Open Label Extension to Bridging Study CTBM100C2303

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00982930
• Collaborator: (none)
• Enrollment: 55
• Locations: 2
• Arm: 1
• Actual Duration (Months): 25.8
• Patients Per Site: 27.5
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This was an open-label, single arm (uncontrolled) study in participants suffering from cystic fibrosis, who had completed their study participation in CTBM100C2303 (all visits) and who were proven infected with Pseudomonas aeruginosa (P. aeruginosa) at enrollment into CTBM100C2303.

Condition or Disease	Intervention/Treatment	Phase
Pseudomonas Aeruginosa; Cystic Fibrosis	Drug: Tobramycin inhalation powder	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Open-Label Extension Study to Assess the Safety and Efficacy of Tobramycin Inhalation Powder After Manufacturing Process Modifications (TIPnew) in Cystic Fibrosis (CF) Subjects Who Completed Participation in Study CTBM100C2303.
• Actual Study Start Date: Aug 12, 2009
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 6, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tobramycin Inhalation Powder (TIP) Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, twice a day (b.i.d.), given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.	Drug: Tobramycin inhalation powder; Tobramycin inhalation powder, 112 mg (4 capsules of 28 mg), inhalation capsules, b.i.d.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs) [From first administration of study drug to study completion (up to approximately 25 weeks)]

   AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal product.

2. Percentage of Participants With Serious Adverse Events (SAEs) [From time of consent to 4 weeks after study completion (up to approximately 29 weeks)]

   SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.

3. Percentage of Death Cases [From time of consent to 4 weeks after study completion (up to approximately 29 weeks)]

4. Percentage of Participants With Adverse Events and Serious Adverse Events Leading to Permanent Study Discontinuation [From first administration of study drug to study completion (up to approximately 25 weeks)]

   AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal product. SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.

5. Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal [From baseline to study completion (up to approximately 25 weeks)]

   Shift from baseline in hematology and biochemistry values to above upper/below lower limit of normal at any time post-baseline were reported. Baseline for safety analyses was defined as the last measurement prior to first dose of study drug in the core study CTBM100C2303. Change to low referred to number of participants with normal or high values at baseline. Change to high referred to number of participants with normal or low values at baseline.

6. Acute Relative Change in Airways Reactivity [Forced Expiratory Value in One Second (FEV1) Percent (%) Predicted] From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug [Pre-dose and 30 minutes Post-dose on Day 1 and Day 29 of every Cycle (2, 3, 4)]

   Airway Reactivity was defined as ≥20% FEV1 relative decrease in percent predicted from pre dose to 30 minutes post dose. FEV1 was defined as the volume of air expired in 1 second. FEV1 % predicted was a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. Relative change in FEV1 % predicted = 100* (30 minutes post dose - pre dose) / pre dose assessed by number and percentage of participants with a decrease in ≥20% FEV1 percent predicted from pre dose to 30 minutes post dose. Baseline for was defined as the last measurement prior to first dose of study drug in the core study CTBM100C2303.

7. Percentage of Participants With Frequency Decrease From Baseline in the Post-baseline Audiology Tests [From first dose of study drug to study completion (up to approximately 25 weeks)]

   Auditory acuity of participants was measured using a standard dual-channel audiometer at frequencies from 250 to 8000 Hertz, and an audiogram (pure-tone air conduction) and tympanogram were performed by an audiologist. The categories reported includes >= 10dB decrease in 3 consecutive frequencies in either ear, >= 15dB decrease in 2 consecutive frequencies in either ear, and >= 20dB decrease in at least one frequency in either ear.

8. Number of Participants With Adverse Events (AEs) Associated With the Use of New Antipseudomonal Antibiotic [From first administration of study drug to study completion (up to approximately 25 weeks)]

   AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal product. SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.

Secondary Outcome Measures

1. Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing at Each Cycle and Study Completion [Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)]

   FEV1 was defined as the volume of air expired in 1 second. FEV1 % predicted was a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. Relative change in FEV1 % predicted = 100* (30 minutes post dose - pre dose) / pre dose assessed by number and percentage of participants with a decrease in ≥20% FEV1 percent predicted from pre dose to 30 minutes post dose. Baseline for was defined as the last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.

2. Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted to End of Dosing at Each Cycle and Study Completion [Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)]

   Relative change from baseline in FVC % predicted to end of dosing in each cycle and study completion were reported. Relative change from baseline was defined as: Relative change = 100* (Post baseline- baseline) / baseline. Baseline was defined as last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.

3. Change From Baseline in Forced Expiratory Flow Rate Over 25 Percent and 75 Percent (FEF25-75%) Predicted to End of Dosing at Each Cycle and Study Completion [Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)]

   Relative change from baseline in FEF25-75% predicted to end of dosing in each cycle and study completion were reported. Relative change from baseline was defined as: Relative change = 100* (Post baseline- baseline) / baseline. Baseline was defined as last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.

4. Absolute Change From Baseline in Sputum Pseudomonas Aeruginosa Density [log10 Colony Forming Units (CFU) Per Gram Sputum] to End of Dosing at Each Cycle and Study Completion [Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)]

   P. aeruginosa sputum density referred to overall density, defined as the sum of biotypes (mucoid, dry and small colony variant). If sub-isolates existed for CFU biotype mucoid or dry, then the sum of sub-isolates was analyzed. Absolute change from baseline was defined as: Absolute change = Post Baseline - Baseline. Baseline was defined as last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.

5. Change From Baseline in Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) to End of Dosing at Each Cycle and Study Completion [Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)]

   Change in tobramycin MIC values for P. aeruginosa were reported for specimens and were used to assess the change in pathogen susceptibility to tobramycin before (baseline) and after (post-baseline) the treatment. Maximum MIC values from all biotypes were used. Change from baseline was defined as: Change = Post-baseline - Baseline. Baseline was defined as last measurement prior to first dose of study drug in the core studyCTBM100C2303.Termination referred to the last available pre dose post-baseline measurement.

6. Percentage of Participants With Anti-Pseudomonal Antibiotic Use During The Treatment Period [From first administration of study drug to study completion (up to approximately 25 weeks)]

7. Number of Days of Hospitalization Due to Respiratory Serious Adverse Events [From first administration of study drug to study completion (up to approximately 25 weeks)]

   SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. For calculation of days in hospitalization due to respiratory events, the end date was defined as the discharge date (if provided and even if after the end of the extension study), and otherwise as the date of last visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Completed all visits in study CTBM100C2303, and visit 4 took place not more than 5 days before enrollment into this study.

• Confirmed diagnosis of cystic fibrosis participants with P. aeruginosa infection.

• Forced Expiratory Volume in One Second (FEV1) at screening (study CTBM100C2303) must be between 25% and 80% of normal predicted values.

Exclusion Criteria:

• Any use of inhaled anti-pseudomonal antibiotics between the termination of the core trial CTMB100C2303 and the enrollment into this study.

• Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Tallin		Estonia
2	Novartis Investigative Site	Yaroslavl		Russian Federation

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00982930
• Other Study ID Numbers: CTBM100C2303E1; 2008-004764-39
• First Posted: Sep 23, 2009
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Tobramycin Inhalation Powder; Cystic fibrosis; Lung diseases; Anti-Bacterial Agents
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Tobramycin

Study Results

Participant Flow

Recruitment Details	Participants who had completed all visits in the core study CTBM100C2303 took part in this extension study at 16 centers in 8 countries Bulgaria, Egypt, Estonia, Latvia, India, Lithuania, Romania and Russia from 12 August 2009 to 6 October 2011.
Pre-assignment Detail	A total of 55 participants who completed all visits in the core study CTBM100C2303 and received one cycle (Cycle 1) of either Tobramycin Inhalation Powder (TIP) or matching placebo entered into the extension study and received 3 additional TIP cycles (Cycles 2, 3 and 4).

Arm/Group Title	Tobramycin Inhalation Powder (TIP)
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, twice a day (b.i.d), given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Period Title: Overall Study
STARTED	55
COMPLETED	51
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Overall Participants	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.9 (4.44)
Sex: Female, Male (Count of Participants)
Female	35 63.6%
Male	20 36.4%
Baseline Forced Expiratory Volume in One Second (FEV1) Percent Predicted (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	59.9 (16.24)
Baseline Forced Vital Capacity (FVC) Percent Predicted (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	75.2 (17.05)
Baseline Forced Expiratory Flow Rate Over 25 and 75 Percent (FEF25-75%) Predicted (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	37.2 (20.19)
Baseline P. aeruginosa Sputum Density (log10 Colony Forming Units (CFU)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log10 Colony Forming Units (CFU)]	7.3 (1.81)
Baseline P. aeruginosa Tobramycin Minimal Inhibitory Concentration (MIC) (microgram/ mL (µg/mL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [microgram/ mL (µg/mL)]	4.6 (14.60)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs)
Description	AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal product.
Time Frame	From first administration of study drug to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Number [percentage of participants]	47.3 86%

