Trial Outcomes & Findings for Long Term Safety of Tobramycin Inhalation Powder in Patients With Cystic Fibrosis (NCT NCT01519661)

NCT ID: NCT01519661

Last Updated: 2015-02-10

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 157 participants
• Primary outcome timeframe: 337 days
• Results posted on: 2015-02-10

Participant Flow

Participant milestones

Measure	Tobramycin Inhalation Powder (TIP) 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.
Overall Study STARTED	157
Overall Study COMPLETED	96
Overall Study NOT COMPLETED	61

Reasons for withdrawal

Measure	Tobramycin Inhalation Powder (TIP) 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.
Overall Study Protocol deviation	6
Overall Study Lost to Follow-up	3
Overall Study Withdrawal by Subject	17
Overall Study Lack of Efficacy	6
Overall Study Adverse Event	29

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
Age, Continuous	27.8 Years STANDARD_DEVIATION 10.82 • n=5 Participants
Sex: Female, Male Female	60 Participants n=5 Participants
Sex: Female, Male Male	97 Participants n=5 Participants
Weight	57.4 kilograms (kg) STANDARD_DEVIATION 13.52 • n=5 Participants
Body Mass Index	20.5 kg/m^2 STANDARD_DEVIATION 3.35 • n=5 Participants
FEV1 % predicted	50.2 percent STANDARD_DEVIATION 13.95 • n=5 Participants
FVC % predicted	73.9 percent STANDARD_DEVIATION 15.88 • n=5 Participants
FEF25-75 % predicted	21.8 percent STANDARD_DEVIATION 12.75 • n=5 Participants
Sputum density of P. aeruginosa - sum of all biotypes	7.6 log10 Colony Forming Units (CFU) STANDARD_DEVIATION 1.65 • n=5 Participants
P. aeruginosa tobramycin minimal inhibitory concentration (MIC) > 8 ug/mL	26.1 percentage of participants n=5 Participants
P. aeruginosa tobramycin minimal inhibitory concentration (MIC) <= 8 ug/mL	73.2 percentage of participants n=5 Participants
P. aeruginosa tobramycin minimal inhibitory concentration (MIC) Missing	0.6 percentage of participants n=5 Participants

PRIMARY outcome

Timeframe: 337 days

Population: Safety set: The safety set included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths Adverse events (serious and non-serious)	85.4 Percentage of participants
Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths Serious adverse events	31.2 Percentage of participants
Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths Deaths	0.0 Percentage of participants

SECONDARY outcome

Timeframe: 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.

Population: Participants from the safety set who had FEV1 percent predicted values at both baseline and the post baseline time points were analyzed at each given time point. The safety set included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 29, Cycle 1 (n=149)	0.8 Percent change Standard Deviation 17.17
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 85, Cycle 2 (n=146)	0.0 Percent change Standard Deviation 17.09
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 141, Cycle 3 (n=128)	0.2 Percent change Standard Deviation 15.13
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 197, Cycle 4 (n=116)	-0.2 Percent change Standard Deviation 15.36
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 253, Cycle 5 (n=105)	-1.5 Percent change Standard Deviation 17.19
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 309, Cycle 6 (n=100)	-1.9 Percent change Standard Deviation 14.55
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Day 337, Completion (n=93)	-3.5 Percent change Standard Deviation 16.81

SECONDARY outcome

Timeframe: 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.

Population: Participants from the safety set who had values at both baseline and the given assessment day were included in the analysis for that assessment day. Therefore, the 'n' for each assessment day is different. The safety set included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
Relative Change From Baseline in FVC Percent Predicted Day 29, Cycle 1 (n=149)	-2.5 Percent change Standard Deviation 12.95
Relative Change From Baseline in FVC Percent Predicted Day 85, Cycle 2 (n=146)	-2.8 Percent change Standard Deviation 12.81
Relative Change From Baseline in FVC Percent Predicted Day 141, Cycle 3 (n=128)	-2.1 Percent change Standard Deviation 12.25
Relative Change From Baseline in FVC Percent Predicted Day 197, Cycle 4 (n=116)	-1.8 Percent change Standard Deviation 12.64
Relative Change From Baseline in FVC Percent Predicted Day 253, Cycle 5 (n=105)	-3.5 Percent change Standard Deviation 13.11
Relative Change From Baseline in FVC Percent Predicted Day 309, Cycle 6 (n=100)	-3.1 Percent change Standard Deviation 12.17
Relative Change From Baseline in FVC Percent Predicted Day 337, Completion (n=93)	-2.8 Percent change Standard Deviation 13.50

SECONDARY outcome

Timeframe: 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.

