Cystic Fibrosis
Conditions
Keywords
cystic fibrosis, P. aeruginosa, tobramycin
Brief summary
The objectives of the study are to demonstrate that Tobrineb®/Actitob®/Bramitob® is non-inferior to TOBI® in the primary efficacy variable, forced expiratory volume in one second (FEV1) percent of predicted normal, and to compare the safety in participants with cystic fibrosis and chronic infection of the lungs with Pseudomonas aeruginosa.
Interventions
DRUGtobramycin / Bramitob
300mg/4ml solution, via a nebuliser, over a 4-week treatment in a twice-daily regimen
DRUGtobramycin / TOBI
300mg/5ml solution administered via nebuliser, over a 4-week treatment in a twice-daily regimen
Sponsors
Chiesi Farmaceutici S.p.A.
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
* Patients of either sex aged ≥ 6; * Clinical diagnosis of cystic fibrosis defined as: (1)Patients preferably registered in the National Registry of CF (or other documents depending on country legislation); (2) Evidence of two or more typical pulmonary clinical features observed in CF, e.g., persistent colonization/infection with typical CF pathogens, chronic cough and sputum production, persistent chest radiography abnormalities, airway obstruction, nasal polyps and/or digital clubbing; * Positive response in the standard sweat test (sweat chloride concentration ≥ 60 mmol/l for the standard method or ≥ 80 mmol/L for a microduct technique) documented in the clinical records and/or gene mutation documented in the clinical records; * Chronic colonization of P. aeruginosa: presence in a sputum or throat culture of a minimum of 2 positive samples for P. aeruginosa over the previous 12 months and/or presence of more than two precipitating antibodies against P. aeruginosa; * Sputum containing P. aeruginosa susceptible to tobramycin (defined as a zone diameter ≥ 16 mm after testing with 10 µg tobramycin disk or as a minimal inhibition concentration based on microdilution testing system) as identified by local laboratory at screening visit; * Forced expiratory volume in 1 sec (FEV₁) ≥ 40% and ≤ 80% of the predicted normal value; * Written informed consent obtained by parents/legal representative according to local regulations) and by the patient (when appropriate).
Exclusion criteria
* Administration of antipseudomonal antibiotic therapy by any route in the previous 4 weeks; * Evidence of impaired renal function (serum creatinine level ≥ 1.5 mg/dl); * Evidence of impaired auditory function (auditory threshold in either ear above 20 dB at frequencies between 250 and 8000Hz); * Sputum culture containing Burkholderia cepacia; * Patients with end-stage lung disease, candidates for heart-lung transplantation; * History of other clinically significant cardiac, renal, neurological, gastrointestinal, hepatic or endocrine disease related to cystic fibrosis, whose sequelae and/or treatment can interfere with the results of the present study; * Female subjects: pregnant or with active desire to be pregnant, lactating mother or lack of efficient contraception in a subject with child-bearing potential (i.e., contraceptive methods other than rod containing a hormone that prevents user from getting pregnant and that will be placed under the skin, syringes that contain a contraceptive hormone, combined birth control pill, i.e., such that contains two hormones, some intrauterine devices (IUDs) and sexual abstinence). A pregnancy test in urine is to be carried out in women of a fertile age at screening and at the last clinic visit; * Known hypersensitivity to aminoglycosides; * Patients with evidence of alcohol or drug abuse, likely to be not compliant with the study protocol or likely to be not compliant with the study treatments; * Participation in another clinical trial with an investigational drug in the four weeks preceding the screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of the Treatment Period of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Day 0 (baseline), Week 4 | Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEV1 values for children were different than the reference normal values used with adult participants. Three measurements were collected and the greatest FEV1 value was recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Day 0 (baseline), Week 2, Week 4, Week 8 | Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Three measurements were collected and the greatest FEV1 value was recorded. Observed values are summarized (without last observation carry forward). |
| Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Day 0 (baseline), Week 2, Week 4, Week 8 | FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. It is measured via spirometry. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FVC values for children were different than the reference normal values used with adult participants. |
| Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Day 0 (baseline), Week 2, Week 4, Week 8 | FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. It is measured via spirometry. |
| Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Day 0 (baseline), Week 2, Week 4, Week 8 | Difference in the forced expiratory flow rate in mid-exhalation as a percent of predicted to standard values measured from baseline to weeks 2 (treated), 4 (treated), and 8 (untreated). Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEF 25-75% values for children were different than the reference normal values used with adult participants. |
| Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Day 0 (baseline), Week 2, Week 4, Week 8 | Difference in the forced expiratory flow rate in mid-exhalation measured from baseline to weeks 2 (treated), 4 (treated), and 8 (untreated). |
| Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum | Day -10 to -1 (baseline), Week 4, Week 8 | If a participant had more than one Pseudomonas aeruginosa (PA) morphotype at a given visit, and therefore more than one bacterial load value, then the bacterial load value corresponding to the highest tobramycin minimal inhibitory concentration (MIC) value regardless of the PA morphotype was used. If the tobramycin MIC value was the same for different PA morphotypes, then the bacterial load value corresponding to morphotype 1 (mucoid colony) was used. If morphotype 1 was not available, bacterial load value corresponding to morphotype 2 (dry colony) was used. |
| Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Day 0 (baseline), Week 2, Week 4, Week 8 | Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEV1 values for children were different than the reference normal values used with adult participants. Three measurements were collected and the greatest FEV1 value was recorded. Observed values are summarized (without last observation carry forward). |
| Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa | Week 4, Week 8 | MIC90 is the concentration of tobramycin required to inhibit 90% of Pseudomonas aeruginosa. MIC values were calculated for three different Pseudomonas aeruginosa (PA) strains: * Morphotype 1: mucoid * Morphotype 2: dry * Morphotype 3: variant Overall MIC90 values are reported. If a participant has more than one PA morphotype at a given visit, then the highest tobramycin MIC value was used, regardless of PA morphotype. If a participant has more than one available result for each morphotype then the highest tobramycin MIC value was used. If the tobramycin MIC values are equal then the MIC value for the isolate with the highest bacterial load value was used. |
| Microbiological Outcome Summary by Visit | Day -10 to -1 (screening), Weeks 4 and 8 | Microbiological outcomes are derived considering all P. aeruginosa (PA) morphotypes together. Week 4 and Week 8 microbiological outcomes: * Eradication = elimination of PA * Persistence = persistence of PA detected at previous visit * Superinfection = appearance of a pathogen (other than PA) not detected at previous visit * Re-infection (week 8 only) = re-appearance of PA detected at Screening and eradicated at Week 4 Superinfection supersedes eradication. Persistence for P. aeruginosa supersedes superinfection. Re-infection for P. aeruginosa supersedes superinfection. |
| Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Day 0 (baseline), Weeks 2, 4 and 8 | Body weight was measured at all study visits as part of the physical examination. |
| Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Day 0 (baseline), Weeks 2, 4 and 8 | — |
| Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 0 to Week 8 | Treatment-Emergent Adverse Events defined as adverse events occurring after the first intake of study treatment (or the same day). The investigator assessed relation to study treatment as a binary question: Reasonable possibility of relatedness or no reasonable possibility of relatedness. The expression reasonable possibility of relatedness is meant to convey in general that there are facts (evidence) or arguments meant to suggest a causal relationship. A serious AE results in death, is life-threatening, requires hospitalization or prolongation of existing inpatient hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or an important medical event. The investigator rates the severity of the AE based on a three point scale: mild, moderate or severe. A severe event prevents any usual routine activity of the participant and causes severe discomfort. |
| Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Day -10 to -1 (screening), Weeks 4 and 8 | The potential ototoxic effects (hearing loss) of tobramycin were investigated by performing audiometric tests. Participants with a loss of auditory acuity greater than the 20 decibels auditory threshold are reported. |
| Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa | Week 4, Week 8 | MIC50 is the concentration of tobramycin required to inhibit 50% of Pseudomonas aeruginosa. MIC values were calculated for three different Pseudomonas aeruginosa (PA) strains: * Morphotype 1: mucoid * Morphotype 2: dry * Morphotype 3: variant Overall MIC50 values are reported. If a participant has more than one PA morphotype at a given visit, then the highest tobramycin MIC value was used, regardless of PA morphotype. If a participant has more than one available result for each morphotype then the highest tobramycin MIC value was used. If the tobramycin MIC values are equal then the MIC value for the isolate with the highest bacterial load value was used. |
Countries
Czechia, France, Germany, Hungary, Poland, Russia, Spain, Ukraine
Participant flow
Pre-assignment details
406 participants screened, 324 participants randomized
Participants by arm
| Arm | Count |
|---|---|
| Bramitob tobramycin / Bramitob administered 300mg twice a day for 4 weeks | 156 |
| TOBI tobramycin / TOBI administered 300mg twice a day for 4 weeks | 168 |
| Total | 324 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 4 Weeks ON Treatment | Adverse Event | 2 | 4 |
| 4 Weeks ON Treatment | Protocol Violation | 1 | 2 |
| 4 Weeks ON Treatment | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | TOBI | Total | Bramitob |
|---|---|---|---|
| Age, Continuous | 15.74 years STANDARD_DEVIATION 7.24 | 15.84 years STANDARD_DEVIATION 6.99 | 15.95 years STANDARD_DEVIATION 6.74 |
| Age, Customized 13-17 years | 62 participants | 112 participants | 50 participants |
| Age, Customized > 17 years | 52 participants | 109 participants | 57 participants |
| Age, Customized 6-12 years | 54 participants | 103 participants | 49 participants |
| Body Mass Index | 17.79 kilograms/meters^2 STANDARD_DEVIATION 3.32 | 17.68 kilograms/meters^2 STANDARD_DEVIATION 3.22 | 17.55 kilograms/meters^2 STANDARD_DEVIATION 3.12 |
| Forced Expiratory Volume in 1 second (FEV1) <50 % predicted | 38 participants | 75 participants | 37 participants |
| Forced Expiratory Volume in 1 second (FEV1) >=50 % predicted | 130 participants | 249 participants | 119 participants |
| Height | 153.41 centimeters STANDARD_DEVIATION 19.88 | 153.24 centimeters STANDARD_DEVIATION 18.66 | 153.05 centimeters STANDARD_DEVIATION 17.31 |
| Race/Ethnicity, Customized White | 168 participants | 324 participants | 156 participants |
| Sex: Female, Male Female | 83 Participants | 167 Participants | 84 Participants |
| Sex: Female, Male Male | 85 Participants | 157 Participants | 72 Participants |
| Time from diagnosis of chronic colonization of P. aeruginosa | 2.36 years STANDARD_DEVIATION 4.23 | 2.31 years STANDARD_DEVIATION 4.22 | 2.27 years STANDARD_DEVIATION 4.22 |
| Time from first Cystic Fibrosis diagnosis | 11.74 years STANDARD_DEVIATION 6.55 | 11.94 years STANDARD_DEVIATION 6.34 | 12.16 years STANDARD_DEVIATION 6.13 |
| Tobramycin Minimal Inhibitory Concentration (MIC) value <16 mcg/mL | 159 participants | 302 participants | 143 participants |
| Tobramycin Minimal Inhibitory Concentration (MIC) value >=16 mcg/mL | 8 participants | 21 participants | 13 participants |
| Tobramycin Minimal Inhibitory Concentration (MIC) value Missing | 1 participants | 1 participants | 0 participants |
| Use of rhDNase No | 49 participants | 95 participants | 46 participants |
| Use of rhDNase Yes | 119 participants | 229 participants | 110 participants |
| Weight | 43.81 kilograms STANDARD_DEVIATION 16.39 | 43.25 kilograms STANDARD_DEVIATION 15.69 | 42.64 kilograms STANDARD_DEVIATION 14.92 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 156 | 10 / 168 |
| serious Total, serious adverse events | 6 / 156 | 2 / 168 |
Outcome results
Primary
Change From Baseline to End of the Treatment Period of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal
Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEV1 values for children were different than the reference normal values used with adult participants. Three measurements were collected and the greatest FEV1 value was recorded.
