Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, CF
Brief summary
To provide efficacy and safety data comparing two dosing schedules of Tobramycin Inhalation Powder (TIP) for the treatment of pulmonary Pseudomonas aeruginosa in patients with cystic fibrosis.
Interventions
Tobramycin Inhalation Powder 112 mg (four 28-mg capsules) taken via inhaler once or twice a day, depending on study arm
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent, HIPPA (Health Insurance Portability and Accountability Act) authorization (where applicable), and assent (as appropriate) prior to the performance of any study-related procedure. 2. Confirmed diagnosis of CF 3. FEV1 at screening (Visit 1) ≥25% and ≤ 80% of normal predicted values for age, sex, and height 4. P. aeruginosa must be present within 6 months prior to screening and at screening 5. Able to comply with all protocol requirements 6. Clinically stable in the opinion of the investigator
Exclusion criteria
1. History of Burkholderia cenocepacia (Bcc) complex within 2 years prior to screening and/or Bcc complex at screening 2. Hemoptysis more than 60 cc at any time within 30 days prior to study drug administration 3. History of hearing loss or chronic tinnitus deemed clinically significant by the investigator 4. Serum creatinine 2 mg/dL or greater, BUN 40 mg/dL or greater, or an abnormal urinalysis defined as 2+ or greater proteinuria at screening 5. Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics 6. Patients who are unable to discontinue previously received inhaled antibiotic regimen(s) (inhaled antibiotics are not allowed other than study drug) 7. Use of inhaled aminoglycosides within 28 days prior to study drug administration (Visit 2) 8. Use of systemic anti-pseudomonal antibiotics within 28 days prior to study drug administration 9. Use of loop diuretics within 7 days prior to study drug administration 10. Administration of any investigational drug within 30 days prior to enrollment or 5 half-lives, whichever is longer 11. Signs and symptoms of acute pulmonary disease, e.g , pneumonia, pneumothorax 12. Hospitalization during the baseline visit 13. History of malignancy 14. Patients with clinically significant laboratory abnormalities (not associated with the study indication) at screening 15. Patients with other clinically significant conditions (not associated with the study indication) which might interfere with the assessment of this study 16. Patients or caregivers with a history of noncompliance to medical regimens and patients or caregivers who are considered potentially unreliable 17. Pregnant or nursing (lactating) women 18. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Expiratory Volume in 1 Second ( FEV1) Percent Predicted | Baseline and Day 168 | The Forced Expiratory Volume in 1 second (FEV1) percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 percent predicted indicates improvement in lung function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Use Anti-pseudomonal Antibiotic | Day 1 to day 168 | Percentage of patients who use anti-pseudomonal antibiotic will be assessed. |
| Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted | Baseline and Day 168 | The Forced Expiratory Volume in 1 second (FEV1) percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 percent predicted indicates improvement in lung function. |
| Percent Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted | Baseline and Day 168 | Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC will be assessed via spirometry. A positive change from baseline in FVC indicates improvement in lung function. |
| Percent Change From Baseline in Forced Expiratory Flow (FEF) 25%-75% Predicted | Baseline and day 168 | The Forced Expiratory Flow (FEF) 25%-75% measurement describes the amount of air expelled from the lungs during the middle half (25% - 75%) of the forced vital capacity test and is measured using spirometry. A positive change from baseline in FEF indicates improvement in lung function. The predicted percent will be assessed. |
| Change From Baseline in Pseudomonas Aeruginosa Sputum Density | Baseline and day 168 | Change from baseline in Pseudomonas aeruginosa sputum density will be measured by log10 colony forming units per gram of sputum. |
| Time to First Usage of Anti-pseudomonal Antibiotic | Day 1 to day 168 | Time to first usage of anti-pseudomonal antibiotic per patient will be assessed by number of days |
| Percentage of Patients With Hospitalizations Due to Respiratory-related Events | Day 1 to day 168 | Percentage of patients with hospitalization due to respiratory-related events |
| Length of Hospital Stay Due to Respiratory-related Events | Day 1 to day 168 | The number of days in length of hospital stay per patient due to respiratory-related events will be measured. |
| Duration of Use of Anti-pseudomonal Antibiotic | Day 1 to day 168 | Number of days of use of anti-pseudomonal antibiotic per patient will be assessed. |
| Change From Baseline in Tobramycin Minimal Inhibitory Concentration for Pseudomonas Aeruginosa | Baseline and day 168 | Change from baseline in tobramycin minimal inhibitory concentration for Pseudomonas aeruginosa will be measured by laboratory testing. |
| Time to First Hospitalization Due to Respiratory-related Events | Day 1 to day 168 | Time to the first hospitalization due to respiratory-related events (number of days) per patient. |
Countries
United States
Participant flow
Recruitment details
The study intended to randomize 200 patients in 18 months; however, after 9 months, only 25 patients were randomized, with a screen fail rate of 50%. Due to premature termination, summaries and analyses planned in the protocol were eliminated in the statistical analysis plan prior to database lock. No inferential analysis will be provided.