Population: Participants from the safety set who had values at both baseline and the given assessment day were included in the analysis for that assessment day. Therefore, the 'n' for each assessment day is different. The safety set included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 29, Cycle 1 (n=149)	10.3 Percent change Standard Deviation 36.05
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 85, Cycle 2 (n=146)	9.4 Percent change Standard Deviation 55.35
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 141, Cycle 3 (n=128)	5.5 Percent change Standard Deviation 31.82
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 197, Cycle 4 (n=116)	6.0 Percent change Standard Deviation 30.96
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 253, Cycle 5 (n=105)	2.9 Percent change Standard Deviation 33.23
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 309, Cycle 6 (n=100)	4.3 Percent change Standard Deviation 32.44
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted Day 337, Completion (n=93)	0.7 Percent change Standard Deviation 33.78

SECONDARY outcome

Timeframe: Baseline, day 1, day 29, day 85, day 141, day 197, day 253, day 309, day 337

Population: Participants from the safety set who had Pa sputum density values at both baseline and the given time point were included in the analysis. The safety set included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes, Day 29, Cycle 1 (n=141)	-1.6 log10 Colony Forming Unit (CFU) Standard Deviation 2.28
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes, Day 85, Cycle 2 (n=135)	-1.1 log10 Colony Forming Unit (CFU) Standard Deviation 1.80
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes, Day 141, Cycle 3 (n=119)	-1.2 log10 Colony Forming Unit (CFU) Standard Deviation 1.98
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes, Day 197, Cycle 4(n=107)	-1.1 log10 Colony Forming Unit (CFU) Standard Deviation 2.11
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes. Day 253, Cycle 5 (n=98)	-1.3 log10 Colony Forming Unit (CFU) Standard Deviation 2.23
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes, Day 309, Cycle 6 (n=89)	-1.2 log10 Colony Forming Unit (CFU) Standard Deviation 2.09
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum Sum of all biotypes, Day 337, Completion (n=85)	-0.4 log10 Colony Forming Unit (CFU) Standard Deviation 2.08

SECONDARY outcome

Timeframe: Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337

Population: Participants from the safety set who had data at each time point/cycle were analyzed at each time point. The safety set included all participants who received at least one dose of study drug.

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.

Outcome measures

Measure	Tobramycin Inhalation Powder (TIP) n=157 Participants 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.
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 Baseline - MIC 50 (n=156)	2 ug/mL
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 Cycle 1, day 29 - MIC 50 (n=144)	2 ug/mL
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 Cycle 2, day 85 - MIC 50 (n=137)	2 ug/mL
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 Cycle 3, day 141 - MIC 50 (n=124)	2 ug/mL
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 Cycle 4, day 197 - MIC 50 (n=108)	2 ug/mL
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 Cycle 5, day 253 - MIC 50 (n=98)	2 ug/mL
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 Cycle 6, day 309 - MIC 50 (n=90)	4 ug/mL
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 Completion, day 337 - MIC 50 (n=89)	2 ug/mL
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 Baseline - MIC 90 (n=156)	128 ug/mL
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 Cycle 1, day 29 - MIC 90 (n=144)	256 ug/mL
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 Cycle 2, day 85 - MIC 90 (n=137)	256 ug/mL
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 Cycle 3, day 141 - MIC 90 (n=124)	256 ug/mL
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 Cycle 4, day 197 - MIC 90 (n=108)	128 ug/mL
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 Cycle 5, day 253 - MIC 90 (n=98)	256 ug/mL
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 Cycle 6, day 309 - MIC 90 (n=90)	256 ug/mL
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 Completion, day 337 - MIC 90 (n=89)	512 ug/mL

SECONDARY outcome

Timeframe: Day 337

Population: Safety set: The safety set included all participants who received at least one dose of study drug.

Outcome measures

Measure

Tobramycin Inhalation Powder (TIP) n=157 Participants 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.

Percentage of Participants Hospitalized Due to Serious Respiratory-related Adverse Events

26.8 Percentage of participants

SECONDARY outcome

Timeframe: Day 337

Population: Safety set: The safety set included all participants who received at least one dose of study drug.

The total number of hospitalization days due to serious respiratory-related adverse events was analyzed.

Outcome measures

Measure

Tobramycin Inhalation Powder (TIP) n=157 Participants 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.

Number of Hospitalization Days Due to Serious Respiratory-related Adverse Events

18.1 Days Standard Deviation 17.14

SECONDARY outcome

Timeframe: Day 337

Population: Safety set The safety set included all participants who received at least one dose of study drug.

