Cystic Fibrosis
Conditions
Keywords
Tobramycin Inhalation Powder, Cystic fibrosis, Lung diseases, Anti-Bacterial Agents, Treatment of infections with P. aeruginosa in cystic fibrosis subjects
Brief summary
This study is designed to show how well tobramycin inhalation powder works and how safe it is when produced by a modified manufacturing process
Interventions
Tobramycin Inhalation Powder as produced by a modified manufacturing process TIP. TIP was provided in hard capsules each containing 28 mg active ingredient (tobramycin); Capsules were packaged in blister cards and administered by the T-326 Inhaler.
DRUGPlacebo
Placebo inhalation powder consisting of the excipients used for TIP. Placebo was provided in hard capsules, containing 20 mg placebo powder, which were packaged in blister cards, matching in appearance to TIP. Capsules were administered by the T-326 Inhaler.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent given by adults or by the parents/legal guardian in combination with the patient's assent, if capable of assenting, before any assessment was performed * Confirmed diagnosis of Cystic Fibrosis (CF) by the presence of one or more clinical features of CF in addition to: * a quantitative pilocarpine iontophoresis sweat chloride test of \>60 mEq/L; or * identification of well-characterized disease-causing mutations in each CFTR gene; or * an abnormal nasal transepithelial potential difference characteristic of CF. * Forced Expiratory Volume in one second (FEV1) at screening must have been ≥25% and ≤80% of normal predicted values for age, sex, and height based on Knudson criteria * P. aeruginosa must have been present in a sputum/deep-throat cough swab culture (or bronchoalveolar lavage \[BAL\]) within 6 months prior to screening and in the sputum/deep-throat cough swab culture at the screening visit * Able to expectorate a sputum sample or provide a deep throat cough swab at screening * Able to comply with all protocol requirements * Use of an effective means of contraception in females of childbearing potential * Clinically stable in the opinion of the investigator to be treated according to this protocol
Exclusion criteria
* FEV1 at baseline (Visit 2) \<25% or \>80% of normal predicted values for age, sex, and height based on Knudson criteria, and/or FEV1 at baseline (Visit 2) deviated by ≥10% from the FEV1 measured at screening (Visit 1) * Any use of inhaled anti-pseudomonal antibiotics within 4 months prior to screening * Any use of systemic anti-pseudomonal antibiotics within 28 days prior to study drug administration * Serum creatinine 2 mg/dL or above, blood urea nitrogen (BUN) 40 mg/dL or above, or an abnormal urinalysis defined as 2+ or greater proteinuria * Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics * Signs and symptoms of acute pulmonary disease, e.g. pneumonia, pneumothorax * Administration of any investigational drug within 30 days prior to enrollment * Any previous exposure to tobramycin dry powder for inhalation (TIP) * Administration of loop diuretics within 7 days prior to study drug administration * Initiation of treatment with chronic macrolide therapy within 28 days prior to study drug administration * Initiation of treatment with dornase alfa within 28 days prior to study drug administration * Initiation of treatment with inhaled steroids (or increased dose) within 28 days prior to study drug administration * Initiation of treatment with inhaled hypertonic saline (HS) within 28 days prior to study drug administration * Personal history of abnormal hearing or family history of abnormal hearing other than typical hearing loss associated with the aging process * Known abnormal result from any audiology testing (defined as either a unilateral puretone audiometry test showing a threshold elevation \>20 dB at any frequency across the frequency range 0.25 kHz to 8 kHz or the absence of emission at the evoked otoacoustic emission test) * History of sputum culture or throat swab (or BAL) culture yielding Burkholderia cepacia (B. cepacia) within 2 years prior to screening and/or sputum culture yielding B. cepacia at screening * Hemoptysis of more than 60 mL at any time within 30 days prior to study drug administration * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of evidence of local recurrence or metastases * Patients with clinically significant laboratory abnormalities (not associated with the study indication) at screening * Patients or caregivers with a history of noncompliance to medical regimens and patients or caregivers who are considered potentially unreliable * Pregnant or nursing (lactating) women * Women of child-bearing potential unless they used two reliable birth control methods Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Baseline, Day 29 | Relative change in percentage predicted FEV1 in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model. ITT Patients with missing or unacceptable Day 29 spirometry measurements had their primary endpoint data imputed with zero. BSL = Baseline, defined as the latest measurement prior to the first dosing of study medication \- Relative change = 100 \* (value - baseline) / baseline There were 3 patients who had no screening nor baseline values (due to inadequate spirometry) and so were excluded from all change from baseline analyses. |
| Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Baseline, Day 29 | Relative change in percentage predicted FEV1 without outlier (outliers with respect to FEV1 values and PK data), in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model. |
| Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Baseline, Day 29 | Absolute change in percentage predicted FEV1 in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model. In the adjusted analysis model: response = treatment + screening FEV1 % predicted (\<50 and \>=50) + age (\<13 and \>=13) + error. Significance for the FEV1 % predicted is reached for p-values \<= 0.05. There were 3 patients who had no screening nor baseline values (due to inadequate spirometry) and so were excluded from all change from baseline analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Baseline, Day 29, Day 57 | Maximum MIC values from all biotypes were used. Absolute values and changes in tobramycin MIC for P. aeruginosa from baseline are summarized by biotype. Overall, a high variability of MIC was observed within each treatment group. For the maximum of all biotypes, large differences in mean changes from baseline at Day 29 were observed between the TIP group and the placebo group. |
| Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Baseline, Study completion | Hematology values shift from baseline to above upper/below lower limit of normal at any time post-baseline. Biochemistry values shift from baseline to above upper/below lower limit of normal at any time post-baseline. |
| Percentage of Participants With Adverse Events (AEs) | First administration of study drug, study completion | Adverse Events (AEs) (on and off treatment) regardless of study relationship by primary system organ and treatment group. Primary system organ classes are sorted in descending order of frequency in the TIP treatment group. A patient with more than one AE within a primary system organ class is counted only once for that class. |
| Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Baseline, Day 29, Day 57 | Results of statistical analysis were calculated from an ANOVA model. Baseline is defined as the latest measurement prior to the first dosing of study medication. Response (percentage change) = treatment + Screening FEV1 percentage predicted (\<50 and \>=50) + age (\<13 and \>=13) + error |
| Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug | Day 1, Day 29 | Relative change = 100 \* (30-m-post-dose - pre-dose)/pre-dose assessed by the number and percentage of patients with a decrease of ≥20 % in FEV1 % predicted from pre dose to 30 minutes post dose. Day 1 is the scheduled visit of first study drug administration. |
| Tobramycin Serum Concentration | Pre-dose, 0 - 1 hour post-dose, 1 -2 hours post-dose, 2 - 6 hours post-dose | Descriptive statistics of serum and sputum concentrations per scheduled sampling time. Detectable concentration values at pre-dose on Day 1 were excluded from the analysis. |
| Percentage of Participants With Serious Adverse Events (SAEs) | Time of consent, 4 weeks after study completion | Serious Adverse Events (on and off treatment) by preferred term and treatment group. Preferred terms are sorted in descending order of frequency in the TIP treatment group. A patient with multiple occurrences of the same preferred term is counted only once in the preferred term. |
| Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Baseline, Day 29, Day 57 | FEF25-75: Forced expiratory flow rate over 25% to 75% of vital capacity For FEF25-75 percentage predicted the relative change is analyzed. If screening FEV1 percentage predicted is missing, it will be imputed by the baseline value. |
| Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Baseline, Day 29, Day 57 | P. aeruginosa sputum density refers to overall density, defined as the sum of biotypes (mucoid, dry and small colony variant). If sub-isolates exist for CFU biotype mucoid or dry, then the sum of sub-isolates is analyzed. |
Countries
Bulgaria, Egypt, Estonia, India, Latvia, Lithuania, Romania, Russia, South Africa
Participant flow
Pre-assignment details
Although 32 patients were randomized to the TIP group and 30 to the Placebo group, the ITT population included 2 patients allocated to the TIP group but received placebo due to Investigator error during the drug dispensation process. The safety population contained 30 patients who were treated with TIP and 32 patients who were treated with placebo.
