Long Term Safety of Tobramycin Inhalation Powder in Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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This study assessed the long term safety data for the use of tobramycin inhalation powder in patients suffering from cystic fibrosis who have a chronic pulmonary infection with Pseudomonas aeruginosa.

Official Title
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A Single Arm, Open-label, Multicenter, Phase IV Trial to Assess Long Term Safety of Tobramycin Inhalation Powder (TIP) in Patients With Cystic Fibrosis

Conditions
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Pulmonary Infections, Pseudomonas Aeruginosa in Cystic Fibrosis

Intervention / Treatment
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* Drug: TBM100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of Cystic Fibrosis FEV1 at screening must be between 25 and 75 percent of normal predicted values for age, sex and height based on the Knudson equation Pseudomonas aeruginosa must be present in a sputum / deep cough throat swab culture or bronchoalveolar lavage within 6 months prior to screening and in the sputum/deep-throat cough swab culture at screening Exclusion Criteria: History of sputum culture or deep cough throat swab culture yielding Burkholderia cenocepacia complex within 2 years prior to screening and /or sputum culture yielding Burkholderia cenocepacia at screening Hemoptysis more than 60mL at any time within 30 days prior to study drug administration History of hearing loss or chronic tinnitus deemed clinically significant Serum creatinine 2mg/dl or more, BUN 40mg/dl or more, or an abnormal urinalysis defined as 2+ or greater proteinuria at screening Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics Patients who are regularly receiving more than 1 class of inhaled anti-pseudomonal antibiotic Any use of inhaled or systemic anti-pseudomonal antibiotic within 28 days prior to study drug administration Use of loop diuretics within 7 days prior to study drug administration Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 6 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tobramycin Inhalation Powder (TIP)<br>Eligible patients were assigned to four capsules of TIP at 28mg dosage strength, inhaled b.i.d. in the morning and in the evening via the T-326 inhaler, for 28 days (on treatment), followed by 28 days of no study treatment (off treatment). Each treatment therefore consisted of 112mg tobramycin (4 capsules of 28mg each) with the total daily dose = 224mg tobramycin (112mg b.i.d.). These 56 days represented 1 cycle of therapy. | Drug: TBM100<br>* Tobramycin inhalation powder was assigned as four capsules at 28mg dosage strength. It was inhaled b.i.d in the morning and in the evening via the T-326 Inhaler.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths | Adverse events were deemed treatment-emergent if the onset date/time was on or after the date and time of first study drug. All adverse events were included after this time during both on and off-treatment periods. | 337 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted | Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recorded at all visits according to American Thoracic Society (ATS) guidelines. FEV1 = the volume of air expired in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. FVC (forced vital capacity) = the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC. Relative change in FEV1 % predicted from baseline to pre-dose day X = ((pre-dose day X FEV1 % predicted - baseline FEV1 % predicted) / baseline FEV1 % predicted) • 100. | Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337. All study visits except baseline and day 337 occurred at the end of a 28-day on-treatment period of a cycle. Day 337 was the end of the final 28-day off treatment period. | 
| Relative Change From Baseline in FVC Percent Predicted | Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recorded at all visits according to American Thoracic Society (ATS) guidelines. FEV1 = the volume of air expired in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. FVC (forced vital capacity) = the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC. Relative change in FVC % predicted from baseline to pre-dose day X = ((pre-dose day X FVC % predicted - baseline FVC % predicted) / baseline FVC % predicted) • 100. | Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337. All study visits except baseline and day 337 occurred at the end of a 28-day on-treatment period of a cycle. Day 337 was the end of the final 28-day off treatment period. | 
| Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted | Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recored at all visits according to American Thoracic Society (ATS) guidelines. FEV1 = the volume of air expired in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. FVC (forced vital capacity) = the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC. Relative change in FEEF25-75 from baseline to pre-dose day X = ((pre-dose day X FEF25-75 - baseline FEF25-75) / baseline FEF25-75) • 100. | Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337. All study visits except baseline and day 337 occurred at the end of a 28-day on-treatment period of a cycle. Day 337 was the end of the final 28-day off treatment period. | 
| Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum | Sputum was collected in sterile containers and cultured for Pseudomonas aeruginosa (Pa.) (quantitative test) and other typical Cystic Fibrosis respiratory pathogens. The Pa. biotypes measured were mucoid, dry and small colony variant. Results are presented for the sum of all biotypes of Pa, with data transformed using a base 10 logarithm. | Baseline, day 1, day 29, day 85, day 141, day 197, day 253, day 309, day 337 | 
| Tobramycin MIC 50 and MIC 90 Values Over All Isolates for the Sum of All Biotypes (Mucoid, Dry and Small Colony Variant) of Pseudomonas Aeruginosa | Tobramycin MIC 50 and MIC 90 values were defined as the lowest concentration of tobramycin required to inhibit 50% and 90%, respectively, of the P. aeruginosa strains tested. | Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337 | 
| Percentage of Participants Hospitalized Due to Serious Respiratory-related Adverse Events |  | Day 337 | 
| Number of Hospitalization Days Due to Serious Respiratory-related Adverse Events | The total number of hospitalization days due to serious respiratory-related adverse events was analyzed. | Day 337 | 
| Time to First Hospitalization Due to Serious Respiratory-related Adverse Events | The day of first hospitalization due to serious respiratory-related adverse events was analyzed. | Day 337 | 
| Percentage of Participants Who Used New Anti-pseudomonal Antibiotics |  | Day 337 | 
| Number of Days of New Anti-pseudomonal Antibiotic Use | The total number of days of new anti-pseudomonal antibiotic use was analyzed. | Day 337 | 
| Time to Use of New Anti-pseudomonal Antibiotic | Time to first use of new anti-pseudomonal antibiotic was analyzed. | Day 337 | 

 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 disease, Anti-bacterial agents