Time frame: Day 0 (baseline), Week 4
Population: Intent-to-Treat (ITT) Population, Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bramitob | Change From Baseline to End of the Treatment Period of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | 6.99 percentage predicted FEV1 | Standard Deviation 9.52 |
| TOBI | Change From Baseline to End of the Treatment Period of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | 7.51 percentage predicted FEV1 | Standard Deviation 9.63 |
Comparison: Based on previous studies, the difference between reference and placebo after 4-week treatment is assumed to be about 12% and the non-inferiority margin safely placed at 4.5%. With a between-patient SD of 13.5% and estimated difference between treatments of zero, sample size of 143 per group allows a 80% power to show the non-inferiority of Bramitob® versus TOBI®. Accounting for an expected dropout rate of 11%, a minimum of 160 participants per group is required.p-value: 0.6495% CI: [-2.58, 1.59]ANCOVA
Secondary
Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal
FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. It is measured via spirometry. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FVC values for children were different than the reference normal values used with adult participants.
Time frame: Day 0 (baseline), Week 2, Week 4, Week 8
Population: Intent-to-Treat (ITT) Population, observed values. Differences in number of participants analyzed to the ITT population represent participants who missed visits, or failed to take the FVC test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Week 2 [n=156, 163] | 4.36 percentage predicted FVC | Standard Deviation 10.81 |
| Bramitob | Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Week 4 [n=153, 161] | 4.83 percentage predicted FVC | Standard Deviation 10.05 |
| Bramitob | Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Week 8 [n=153,159] | 2.70 percentage predicted FVC | Standard Deviation 12.3 |
| TOBI | Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Week 2 [n=156, 163] | 5.36 percentage predicted FVC | Standard Deviation 10.03 |
| TOBI | Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Week 4 [n=153, 161] | 5.58 percentage predicted FVC | Standard Deviation 10.86 |
| TOBI | Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | Week 8 [n=153,159] | 5.04 percentage predicted FVC | Standard Deviation 12.21 |
Comparison: Analysis for Week 4p-value: 0.6395% CI: [-2.78, 1.69]ANCOVA
Secondary
Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI)
Time frame: Day 0 (baseline), Weeks 2, 4 and 8
Population: Intent-to-Treat (ITT) Population, observed values. Two participants from both treatment arms were missing data at Week 4. Three participants from Bramitob and 4 participants from TOBI were missing data at Week 8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Week 2 [n=158, 163] | 0.10 kilograms/meters^2 | Standard Deviation 0.28 |
| Bramitob | Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Week 4 [n=156, 161] | 0.12 kilograms/meters^2 | Standard Deviation 0.37 |
| Bramitob | Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Week 8 [n=155,159] | 0.16 kilograms/meters^2 | Standard Deviation 0.48 |
| TOBI | Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Week 2 [n=158, 163] | 0.10 kilograms/meters^2 | Standard Deviation 0.29 |
| TOBI | Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Week 4 [n=156, 161] | 0.13 kilograms/meters^2 | Standard Deviation 0.38 |
| TOBI | Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) | Week 8 [n=155,159] | 0.14 kilograms/meters^2 | Standard Deviation 0.49 |
Secondary
Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight
Body weight was measured at all study visits as part of the physical examination.
Time frame: Day 0 (baseline), Weeks 2, 4 and 8
Population: Intent-to-Treat (ITT) Population, observed values. Two participants from both treatment arms were missing data at Week 4. Three participants from Bramitob and 4 participants from TOBI were missing data at Week 8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Week 2 [n=158, 163] | 0.24 kilograms | Standard Deviation 0.68 |
| Bramitob | Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Week 4 [n=156, 161] | 0.39 kilograms | Standard Deviation 0.9 |
| Bramitob | Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Week 8 [n=155,159] | 0.60 kilograms | Standard Deviation 1.14 |
| TOBI | Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Week 2 [n=158, 163] | 0.22 kilograms | Standard Deviation 0.72 |
| TOBI | Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Week 4 [n=156, 161] | 0.42 kilograms | Standard Deviation 0.97 |
| TOBI | Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Week 8 [n=155,159] | 0.53 kilograms | Standard Deviation 1.27 |
Secondary
Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1)
Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Three measurements were collected and the greatest FEV1 value was recorded. Observed values are summarized (without last observation carry forward).