Participants by arm
| Arm | Count |
|---|---|
| TIP (Tobramycin Inhalation Powder) Tobramycin 28 mg powder. The TIP dose of 112 mg twice a day (bis in diem = b.i.d.), given in a cycle of 28 days on treatment followed by 28 days off treatment. | 30 |
| Placebo Placebo 20 mg powder capsules. The dose regimen for the reference product was inhaling the contents of four capsules twice a day (bis in diem = b.i.d.) in the morning and in the evening for 28 days (on treatment), followed by 28 days of no study treatment (off treatment). | 32 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | TIP (Tobramycin Inhalation Powder) | Placebo | Total |
|---|---|---|---|
| Age Continuous | 12.9 years STANDARD_DEVIATION 4.25 | 12.9 years STANDARD_DEVIATION 4.68 | 12.9 years STANDARD_DEVIATION 4.44 |
| Age, Customized <13 years | 15 participants | 15 participants | 30 participants |
| Age, Customized >= 13 years | 15 participants | 17 participants | 32 participants |
| Baseline Forced Expiratory Volume in one second (FEV1) percentage predicted | 59.1 Percentage STANDARD_DEVIATION 18.18 | 59.3 Percentage STANDARD_DEVIATION 16.61 | 59.2 Percentage STANDARD_DEVIATION 17.25 |
| Baseline P. aeruginosa sputum density | 7.4 Log10 CFU (colony forming unit) STANDARD_DEVIATION 1.53 | 7.4 Log10 CFU (colony forming unit) STANDARD_DEVIATION 1.55 | 7.4 Log10 CFU (colony forming unit) STANDARD_DEVIATION 1.52 |
| Sex: Female, Male Female | 21 Participants | 19 Participants | 40 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 30 | 6 / 32 |
| serious Total, serious adverse events | 0 / 30 | 2 / 32 |
Outcome results
Primary
Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier
Relative change in percentage predicted FEV1 without outlier (outliers with respect to FEV1 values and PK data), in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model.
Time frame: Baseline, Day 29
Population: ITT: All randomized patients (pts) received at least one dose of study drug. Missing or unacceptable Day 29 spirometry test -change from baseline FEV1 % predicted imputed using last available post-baseline value or 0. mITT: Pts with unacceptable FEV1 measurements excluded. Observed cases: Pts with missing or unacceptable FEV1 measurements excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Participants analyzed: ITT Population (30, 28) | 10.4 change in percentage | Standard Error 2.81 |
| TIP (Tobramycin Inhalation Powder) | Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Parts. analyzed: Modified ITT Pop (24, 27) | 12.4 change in percentage | Standard Error 3.14 |
| TIP (Tobramycin Inhalation Powder) | Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Parts. analyzed: Observed Cases, ITT Pop (26, 27) | 13.1 change in percentage | Standard Error 3.25 |
| Placebo | Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Participants analyzed: ITT Population (30, 28) | 3.1 change in percentage | Standard Error 2.92 |
| Placebo | Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Parts. analyzed: Modified ITT Pop (24, 27) | 3.5 change in percentage | Standard Error 3.05 |
| Placebo | Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier | Parts. analyzed: Observed Cases, ITT Pop (26, 27) | 3.4 change in percentage | Standard Error 3.08 |
Primary
Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29)
Absolute change in percentage predicted FEV1 in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model. In the adjusted analysis model: response = treatment + screening FEV1 % predicted (\<50 and \>=50) + age (\<13 and \>=13) + error. Significance for the FEV1 % predicted is reached for p-values \<= 0.05. There were 3 patients who had no screening nor baseline values (due to inadequate spirometry) and so were excluded from all change from baseline analyses.
Time frame: Baseline, Day 29
Population: ITT: All randomized patients (pts) received at least one dose of study drug. Missing or unacceptable Day 29 spirometry test -change from baseline FEV1 % predicted imputed using last available post-baseline value or 0. mITT: Pts with unacceptable FEV1 measurements excluded. Observed cases: Pts with missing or unacceptable FEV1 measurements excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Participants analyzed: ITT Population (31, 28) | 4.9 change in percentage | Standard Error 1.59 |
| TIP (Tobramycin Inhalation Powder) | Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Parts. analyzed: Modified ITT Pop (25, 27) | 5.7 change in percentage | Standard Error 1.78 |
| TIP (Tobramycin Inhalation Powder) | Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Parts. analyzed: Observed Cases, ITT Pop (27, 27) | 6.1 change in percentage | Standard Error 1.84 |
| Placebo | Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Participants analyzed: ITT Population (31, 28) | 0.5 change in percentage | Standard Error 1.7 |
| Placebo | Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Parts. analyzed: Modified ITT Pop (25, 27) | 0.6 change in percentage | Standard Error 1.79 |
| Placebo | Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) | Parts. analyzed: Observed Cases, ITT Pop (27, 27) | 0.5 change in percentage | Standard Error 1.8 |
Primary
Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29)
Relative change in percentage predicted FEV1 in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model. ITT Patients with missing or unacceptable Day 29 spirometry measurements had their primary endpoint data imputed with zero. BSL = Baseline, defined as the latest measurement prior to the first dosing of study medication \- Relative change = 100 \* (value - baseline) / baseline There were 3 patients who had no screening nor baseline values (due to inadequate spirometry) and so were excluded from all change from baseline analyses.