Participants by arm
| Arm | Count |
|---|---|
| Tobramycin Inhalation Powder Once Daily Tobramycin Inhalation Powder (112 mg) once daily during 168 days | 16 |
| Tobramycin Inhalation Powder Twice Daily Tobramycin Inhalation Powder (112 mg) twice daily on days 1-28, days 57-84 and days 113-140 | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 10 | 11 |
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | unsatisfactory therapeutic effect | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Tobramycin Inhalation Powder Once Daily | Tobramycin Inhalation Powder Twice Daily | Total |
|---|---|---|---|
| Age, Continuous | 34.9 year STANDARD_DEVIATION 14.31 | 26.5 year STANDARD_DEVIATION 11.09 | 30.7 year STANDARD_DEVIATION 13.3 |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 16 | 12 / 15 | 25 / 31 |
| serious Total, serious adverse events | 3 / 16 | 1 / 15 | 4 / 31 |
Outcome results
Primary
Change From Baseline in Forced Expiratory Volume in 1 Second ( FEV1) Percent Predicted
The Forced Expiratory Volume in 1 second (FEV1) percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 percent predicted indicates improvement in lung function.
Time frame: Baseline and Day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Change From Baseline in Pseudomonas Aeruginosa Sputum Density
Change from baseline in Pseudomonas aeruginosa sputum density will be measured by log10 colony forming units per gram of sputum.
Time frame: Baseline and day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Change From Baseline in Tobramycin Minimal Inhibitory Concentration for Pseudomonas Aeruginosa
Change from baseline in tobramycin minimal inhibitory concentration for Pseudomonas aeruginosa will be measured by laboratory testing.
Time frame: Baseline and day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Duration of Use of Anti-pseudomonal Antibiotic
Number of days of use of anti-pseudomonal antibiotic per patient will be assessed.
Time frame: Day 1 to day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Length of Hospital Stay Due to Respiratory-related Events
The number of days in length of hospital stay per patient due to respiratory-related events will be measured.
Time frame: Day 1 to day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Percentage of Patients Who Use Anti-pseudomonal Antibiotic
Percentage of patients who use anti-pseudomonal antibiotic will be assessed.
Time frame: Day 1 to day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Percentage of Patients With Hospitalizations Due to Respiratory-related Events
Percentage of patients with hospitalization due to respiratory-related events
Time frame: Day 1 to day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Percent Change From Baseline in Forced Expiratory Flow (FEF) 25%-75% Predicted
The Forced Expiratory Flow (FEF) 25%-75% measurement describes the amount of air expelled from the lungs during the middle half (25% - 75%) of the forced vital capacity test and is measured using spirometry. A positive change from baseline in FEF indicates improvement in lung function. The predicted percent will be assessed.
Time frame: Baseline and day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Percent Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
The Forced Expiratory Volume in 1 second (FEV1) percent predicted expresses FEV1 as a percentage of the predicted values for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 percent predicted indicates improvement in lung function.
Time frame: Baseline and Day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Percent Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted
Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC will be assessed via spirometry. A positive change from baseline in FVC indicates improvement in lung function.
Time frame: Baseline and Day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Time to First Hospitalization Due to Respiratory-related Events
Time to the first hospitalization due to respiratory-related events (number of days) per patient.
Time frame: Day 1 to day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)
Secondary
Time to First Usage of Anti-pseudomonal Antibiotic
Time to first usage of anti-pseudomonal antibiotic per patient will be assessed by number of days
Time frame: Day 1 to day 168
Population: The study intended to randomize 200 patients within 18 months; however, after 9 months, only 32 patients were successfully randomized, with a screen fail rate of 50%. Study was terminated with only safety data analyzed. No data collected met the pre-specified powering of 200 patients needed for analysis (only 32 patients randomized)