Time frame: Day 0 (baseline), Week 2, Week 4, Week 8
Population: Intent-to-Treat (ITT) Population, observed values. Differences in number of participants analyzed to the ITT population represent participants who missed visits, or failed to take the FEV1 test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Week 2 [n=158, 163] | 0.18 liters | Standard Deviation 0.27 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Week 4 [n=155, 161] | 0.20 liters | Standard Deviation 0.29 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Week 8 [n=155,159] | 0.16 liters | Standard Deviation 0.33 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Week 2 [n=158, 163] | 0.19 liters | Standard Deviation 0.27 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Week 4 [n=155, 161] | 0.22 liters | Standard Deviation 0.28 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Week 8 [n=155,159] | 0.16 liters | Standard Deviation 0.32 |
Comparison: Analysis for Week 4p-value: 0.63495% CI: [-0.08, 0.05]ANCOVA
Secondary
Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC)
FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. It is measured via spirometry.
Time frame: Day 0 (baseline), Week 2, Week 4, Week 8
Population: Intent-to-Treat (ITT) Population, observed values. Differences in number of participants analyzed to the ITT population represent participants who missed visits, or failed to take the FVC test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Week 2 [n=156, 163] | 0.14 liters | Standard Deviation 0.34 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Week 4 [n=153, 161] | 0.16 liters | Standard Deviation 0.34 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Week 8 [n=153,159] | 0.10 liters | Standard Deviation 0.38 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Week 2 [n=156, 163] | 0.16 liters | Standard Deviation 0.32 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Week 4 [n=153, 161] | 0.18 liters | Standard Deviation 0.36 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | Week 8 [n=153,159] | 0.16 liters | Standard Deviation 0.39 |
Comparison: Analysis for Week 4p-value: 0.69395% CI: [-0.09, 0.06]ANCOVA
Secondary
Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%)
Difference in the forced expiratory flow rate in mid-exhalation measured from baseline to weeks 2 (treated), 4 (treated), and 8 (untreated).
Time frame: Day 0 (baseline), Week 2, Week 4, Week 8
Population: Intent-to-Treat (ITT) Population, observed values. Differences in number of participants analyzed to the ITT population represent participants who missed visits, or failed to take the FEF 25-75% test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Week 2 [n=156, 162] | 0.32 liters/second | Standard Deviation 0.5 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Week 4 [n=154, 159] | 0.34 liters/second | Standard Deviation 0.48 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Week 8 [n=154,158] | 0.28 liters/second | Standard Deviation 0.57 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Week 2 [n=156, 162] | 0.28 liters/second | Standard Deviation 0.56 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Week 4 [n=154, 159] | 0.29 liters/second | Standard Deviation 0.57 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Week 8 [n=154,158] | 0.21 liters/second | Standard Deviation 0.67 |
Comparison: Analysis for Week 4p-value: 0.50595% CI: [-0.08, 0.15]ANCOVA
Secondary
Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal
Difference in the forced expiratory flow rate in mid-exhalation as a percent of predicted to standard values measured from baseline to weeks 2 (treated), 4 (treated), and 8 (untreated). Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEF 25-75% values for children were different than the reference normal values used with adult participants.
Time frame: Day 0 (baseline), Week 2, Week 4, Week 8
Population: Intent-to-Treat (ITT) Population, observed values. Differences in number of participants analyzed to the ITT population represent participants who missed visits, or failed to take the FEF 25-75% test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Week 2 [n=156, 162] | 10.30 percentage predicted FEF 25-75% | Standard Deviation 17.07 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Week 4 [n=154, 159] | 10.44 percentage predicted FEF 25-75% | Standard Deviation 15.17 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Week 8 [n=154,158] | 9.05 percentage predicted FEF 25-75% | Standard Deviation 19.59 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Week 2 [n=156, 162] | 8.57 percentage predicted FEF 25-75% | Standard Deviation 19 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Week 4 [n=154, 159] | 9.32 percentage predicted FEF 25-75% | Standard Deviation 17.99 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Week 8 [n=154,158] | 6.41 percentage predicted FEF 25-75% | Standard Deviation 20.46 |
Comparison: Analysis for Week 4p-value: 0.77795% CI: [-3.06, 4.09]ANCOVA
Secondary
Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal
Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEV1 values for children were different than the reference normal values used with adult participants. Three measurements were collected and the greatest FEV1 value was recorded. Observed values are summarized (without last observation carry forward).