2. Primary Outcome

Title	Percentage of Participants With Serious Adverse Events (SAEs)
Description	SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.
Time Frame	From time of consent to 4 weeks after study completion (up to approximately 29 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Number [percentage of participants]	5.5 10%

3. Primary Outcome

Title	Percentage of Death Cases
Time Frame	From time of consent to 4 weeks after study completion (up to approximately 29 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Number [percentage of participants]	0 0%

4. Primary Outcome

Title	Percentage of Participants With Adverse Events and Serious Adverse Events Leading to Permanent Study Discontinuation
Description	AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal product. SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.
Time Frame	From first administration of study drug to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Discontinuation Due to Adverse Events	1.8 3.3%
Discontinuation Due to Serious Adverse Events	0 0%

5. Primary Outcome

Title	Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal
Description	Shift from baseline in hematology and biochemistry values to above upper/below lower limit of normal at any time post-baseline were reported. Baseline for safety analyses was defined as the last measurement prior to first dose of study drug in the core study CTBM100C2303. Change to low referred to number of participants with normal or high values at baseline. Change to high referred to number of participants with normal or low values at baseline.
Time Frame	From baseline to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Hematology (Hem): Absolute Basophils - low	0.0 0%
Hem: Absolute Basophils - high	16.0 29.1%
Hem: Absolute Eosinophils - low	0.0 0%
Hem: Absolute Eosinophils - high	33.3 60.5%
Hem: Absolute Lymphocytes - low	10.6 19.3%
Hem: Absolute Lymphocytes - high	32.4 58.9%
Hem: Absolute Monocytes - low	0.0 0%
Hem: Absolute Monocytes - high	20.9 38%
Hem: Absolute Neutrophils (Seg. + Bands) - low	28.3 51.5%
Hem: Absolute Neutrophils (Seg. + Bands) - high	35.7 64.9%
Hem: Basophils - low	0.0 0%
Hem: Basophils - high	70.4 128%
Hem: Eosinophils - low	0.0 0%
Hem: Eosinophils - high	37.8 68.7%
Hem: Hematocrit - low	0.0 0%
Hem: Hematocrit - high	29.5 53.6%
Hem: Hemoglobin - low	5.8 10.5%
Hem: Hemoglobin - high	6.0 10.9%
Hem: Lymphocytes - low	12.8 23.3%
Hem: Lymphocytes - high	39.5 71.8%
Hem: Monocytes - low	14.9 27.1%
Hem: Monocytes - high	42.5 77.3%
Hem: Neutrophils (Seg. + Bands) - low	37.8 68.7%
Hem: Neutrophils (Seg. + Bands) - high	10.4 18.9%
Hem: Platelet count (direct) - low	2.0 3.6%
Hem: Platelet count (direct) - high	24.0 43.6%
Hem: RBC- low	0.0 0%
Hem: RBC- high	27.8 50.5%
Hem: WBC (total)- low	20.5 37.3%
Hem: WBC (total)- high	31.7 57.6%
Biochemistry (Bio): Albumin - low	0.0 0%
Bio: Albumin - high	32.4 58.9%
Bio: Alkaline phosphatase, serum - low	0.0 0%
Bio: Alkaline phosphatase, serum - high	22.0 40%
Bio: Bilirubin (direct/conjugated) -low	0.0 0%
Bio: Bilirubin (direct/conjugated) -high	11.8 21.5%
Bio: Bilirubin (total) - low	0.0 0%
Bio: Bilirubin (total) - high	7.4 13.5%
Bio: Blood Urea Nitrogen (BUN) - low	16.7 30.4%
Bio: Blood Urea Nitrogen (BUN) - high	10.9 19.8%
Bio: Calcium -low	12.7 23.1%
Bio: Calcium - high	11.1 20.2%
Bio: Chloride - low	9.1 16.5%
Bio: Chloride - high	1.8 3.3%
Bio: Creatinine - low	36.4 66.2%
Bio: Creatinine - high	1.9 3.5%
Bio: Gamma Glutamyltransferase - low	1.9 3.5%
Bio: Gamma Glutamyltransferase - high	10.4 18.9%
Bio: Glucose - low	24.0 43.6%
Bio: Glucose - high	15.1 27.5%
Bio: Phosphate (Inorganic Phosphorus) - low	1.8 3.3%
Bio: Phosphate (Inorganic Phosphorus) - high	47.1 85.6%
Bio: Potassium - low	3.8 6.9%
Bio: Potassium - high	7.4 13.5%
Bio: SGOT (AST) - low	3.7 6.7%
Bio: SGOT (AST) - high	30.4 55.3%
Bio: SGPT (ALT) - low	0.0 0%
Bio: SGPT (ALT) - high	39.0 70.9%
Bio: Serum bicarbonate - low	45.9 83.5%
Bio: Serum bicarbonate - high	0.0 0%
Bio: Sodium - low	10.9 19.8%
Bio: Sodium - high	5.5 10%
Bio: Total Protein (Serum) - low	1.8 3.3%
Bio: Total Protein (Serum) - high	27.9 50.7%
Bio: Uric Acid - low	1.8 3.3%
Bio: Uric Acid - high	16.0 29.1%