Time frame: Baseline, Day 29
Population: ITT: All randomized patients (pts) received at least one dose of study drug. Missing or unacceptable Day 29 spirometry test -change from baseline FEV1 % predicted imputed using last available post-baseline value or 0. mITT: Pts with unacceptable FEV1 measurements excluded. Observed cases: Pts with missing or unacceptable FEV1 measurements excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Participants analyzed: ITT Population (31, 28) | 8.2 change in percentage | Standard Error 2.93 |
| TIP (Tobramycin Inhalation Powder) | Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Parts. analyzed: Modified ITT Pop (27, 27) | 9.7 change in percentage | Standard Error 3.3 |
| TIP (Tobramycin Inhalation Powder) | Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Parts analyzed: Observed Cases in ITT Pop (25, 27) | 10.3 change in percentage | Standard Error 3.42 |
| Placebo | Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Participants analyzed: ITT Population (31, 28) | 2.3 change in percentage | Standard Error 3.13 |
| Placebo | Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Parts. analyzed: Modified ITT Pop (27, 27) | 2.5 change in percentage | Standard Error 3.3 |
| Placebo | Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) | Parts analyzed: Observed Cases in ITT Pop (25, 27) | 2.4 change in percentage | Standard Error 3.35 |
Secondary
Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum)
P. aeruginosa sputum density refers to overall density, defined as the sum of biotypes (mucoid, dry and small colony variant). If sub-isolates exist for CFU biotype mucoid or dry, then the sum of sub-isolates is analyzed.
Time frame: Baseline, Day 29, Day 57
Population: Intent-to-treat (ITT) population: All randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Number of participants analyzed (29, 28): Baseline | 7.5 Log10 CFU (colony forming unit) | Standard Error 1.49 |
| TIP (Tobramycin Inhalation Powder) | Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Number of participants analyzed (14, 27): Day 29 | -2.4 Log10 CFU (colony forming unit) | Standard Error 1.54 |
| TIP (Tobramycin Inhalation Powder) | Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Number of participants analyzed (19, 24): Day 57 | -0.9 Log10 CFU (colony forming unit) | Standard Error 2.09 |
| Placebo | Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Number of participants analyzed (29, 28): Baseline | 7.3 Log10 CFU (colony forming unit) | Standard Error 1.58 |
| Placebo | Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Number of participants analyzed (14, 27): Day 29 | 0.0 Log10 CFU (colony forming unit) | Standard Error 0.89 |
| Placebo | Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) | Number of participants analyzed (19, 24): Day 57 | -0.2 Log10 CFU (colony forming unit) | Standard Error 1.2 |
Secondary
Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug
Relative change = 100 \* (30-m-post-dose - pre-dose)/pre-dose assessed by the number and percentage of patients with a decrease of ≥20 % in FEV1 % predicted from pre dose to 30 minutes post dose. Day 1 is the scheduled visit of first study drug administration.
Time frame: Day 1, Day 29
Population: Safety population: All randomized patients who received at least one dose of study drug.In all safety analyses patients were analyzed according to the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug | Day 1 | 4.8 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug | Day 29 | 0.0 Percentage of participants |
| Placebo | Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug | Day 1 | 0.0 Percentage of participants |
| Placebo | Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug | Day 29 | 8.0 Percentage of participants |
Secondary
Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57)
FEF25-75: Forced expiratory flow rate over 25% to 75% of vital capacity For FEF25-75 percentage predicted the relative change is analyzed. If screening FEV1 percentage predicted is missing, it will be imputed by the baseline value.