Time frame: Day 0 (baseline), Week 2, Week 4, Week 8
Population: Intent-to-Treat (ITT) Population, observed values. Differences in number of participants analyzed to the ITT population represent participants who missed visits, or failed to take the FEV1 test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Week 2 [n=158, 163] | 6.70 percentage predicted FEV1 | Standard Deviation 9.99 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Week 4 [N=155, 161] | 7.10 percentage predicted FEV1 | Standard Deviation 9.57 |
| Bramitob | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Week 8 [n=155, 159] | 5.47 percentage predicted FEV1 | Standard Deviation 11.88 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Week 2 [n=158, 163] | 6.93 percentage predicted FEV1 | Standard Deviation 9.4 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Week 4 [N=155, 161] | 7.63 percentage predicted FEV1 | Standard Deviation 9.61 |
| TOBI | Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Week 8 [n=155, 159] | 5.37 percentage predicted FEV1 | Standard Deviation 11.11 |
Secondary
Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum
If a participant had more than one Pseudomonas aeruginosa (PA) morphotype at a given visit, and therefore more than one bacterial load value, then the bacterial load value corresponding to the highest tobramycin minimal inhibitory concentration (MIC) value regardless of the PA morphotype was used. If the tobramycin MIC value was the same for different PA morphotypes, then the bacterial load value corresponding to morphotype 1 (mucoid colony) was used. If morphotype 1 was not available, bacterial load value corresponding to morphotype 2 (dry colony) was used.
Time frame: Day -10 to -1 (baseline), Week 4, Week 8
Population: Intent-to-Treat (ITT) Population; At Week 4, six Bramitob patients and seven TOBI patients were missing sputum samples. At Week 8, 11 Bramitob patients and 16 TOBI patients were missing sputum samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bramitob | Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum | Week 4 [n=152, 156] | -2.14 colony forming units/gram | Standard Deviation 2.41 |
| Bramitob | Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum | Week 8 [n=147, 147] | -0.72 colony forming units/gram | Standard Deviation 2.17 |
| TOBI | Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum | Week 4 [n=152, 156] | -2.07 colony forming units/gram | Standard Deviation 2.2 |
| TOBI | Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum | Week 8 [n=147, 147] | -0.87 colony forming units/gram | Standard Deviation 2.23 |
Comparison: Analysis of Week 4 datap-value: 0.8295% CI: [-0.31, 0.39]ANCOVA
Secondary
Count of Participants With Treatment-Emergent Adverse Events (TEAEs)
Treatment-Emergent Adverse Events defined as adverse events occurring after the first intake of study treatment (or the same day). The investigator assessed relation to study treatment as a binary question: Reasonable possibility of relatedness or no reasonable possibility of relatedness. The expression reasonable possibility of relatedness is meant to convey in general that there are facts (evidence) or arguments meant to suggest a causal relationship. A serious AE results in death, is life-threatening, requires hospitalization or prolongation of existing inpatient hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or an important medical event. The investigator rates the severity of the AE based on a three point scale: mild, moderate or severe. A severe event prevents any usual routine activity of the participant and causes severe discomfort.
Time frame: Day 0 to Week 8
Population: Safety population: all randomised patients who took at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bramitob | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Related TEAE | 6.4 percentage of participants |
| Bramitob | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 1.9 percentage of participants |
| Bramitob | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 3.8 percentage of participants |
| Bramitob | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to withdrawal | 0.6 percentage of participants |
| Bramitob | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE | 31.4 percentage of participants |
| TOBI | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to withdrawal | 3.0 percentage of participants |
| TOBI | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE | 28.0 percentage of participants |
| TOBI | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Related TEAE | 6.0 percentage of participants |
| TOBI | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 1.2 percentage of participants |
| TOBI | Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 1.2 percentage of participants |
Secondary
Microbiological Outcome Summary by Visit
Microbiological outcomes are derived considering all P. aeruginosa (PA) morphotypes together. Week 4 and Week 8 microbiological outcomes: * Eradication = elimination of PA * Persistence = persistence of PA detected at previous visit * Superinfection = appearance of a pathogen (other than PA) not detected at previous visit * Re-infection (week 8 only) = re-appearance of PA detected at Screening and eradicated at Week 4 Superinfection supersedes eradication. Persistence for P. aeruginosa supersedes superinfection. Re-infection for P. aeruginosa supersedes superinfection.
