS | Proportion of Participants With a Pa Positive Culture | 1 Pa positive culture | 38 Participants |
| Culture-Based TIS | Proportion of Participants With a Pa Positive Culture | Missing | 2 Participants |
| Culture-Based TIS | Proportion of Participants With a Pa Positive Culture | 3 or more Pa positive cultures | 9 Participants |
| Culture-Based TIS | Proportion of Participants With a Pa Positive Culture | 2 Pa positive cultures | 18 Participants |
| Oral Ciprofloxacin | Proportion of Participants With a Pa Positive Culture | No Pa positive cultures | 97 Participants |
| Oral Ciprofloxacin | Proportion of Participants With a Pa Positive Culture | 1 Pa positive culture | 22 Participants |
| Oral Ciprofloxacin | Proportion of Participants With a Pa Positive Culture | 2 Pa positive cultures | 13 Participants |
| Oral Ciprofloxacin | Proportion of Participants With a Pa Positive Culture | Missing | 6 Participants |
| Oral Ciprofloxacin | Proportion of Participants With a Pa Positive Culture | 3 or more Pa positive cultures | 14 Participants |
| Oral Placebo | Proportion of Participants With a Pa Positive Culture | 3 or more Pa positive cultures | 8 Participants |
| Oral Placebo | Proportion of Participants With a Pa Positive Culture | 2 Pa positive cultures | 14 Participants |
| Oral Placebo | Proportion of Participants With a Pa Positive Culture | Missing | 0 Participants |
| Oral Placebo | Proportion of Participants With a Pa Positive Culture | 1 Pa positive culture | 33 Participants |
| Oral Placebo | Proportion of Participants With a Pa Positive Culture | No Pa positive cultures | 97 Participants |
Comparison: Null hypothesis is that there is no difference between pooled cycled and culture-based treatment groups in the odds of a Pa positive culture over the 18 month study.p-value: 0.2895% CI: [0.49, 1.23]Regression, Logistic
Comparison: Null hypothesis is that there is no difference between pooled cipro and placebo treatment groups in the odds of a Pa positive culture over the 18 month study.p-value: 0.6795% CI: [0.71, 1.71]Regression, Logistic