6. Primary Outcome

Title	Acute Relative Change in Airways Reactivity [Forced Expiratory Value in One Second (FEV1) Percent (%) Predicted] From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug
Description	Airway Reactivity was defined as ≥20% FEV1 relative decrease in percent predicted from pre dose to 30 minutes post dose. FEV1 was defined as the volume of air expired in 1 second. FEV1 % predicted was a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. Relative change in FEV1 % predicted = 100* (30 minutes post dose - pre dose) / pre dose assessed by number and percentage of participants with a decrease in ≥20% FEV1 percent predicted from pre dose to 30 minutes post dose. Baseline for was defined as the last measurement prior to first dose of study drug in the core study CTBM100C2303.
Time Frame	Pre-dose and 30 minutes Post-dose on Day 1 and Day 29 of every Cycle (2, 3, 4)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Cycle 2: Day 1	0.0 (12.07)
Cycle 2: Day 29	-3.0 (7.21)
Cycle 3: Day 1	-1.4 (13.33)
Cycle 3: Day 29	-1.8 (6.67)
Cycle 4: Day 1	-3.0 (11.01)
Cycle 4: Day 29	-0.6 (6.82)

7. Primary Outcome

Title	Percentage of Participants With Frequency Decrease From Baseline in the Post-baseline Audiology Tests
Description	Auditory acuity of participants was measured using a standard dual-channel audiometer at frequencies from 250 to 8000 Hertz, and an audiogram (pure-tone air conduction) and tympanogram were performed by an audiologist. The categories reported includes >= 10dB decrease in 3 consecutive frequencies in either ear, >= 15dB decrease in 2 consecutive frequencies in either ear, and >= 20dB decrease in at least one frequency in either ear.
Time Frame	From first dose of study drug to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population (Audiology Subgroup) included all participants in the safety population with at least one audiology testing. Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with normal hearing at baseline with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	22
Cycle 2: Day 1; ˃= 10 dB Decrease in 3 Consecutive Frequencies in Either Ear	5.6 10.2%
Cycle 2: Day 1: >= 15 dB Decrease In 2 Consecutive Frequencies in Either Ear	0.0 0%
Cycle 2: Day 1; >= 20 dB Decrease in at Least One Frequency In Either Ear	0.0 0%
Cycle 2: Day 29; ˃= 10 dB decrease in 3 Consecutive Frequencies in Either Ear	5.0 9.1%
Cycle 2: Day 29; >= 15 dB Decrease In 2 Consecutive Frequencies in Either Ear	0.0 0%
Cycle 2: Day 29; >= 20 dB Decrease in at Least One Frequency In Either Ear	0.0 0%
Cycle 3: Day 29; ˃= 10 dB Decrease in 3 Consecutive Frequencies in Either Ear	9.1 16.5%
Cycle 3: Day 29; >= 15 dB Decrease In 2 Consecutive Frequencies in Either Ear	4.5 8.2%
Cycle 3: Day 29; >= 20 dB Decrease in at Least One Frequency In Either Ear	4.5 8.2%
Cycle 4: Day 29; ˃= 10 dB decrease in 3 Consecutive Frequencies in Either Ear	4.5 8.2%
Cycle 4: Day 29; >= 15 dB Decrease In 2 Consecutive Frequencies in Either Ear	0.0 0%
Cycle 4: Day 29; >= 20 dB Decrease in at Least One Frequency In Either Ear	0.0 0%
Follow Up: Day 57; ˃= 10 dB decrease in 3 Consecutive Frequencies in Either Ear	0.0 0%
Follow Up: Day 57: >= 15 dB Decrease in 2 Consecutive Frequencies in Either Ear	0.0 0%
Follow Up: Day 57; >= 20 dB Decrease in at Least One Frequency In Either Ear	0.0 0%

8. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) Associated With the Use of New Antipseudomonal Antibiotic
Description	AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal product. SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.
Time Frame	From first administration of study drug to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Mild, Yes	1 1.8%
Mild, No	13 23.6%
Moderate, Yes	3 5.5%
Moderate, No	9 16.4%
Severe, Yes	0 0%
Severe, No	0 0%

9. Secondary Outcome

Title	Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing at Each Cycle and Study Completion
Description	FEV1 was defined as the volume of air expired in 1 second. FEV1 % predicted was a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. Relative change in FEV1 % predicted = 100* (30 minutes post dose - pre dose) / pre dose assessed by number and percentage of participants with a decrease in ≥20% FEV1 percent predicted from pre dose to 30 minutes post dose. Baseline for was defined as the last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.
Time Frame	Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Cycle 2: Day 29	13.5 (23.42)
Cycle 3: Day 29	14.8 (22.40)
Cycle 4: Day 29	17.3 (23.56)
Follow Up: Day 57	13.5 (20.62)
Termination	13.9 (21.86)

10. Secondary Outcome

Title	Change From Baseline in Forced Vital Capacity (FVC) Percent (%) Predicted to End of Dosing at Each Cycle and Study Completion
Description	Relative change from baseline in FVC % predicted to end of dosing in each cycle and study completion were reported. Relative change from baseline was defined as: Relative change = 100* (Post baseline- baseline) / baseline. Baseline was defined as last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.
Time Frame	Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Cycle 2: Day 29	7.0 (17.46)
Cycle 3: Day 29	7.2 (16.89)
Cycle 4: Day 29	9.6 (16.87)
Follow Up: Day 57	7.4 (14.99)
Termination	7.9 (15.24)

11. Secondary Outcome

Title	Change From Baseline in Forced Expiratory Flow Rate Over 25 Percent and 75 Percent (FEF25-75%) Predicted to End of Dosing at Each Cycle and Study Completion
Description	Relative change from baseline in FEF25-75% predicted to end of dosing in each cycle and study completion were reported. Relative change from baseline was defined as: Relative change = 100* (Post baseline- baseline) / baseline. Baseline was defined as last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.
Time Frame	Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Cycle 2: Day 29	35.2 (55.86)
Cycle 3: Day 29	44.7 (58.17)
Cycle 4; Day 29	40.5 (59.21)
Follow Up: Day 57	35.9 (58.08)
Termination	34.7 (57.98)

12. Secondary Outcome

Title	Absolute Change From Baseline in Sputum Pseudomonas Aeruginosa Density [log10 Colony Forming Units (CFU) Per Gram Sputum] to End of Dosing at Each Cycle and Study Completion
Description	P. aeruginosa sputum density referred to overall density, defined as the sum of biotypes (mucoid, dry and small colony variant). If sub-isolates existed for CFU biotype mucoid or dry, then the sum of sub-isolates was analyzed. Absolute change from baseline was defined as: Absolute change = Post Baseline - Baseline. Baseline was defined as last measurement prior to first dose of study drug in the core study CTBM100C2303. Termination referred to the last available pre dose post-baseline measurement.
Time Frame	Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Cycle 2: Day 29	-3.7 (2.76)
Cycle 3: Day 29	-3.5 (3.04)
Cycle 4: Day 29	-3.9 (2.82)
Follow Up: Day 57	-1.1 (2.82)
Termination	-2.9 (3.16)