Time frame: Day -10 to -1 (screening), Weeks 4 and 8
Population: Intent-to-Treat Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bramitob | Microbiological Outcome Summary by Visit | Screening: Presence of P aeruginosa | 100 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 4: Eradication | 9.2 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 4: Persistence | 82.9 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 4: Superinfection | 7.9 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 8: Eradication | 2.7 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 8: Persistence | 78.9 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 8: Superinfection | 9.5 percentage of participants |
| Bramitob | Microbiological Outcome Summary by Visit | Week 8: Re-infection | 8.8 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 8: Re-infection | 4.1 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Screening: Presence of P aeruginosa | 100 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 8: Eradication | 3.4 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 4: Eradication | 7.1 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 8: Superinfection | 9.5 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 4: Persistence | 85.3 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 8: Persistence | 83.0 percentage of participants |
| TOBI | Microbiological Outcome Summary by Visit | Week 4: Superinfection | 7.7 percentage of participants |
Comparison: Week 4p-value: 0.692Cochran-Mantel-Haenszel
Comparison: Week 8p-value: 0.128Cochran-Mantel-Haenszel
Secondary
Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa
MIC50 is the concentration of tobramycin required to inhibit 50% of Pseudomonas aeruginosa. MIC values were calculated for three different Pseudomonas aeruginosa (PA) strains: * Morphotype 1: mucoid * Morphotype 2: dry * Morphotype 3: variant Overall MIC50 values are reported. If a participant has more than one PA morphotype at a given visit, then the highest tobramycin MIC value was used, regardless of PA morphotype. If a participant has more than one available result for each morphotype then the highest tobramycin MIC value was used. If the tobramycin MIC values are equal then the MIC value for the isolate with the highest bacterial load value was used.
Time frame: Week 4, Week 8
Population: Intent-to-Treat (ITT) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bramitob | Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa | Week 4 [n=126, 134] | 1 micrograms/milliliters |
| Bramitob | Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa | Week 8 [n=129, 128] | 1 micrograms/milliliters |
| TOBI | Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa | Week 4 [n=126, 134] | 0.5 micrograms/milliliters |
| TOBI | Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa | Week 8 [n=129, 128] | 1 micrograms/milliliters |
Secondary
Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa
MIC90 is the concentration of tobramycin required to inhibit 90% of Pseudomonas aeruginosa. MIC values were calculated for three different Pseudomonas aeruginosa (PA) strains: * Morphotype 1: mucoid * Morphotype 2: dry * Morphotype 3: variant Overall MIC90 values are reported. If a participant has more than one PA morphotype at a given visit, then the highest tobramycin MIC value was used, regardless of PA morphotype. If a participant has more than one available result for each morphotype then the highest tobramycin MIC value was used. If the tobramycin MIC values are equal then the MIC value for the isolate with the highest bacterial load value was used.
Time frame: Week 4, Week 8
Population: Intent-to-Treat (ITT) Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bramitob | Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa | Week 4 [n=126, 134] | 32 micrograms/milliliters |
| Bramitob | Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa | Week 8 [n=129, 128] | 32 micrograms/milliliters |
| TOBI | Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa | Week 4 [n=126, 134] | 32 micrograms/milliliters |
| TOBI | Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa | Week 8 [n=129, 128] | 32 micrograms/milliliters |
Secondary
Participants With a Hearing Threshold >20 Decibel in at Least One Ear
The potential ototoxic effects (hearing loss) of tobramycin were investigated by performing audiometric tests. Participants with a loss of auditory acuity greater than the 20 decibels auditory threshold are reported.
Time frame: Day -10 to -1 (screening), Weeks 4 and 8
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bramitob | Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Screening | 0 percentage of participants |
| Bramitob | Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Week 4 | 1.9 percentage of participants |
| Bramitob | Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Week 8 | 1.3 percentage of participants |
| TOBI | Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Screening | 0 percentage of participants |
| TOBI | Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Week 4 | 1.2 percentage of participants |
| TOBI | Participants With a Hearing Threshold >20 Decibel in at Least One Ear | Week 8 | 1.2 percentage of participants |