Time frame: Baseline, Day 29, Day 57
Population: Intent-to-treat (ITT) population: All randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Number of participants analyzed (31, 28): Baseline | 36.2 percentage change | Standard Error 20.15 |
| TIP (Tobramycin Inhalation Powder) | Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Number of participants analyzed (25, 27): Day 29 | 21.00 percentage change | Standard Error 36.55 |
| TIP (Tobramycin Inhalation Powder) | Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Number of participants analyzed (28, 23): Day 57 | 23.9 percentage change | Standard Error 35.57 |
| Placebo | Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Number of participants analyzed (31, 28): Baseline | 35.9 percentage change | Standard Error 20.67 |
| Placebo | Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Number of participants analyzed (25, 27): Day 29 | 7.8 percentage change | Standard Error 29.65 |
| Placebo | Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) | Number of participants analyzed (28, 23): Day 57 | 17.7 percentage change | Standard Error 37.4 |
Secondary
Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57)
Results of statistical analysis were calculated from an ANOVA model. Baseline is defined as the latest measurement prior to the first dosing of study medication. Response (percentage change) = treatment + Screening FEV1 percentage predicted (\<50 and \>=50) + age (\<13 and \>=13) + error
Time frame: Baseline, Day 29, Day 57
Population: Intent-to-treat (ITT) population: All randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Number of participants analyzed (31, 28): Baseline | 73.3 percentage change | Standard Error 19.19 |
| TIP (Tobramycin Inhalation Powder) | Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Number of participants analyzed (25, 27): Day 29 | 7.2 percentage change | Standard Error 9.94 |
| TIP (Tobramycin Inhalation Powder) | Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Number of participants analyzed (28, 23): Day 57 | 5.2 percentage change | Standard Error 16.99 |
| Placebo | Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Number of participants analyzed (31, 28): Baseline | 76.9 percentage change | Standard Error 15.16 |
| Placebo | Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Number of participants analyzed (25, 27): Day 29 | 1.6 percentage change | Standard Error 14.74 |
| Placebo | Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) | Number of participants analyzed (28, 23): Day 57 | 3.1 percentage change | Standard Error 15.05 |
Secondary
Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC)
Maximum MIC values from all biotypes were used. Absolute values and changes in tobramycin MIC for P. aeruginosa from baseline are summarized by biotype. Overall, a high variability of MIC was observed within each treatment group. For the maximum of all biotypes, large differences in mean changes from baseline at Day 29 were observed between the TIP group and the placebo group.
Time frame: Baseline, Day 29, Day 57
Population: Intent-to-treat (ITT) population: All randomized patients who received at least one dose of study drug. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Number of participants analyzed (28, 29):Baseline | 0.8 μg/mL | Standard Deviation 1.49 |
| TIP (Tobramycin Inhalation Powder) | Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Number of participants analyzed (13, 27): Day 29 | 0.1 μg/mL | Standard Deviation 0.73 |
| TIP (Tobramycin Inhalation Powder) | Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Number of participants analyzed (19, 24): Day 57 | 0.5 μg/mL | Standard Deviation 1.49 |
| Placebo | Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Number of participants analyzed (28, 29):Baseline | 2.7 μg/mL | Standard Deviation 11.81 |
| Placebo | Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Number of participants analyzed (13, 27): Day 29 | 10.0 μg/mL | Standard Deviation 38.32 |
| Placebo | Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) | Number of participants analyzed (19, 24): Day 57 | 1.4 μg/mL | Standard Deviation 6.58 |
Secondary
Percentage of Participants With Adverse Events (AEs)
Adverse Events (AEs) (on and off treatment) regardless of study relationship by primary system organ and treatment group. Primary system organ classes are sorted in descending order of frequency in the TIP treatment group. A patient with more than one AE within a primary system organ class is counted only once for that class.