13. Secondary Outcome

Title	Change From Baseline in Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) to End of Dosing at Each Cycle and Study Completion
Description	Change in tobramycin MIC values for P. aeruginosa were reported for specimens and were used to assess the change in pathogen susceptibility to tobramycin before (baseline) and after (post-baseline) the treatment. Maximum MIC values from all biotypes were used. Change from baseline was defined as: Change = Post-baseline - Baseline. Baseline was defined as last measurement prior to first dose of study drug in the core studyCTBM100C2303.Termination referred to the last available pre dose post-baseline measurement.
Time Frame	Baseline, Day 29 of Cycle 2, 3, 4, Day 57 of Follow Up and Termination (Study Completion)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study. Number analyzed were the number of participants with data available for analyses at given time point.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Cycle 2: Day 29	15.1 (82.45)
Cycle 3: Day 29	30.7 (112.32)
Cycle 4: Day 29	24.0 (90.13)
Follow Up: Day 57	28.6 (111.71)
Termination	22.3 (101.38)

14. Secondary Outcome

Title	Percentage of Participants With Anti-Pseudomonal Antibiotic Use During The Treatment Period
Time Frame	From first administration of study drug to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Number [percentage of participants]	9.1 16.5%

15. Secondary Outcome

Title	Number of Days of Hospitalization Due to Respiratory Serious Adverse Events
Description	SAEs included adverse events that resulted in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. For calculation of days in hospitalization due to respiratory events, the end date was defined as the discharge date (if provided and even if after the end of the extension study), and otherwise as the date of last visit.
Time Frame	From first administration of study drug to study completion (up to approximately 25 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study.

Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
Measure Participants	55
Median (Full Range) [days]	13.0

Adverse Events

Time Frame	From first administration of study drug to study completion (up to approximately 25 weeks)
Adverse Event Reporting Description	Safety Population included all enrolled participants who completed their participation in the core study (CTBM100C2303) and received at least one dose of study drug in the extension study.
Arm/Group Title	Tobramycin Inhalation Powder
Arm/Group Description	Participants received 112 mg (four 28 mg capsules) of TIP administered by the T-326 Inhaler, b.i.d., given in a cycle of 28 days on treatment followed by 28 days off treatment (one cycle = 56 days) for up to 3 cycles.
All Cause Mortality
	Tobramycin Inhalation Powder
	Affected / at Risk (%)	# Events
Total	0/55 (0%)
Serious Adverse Events
	Tobramycin Inhalation Powder
	Affected / at Risk (%)	# Events
Total	3/55 (5.5%)
Infections and infestations
Aspergillosis	1/55 (1.8%)
Lung infection	1/55 (1.8%)
Pneumonia	1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	Tobramycin Inhalation Powder
	Affected / at Risk (%)	# Events
Total	24/55 (43.6%)
Ear and labyrinth disorders
Hypoacusis	3/55 (5.5%)
Middle ear effusion	1/55 (1.8%)
Gastrointestinal disorders
Abdominal pain	2/55 (3.6%)
Diarrhoea	2/55 (3.6%)
General disorders
Pyrexia	2/55 (3.6%)
Infections and infestations
Ascariasis	1/55 (1.8%)
Bronchitis	1/55 (1.8%)
Bronchopulmonary aspergillosis	2/55 (3.6%)
Gastrointestinal candidiasis	1/55 (1.8%)
Nasopharyngitis	1/55 (1.8%)
Respiratory tract infection	5/55 (9.1%)
Respiratory tract infection viral	1/55 (1.8%)
Sinusitis	1/55 (1.8%)
Stenotrophomonas infection	1/55 (1.8%)
Upper respiratory tract infection	1/55 (1.8%)
Viral rhinitis	1/55 (1.8%)
Injury, poisoning and procedural complications
Vaccination complication	1/55 (1.8%)
Investigations
Blood calcium decreased	1/55 (1.8%)
Hepatic enzyme increased	1/55 (1.8%)
Protein urine	1/55 (1.8%)
Protein urine present	2/55 (3.6%)
White blood cell count increased	1/55 (1.8%)
Metabolism and nutrition disorders
Hypoglycaemia	1/55 (1.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/55 (1.8%)
Nervous system disorders
Headache	2/55 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	5/55 (9.1%)
Dysphonia	3/55 (5.5%)
Dyspnoea	1/55 (1.8%)
Productive cough	1/55 (1.8%)
Sinus polyp	2/55 (3.6%)
Skin and subcutaneous tissue disorders
Rash	1/55 (1.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.