A Study of Tobramycin Inhalation Powder From a Modified Manufacturing Process Versus Placebo

Study Overview
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Brief Summary
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This study is designed to show how well tobramycin inhalation powder works and how safe it is when produced by a modified manufacturing process

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase III Study in Cystic Fibrosis (CF) Subjects to Assess Efficacy, Safety and Pharmacokinetics of Tobramycin Inhalation Powder From a Modified Manufacturing Process (TIPnew).

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Tobramycin Inhalation Powder
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIP (Tobramycin Inhalation Powder)<br>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. | Drug: Tobramycin Inhalation Powder<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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). | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 29 | 
| 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. | Baseline, Day 29 | 
| 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. | Baseline, Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Baseline, Day 29, Day 57 | 
| 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. | Baseline, Day 29, Day 57 | 
| 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. | Baseline, Day 29, Day 57 | 
| 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. | Baseline, Day 29, Day 57 | 
| 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. | Baseline, Study completion | 
| 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. | First administration of study drug, study completion | 
| 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 of consent, 4 weeks after study completion | 
| 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. | Day 1, Day 29 | 
| 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. | Pre-dose, 0 - 1 hour post-dose, 1 -2 hours post-dose, 2 - 6 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tobramycin Inhalation Powder, Cystic fibrosis, Lung diseases, Anti-Bacterial Agents, Treatment of infections with P. aeruginosa in cystic fibrosis subjects