The day of first hospitalization due to serious respiratory-related adverse events was analyzed.

Outcome measures

Measure

Tobramycin Inhalation Powder (TIP) n=157 Participants 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.

Time to First Hospitalization Due to Serious Respiratory-related Adverse Events

NA Days The median was not estimable due to an insufficient number of events.

SECONDARY outcome

Timeframe: Day 337

Population: Safety set: The safety set included all participants who received at least one dose of study drug.

Outcome measures

Measure

Tobramycin Inhalation Powder (TIP) n=157 Participants 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.

Percentage of Participants Who Used New Anti-pseudomonal Antibiotics

65.6 Percentage of participants

SECONDARY outcome

Timeframe: Day 337

Population: Safety set: The safety set included all participants who received at least one dose of study drug.

The total number of days of new anti-pseudomonal antibiotic use was analyzed.

Outcome measures

Measure

Tobramycin Inhalation Powder (TIP) n=157 Participants 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.

Number of Days of New Anti-pseudomonal Antibiotic Use

33.1 Days Standard Deviation 25.17

SECONDARY outcome

Timeframe: Day 337

Population: Safety set The safety set included all participants who received at least one dose of study drug.

Time to first use of new anti-pseudomonal antibiotic was analyzed.

Outcome measures

Measure

Tobramycin Inhalation Powder (TIP) n=157 Participants 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.

Time to Use of New Anti-pseudomonal Antibiotic

136 Days Interval 97.0 to 170.0

Adverse Events

Tobramycin Inhalation Powder (TIP)

Serious events: 49 serious events

Other events: 121 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tobramycin Inhalation Powder (TIP) n=157 participants at risk 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.
Cardiac disorders Supraventricular tachycardia	0.64% 1/157
Cardiac disorders Tachyarrhythmia	0.64% 1/157
Ear and labyrinth disorders Deafness unilateral	0.64% 1/157
Ear and labyrinth disorders Tinnitus	0.64% 1/157
Gastrointestinal disorders Gastritis	0.64% 1/157
Gastrointestinal disorders Gastrooesophageal reflux disease	0.64% 1/157
Gastrointestinal disorders Pancreatitis	0.64% 1/157
Gastrointestinal disorders Subileus	0.64% 1/157
Infections and infestations Bronchopneumonia	0.64% 1/157
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	24.8% 39/157
Infections and infestations Influenza	1.3% 2/157
Infections and infestations Pneumonia	1.9% 3/157
Injury, poisoning and procedural complications Rib fracture	0.64% 1/157
Metabolism and nutrition disorders Hyperamylasaemia	0.64% 1/157
Reproductive system and breast disorders Ovarian cyst	0.64% 1/157
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.64% 1/157
Respiratory, thoracic and mediastinal disorders Haemoptysis	3.2% 5/157
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.64% 1/157
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.64% 1/157

Other adverse events

Measure	Tobramycin Inhalation Powder (TIP) n=157 participants at risk 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.
Gastrointestinal disorders Abdominal pain	3.8% 6/157
Gastrointestinal disorders Diarrhoea	7.0% 11/157
Gastrointestinal disorders Nausea	5.1% 8/157
Gastrointestinal disorders Vomiting	4.5% 7/157
General disorders Chest discomfort	5.7% 9/157
General disorders Fatigue	5.7% 9/157
General disorders Pyrexia	7.6% 12/157
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	42.0% 66/157
Infections and infestations Nasopharyngitis	12.7% 20/157
Infections and infestations Pharyngitis	3.2% 5/157
Infections and infestations Rhinitis	3.8% 6/157
Infections and infestations Upper respiratory tract infection	9.6% 15/157
Investigations Forced expiratory volume decreased	5.1% 8/157
Nervous system disorders Headache	7.0% 11/157
Respiratory, thoracic and mediastinal disorders Cough	23.6% 37/157
Respiratory, thoracic and mediastinal disorders Dysphonia	4.5% 7/157
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.0% 11/157
Respiratory, thoracic and mediastinal disorders Haemoptysis	21.0% 33/157
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	7.6% 12/157
Respiratory, thoracic and mediastinal disorders Respiratory tract congestion	3.2% 5/157
Respiratory, thoracic and mediastinal disorders Sputum increased	10.2% 16/157
Respiratory, thoracic and mediastinal disorders Wheezing	5.1% 8/157

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee 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 or disclosure of trial results in their entirety.
• Publication restrictions are in place

Restriction type: OTHER