Time frame: First administration of study drug, study completion
Population: Safety population: All randomized patients who received at least one dose of study drug.In all safety analyses patients were analyzed according to the treatment received
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Gastrointestinal disorders | 3.3 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Renal and urinary disorders | 3.3 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Infections and infestations | 10.0 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Skin and subcutaneous tissue disorder | 3.3 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Metabolism and nutrition disorders | 3.3 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Blood and lymphatic system disorder | 0.0 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Ear and labyrinth disorders | 10.0 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Injury, poisoning and procedural complications | 0.0 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Nervous system disorders | 3.3 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Investigation | 0.0 Percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Adverse Events (AEs) | Respiratory, thoracic & mediastinal disorders | 13.3 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Investigation | 3.1 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Respiratory, thoracic & mediastinal disorders | 3.1 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Ear and labyrinth disorders | 6.3 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Infections and infestations | 25.0 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Gastrointestinal disorders | 3.1 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Metabolism and nutrition disorders | 3.1 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Nervous system disorders | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Renal and urinary disorders | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Skin and subcutaneous tissue disorder | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Blood and lymphatic system disorder | 3.1 Percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Injury, poisoning and procedural complications | 3.1 Percentage of participants |
Secondary
Percentage of Participants With Serious Adverse Events (SAEs)
Serious Adverse Events (on and off treatment) by preferred term and treatment group. Preferred terms are sorted in descending order of frequency in the TIP treatment group. A patient with multiple occurrences of the same preferred term is counted only once in the preferred term.
Time frame: Time of consent, 4 weeks after study completion
Population: Safety population: All randomized patients who received at least one dose of study drug. In all safety analyses patients were analyzed according to the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Serious Adverse Events (SAEs) | Lower limb fracture | 0.0 percentage of participants |
| TIP (Tobramycin Inhalation Powder) | Percentage of Participants With Serious Adverse Events (SAEs) | Pneumonia | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Serious Adverse Events (SAEs) | Lower limb fracture | 3.1 percentage of participants |
| Placebo | Percentage of Participants With Serious Adverse Events (SAEs) | Pneumonia | 3.1 percentage of participants |
Secondary
Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal
Hematology values shift from baseline to above upper/below lower limit of normal at any time post-baseline. Biochemistry values shift from baseline to above upper/below lower limit of normal at any time post-baseline.
Time frame: Baseline, Study completion
Population: Safety population: All randomized patients who received at least one dose of study drug. In all safety analyses patients were analyzed according to the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: WBC (total)- low | 9.5 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Neutrophils (Seg. + Bands) - high | 11.1 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Basophils - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Basophils - high | 60.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Eosinophils - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Eosinophils - high | 28.6 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Lymphocytes -low | 4.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Lymphocytes - high | 14.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Monocytes - low | 8.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Monocytes - high | 27.8 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Neutrophils (Seg. + Bands) - low | 13.6 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Neutrophils (Seg. + Bands) - high | 4.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Platelet count (direct) - low | 4.5 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Platelet count (direct) - high | 7.7 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: RBC- low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: RBC- high | 16.7 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Neutrophils (Seg. + Bands) - low | 9.5 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: WBC (total) - high | 5.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hematocrit - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hematocrit - high | 14.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hemoglobin - low | 3.8 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hemoglobin - high | 4.2 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Biochemistry (Bio): Album - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Album - high | 20.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Alkaline phosphatase, serum - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Alkaline phosphatase, serum - high | 14.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (direct/conjugated) -low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (direct/conjugated) -high | 7.7 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (total) - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (total) - high | 3.4 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Blood Urea Nitrogen (BUN) - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Blood Urea Nitrogen (BUN) - high | 3.4 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Calcium -low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Calcium -high | 6.9 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Chloride - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Chloride - high | 10.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Creatinine - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Creatinine - high | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Gamma Glutamyltransferase - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Gamma Glutamyltransferase - high | 4.2 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Glucose - low | 12.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Glucose - high | 11.1 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Phosphate (Inorganic Phosphorus) - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Phosphate (Inorganic Phosphorus) - high | 19.2 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Potassioum - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Potassioum - high | 7.1 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGOT (AST) - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGOT (AST) - high | 12.5 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGPT (ALT) - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGPT (ALT) - high | 9.5 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Serum bicarbonate - low | 47.6 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Serum bicarbonate - high | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Sodium - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Sodium - high | 10.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Total Protein (Serum) - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Total Protein (Serum) - high | 4.2 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Uric Acid - low | 3.6 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Uric Acid - high | 10.7 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hematology (Hem): Absolute Basophilis- low - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Basophilis - high | 8.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Eosinophils - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Eosinophils - high | 14.3 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Lymphocytes - low | 4.2 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Lymphocytes - high | 11.1 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Monocytes - low | 0.0 percentage of participants at risk |
