Safety of Tobramycin Inhalation Powder (TIP) vs Tobramycin Solution for Inhalation in Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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This study compares the safety of the tobramycin solution for inhalation with the tobramycin dry powder formulation, used with a simple inhaler

Official Title
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A Randomized, Open-label Multicentre Phase 3 Trial to Assess the Safety of Tobramycin Inhalation Powder Compared to Tobramycin Solution for Inhalation in Cystic Fibrosis Subjects

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Tobramycin Inhalation Powder
* Drug: Tobramycin Solution for Inhalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of cystic fibrosis Male and female patients at least 6 years of age at the time of screening. Forced expiratory volume in one second (FEV1) at screening must be at least 25% and less than or equal to 75% of normal predicted values for age, sex, and height based on Knudson criteria. Pseudomonas aeruginosa, a type of bacteria, must be 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 comply with all protocol requirements. Clinically stable in the opinion of the investigator. Use of an effective means of contraception in females of childbearing potential. Provide written informed consent, Health Authority Portability and Accountability Act (HIPAA) authorization (where applicable), and assent (as appropriate) prior to the performance of any study-related procedure. Exclusion Criteria: History of sputum culture or deep-throat cough swab (or BAL) culture yielding Burkholderia cepacia (B cepacia), a type of bacteria, within 2 years prior to screening and/or sputum culture yielding B cepacia at screening. Coughing up more than 60 cc of blood from the respiratory tract at any time within 30 days prior to study drug administration. Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics. Females who are pregnant (positive pregnancy test), lactating, or are planning to become pregnant during the study. History of hearing loss or chronic ringing in the ears deemed clinically significant by the investigator. Use of systemic or inhaled antipseudomonal antibiotics within 28 days prior to study drug administration. Use of loop diuretics within 7 days prior to study drug administration. Use of any investigational treatment within 28 days prior to study drug administration. Initiation of treatment with chronic macrolide therapy, dornase alpha treatment or inhaled corticosteroids within 28 days prior to study drug administration (patients may be taking these therapies at the time of enrollment, but they must have initiated treatment more than 28 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tobramycin inhalation powder (TIP)<br>Participants received four 28 mg capsules of tobramycin inhalation powder (TIP) delivered with the T-326 inhaler twice daily for 28 days followed by 28 days off therapy (one cycle) for a total of three cycles. | Drug: Tobramycin Inhalation Powder<br>* Tobramycin Inhalation Powder (TIP) capsules for inhalation.<br>|
| Active Comparator: Tobramycin solution for inhalation (TOBI)<br>Participants received one 300 mg (in 5 mL) ampoule of tobramycin solution for inhalation (TOBI) delivered with a nebulizer twice daily for 28 days followed by 28 days off therapy (one cycle) for a total of three cycles. | Drug: Tobramycin Solution for Inhalation<br>* Tobramycin solution for inhalation (TOBI), supplied as 300 mg/5mL ampoules administered with a nebulizer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events | An adverse event (AE) is any untoward medical occurrence, including any unfavorable and unintended sign, symptom or disease temporally associated with the use of the study medication that does not necessarily have a causal relationship with study medication. A serious AE (SAE) is an event that results in death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability, is a congenital anomaly or defect, or is a significant medical event that may jeopardize the patient or require intervention to prevent one of the outcomes listed above. | 25 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Tobramycin Concentrations | Serum tobramycin concentrations were measured in a subset of participants at Week 1 (start of cycle 1), Week 5 (End of Cycle 1), Week 17 (start of cycle 3) and Week 21 (end of cycle 3). Serum samples were collected at pre-dose and post-dose at specified intervals; one specimen between 0 to 2 hours; two additional specimens between 2 and 5 hours (sample times must have been a minimum of 2 hours apart). | Weeks 1, 5, 17 and 21 | 
| Percentage of Participants With a Decrease From Baseline in Auditory Acuity | Audiology testing was performed only at selected centers. Auditory acuity was measured from 250 to 8000 Hertz using a standard dual-channel audiometer. | Baseline and Day 28 of Cycles 1, 2 and 3 (Weeks 5, 13 and 21) | 
| Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in One Second (%FEV1) | Forced expiratory volume in one second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 is then converted to a percentage of normal (percent predicted) based on height, weight, and race. FEV1 was measured at Baseline (prior to beginning study treatment) and predose on Day 28 of Cycles 1, 2 and 3 and at the follow-up visit. Relative change = 100 * ((Day 28 of Cycle 3 value - Baseline value)/ Baseline value). | Baseline and Day 28 of Cycles 1, 2 and 3 (Weeks 5, 13 and 21) and Final Visit (Week 25) | 
| Patient Satisfaction Assessed Using the Treatment Satisfaction Questionnaire for Medication | Patient's self-reported treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM, a validated instrument) which was modified by adding four study-specific questions; the standard fourteen questions of the TSQM were not altered. Responses to nearly all items are rated on a five-point or seven-point rating scale and the items are factored into 4 domains. The TSQM domain scores range from 0 to 100 with higher scores representing higher satisfaction for that domain. | Day 28 of Cycles 1, 2 and 3 (Weeks 5, 13 and 21). | 
| Change From Baseline in Pseudomonas Aeruginosa Sputum Density | Three Pseudomonas aeruginosa biotypes were assessed in patient's sputum; mucoid, dry and small colony variant. Overall density is defined as the sum of all bio-types in Pseudomonas aeruginosa density. | Baseline and Day 28 of Cycles 1, 2 and 3 (Weeks 5, 13 and 21) and Final Visit (Week 25). | 
| Change From Baseline in Tobramycin Minimum Inhibitory Concentration | The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. The MIC of tobramycin against total Pseudomonas aeruginosa colonization was assessed over the course of the study. | Baseline and Day 28 of Cycles 1, 2 and 3 (Weeks 5, 13 and 21) and Final Visit (Week 25) | 
| Antipseudomonal Antibiotic Usage During the Study | The average number of days patients required antipseudomonal antibiotics during the course of the study. | 25 Weeks | 
| Hospitalization Due to Respiratory Events During the Study | The average number of days patients were hospitalized due to respiratory events during the course of the study. | 25 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tobramycin