| TIP (Tobramycin Inhalation Powder) | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Monocytes - high | 9.5 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGPT (ALT) - high | 13.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Neutrophils (Seg. + Bands) - low | 10.3 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Calcium -high | 6.7 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Neutrophils (Seg. + Bands) - high | 25.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Monocytes - high | 19.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Basophils - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Chloride - low | 6.5 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Basophils - high | 40.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Serum bicarbonate - low | 23.8 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Eosinophils - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Chloride - high | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Eosinophils - high | 14.8 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hematology (Hem): Absolute Basophilis- low - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Lymphocytes -low | 14.3 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Creatinine - low | 50.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Lymphocytes - high | 7.7 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Serum bicarbonate - high | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Monocytes - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Creatinine - high | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Monocytes - high | 24.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Lymphocytes - low | 3.7 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Neutrophils (Seg. + Bands) - low | 11.1 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Gamma Glutamyltransferase - low | 3.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Neutrophils (Seg. + Bands) - high | 6.9 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Sodium - low | 6.5 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Platelet count (direct) - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Gamma Glutamyltransferase - high | 3.8 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Platelet count (direct) - high | 13.3 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Basophilis - high | 10.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: RBC- low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Glucose - low | 20.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: RBC- high | 9.1 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Sodium - high | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: WBC (total)- low | 3.7 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Glucose - high | 6.7 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: WBC (total) - high | 26.1 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Monocytes - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hematocrit - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Phosphate (Inorganic Phosphorus) - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hematocrit - high | 14.8 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Total Protein (Serum) - low | 3.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hemoglobin - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Phosphate (Inorganic Phosphorus) - high | 13.8 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Hemoglobin - high | 3.3 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Eosinophils - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Biochemistry (Bio): Album - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Potassioum - low | 3.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Album - high | 10.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Total Protein (Serum) - high | 29.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Alkaline phosphatase, serum - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Potassioum - high | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Alkaline phosphatase, serum - high | 4.3 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Lymphocytes - high | 9.5 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (direct/conjugated) -low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGOT (AST) - low | 3.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (direct/conjugated) -high | 7.1 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Uric Acid - low | 3.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (total) - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGOT (AST) - high | 12.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Bilirubin (total) - high | 3.3 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Hem: Absolute Eosinophils - high | 7.4 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Blood Urea Nitrogen (BUN) - low | 13.8 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: SGPT (ALT) - low | 0.0 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Blood Urea Nitrogen (BUN) - high | 3.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Uric Acid - high | 19.2 percentage of participants at risk |
| Placebo | Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal | Bio: Calcium -low | 12.9 percentage of participants at risk |
Secondary
Tobramycin Serum Concentration
Descriptive statistics of serum and sputum concentrations per scheduled sampling time. Detectable concentration values at pre-dose on Day 1 were excluded from the analysis.
Time frame: Pre-dose, 0 - 1 hour post-dose, 1 -2 hours post-dose, 2 - 6 hours post-dose
Population: Safety population: All randomized patients who received at least one dose of study drug. In all safety analyses patients were analyzed according to the treatment received.~This measures the concentration of active substance in the body at different time-point to evaluate there is abnormal accumulation of active substance. Not for Placebo Patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day 29: 2 -6 hrs post dose (27, 0) | 1.14 μg/mL | Standard Deviation 0.65 |
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day1: 0 -1 hour (hr) post dose (28, 0) | 0.83 μg/mL | Standard Deviation 0.4 |
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day 1: 1 -2 hours (hr) post dose (28, 0) | 0.93 μg/mL | Standard Deviation 0.44 |
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day 1: 2 -6 hours (hr) post dose (29, 0) | 0.73 μg/mL | Standard Deviation 0.39 |
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day 29: Pre-dose (27, 0) | 0.41 μg/mL | Standard Deviation 0.51 |
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day 29: 0 -1 hr post dose (28, 0) | 1.48 μg/mL | Standard Deviation 0.69 |
| TIP (Tobramycin Inhalation Powder) | Tobramycin Serum Concentration | Day 29: 1 -2 hrs post dose (29, 0) | 1.37 μg/mL | Standard Deviation 0.64 |