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Ext. Long-term Safety Study in CF Patients: Single Arm TIP

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ClinicalTrials.gov Identifier: NCT01775137
Recruitment Status : Completed
First Posted : January 24, 2013
Results First Posted : November 6, 2015
Last Update Posted : November 6, 2015
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label)
Condition Long-term Safety of TIP
Intervention Drug: TBM100
Enrollment 45
Recruitment Details The study was conducted at 22 centers in 9 countries.
Pre-assignment Details Of 96 participants who completed the core study (CTBM100C2401), NCT01519661; 45 participants were enrolled in the extension study.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description Participants inhaled four capsules of tobramycin inhalation powder (28 mg) twice daily (bid) via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Period Title: Overall Study
Started 45
Completed 34
Not Completed 11
Reason Not Completed
Death             1
Protocol deviation             2
Unsatisfactory therapeutic effect             2
Adverse Event             1
Withdrawal by participants             5
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Baseline Participants 45
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 45 participants
<=18 years
12
  26.7%
Between 18 and 65 years
33
  73.3%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 45 participants
24.5  (10.79)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 45 participants
Female
20
  44.4%
Male
25
  55.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 45 participants
Canada 1
Argentina 9
Hungary 1
United States 6
Italy 7
Mexico 5
Australia 5
Germany 5
Spain 6
Pseudomonas aeruginosa tobramycin minimal inhibitory concentration (MIC)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 45 participants
> 8 microgram/milliliter(ug/mL) 12
<= 8 ug/mL 33
Forced expiratory volume in one second (FEV1) percent (%) predicted  
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 45 participants
52.2  (15.01)
Forced vital capacity (FVC) % predicted  
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 45 participants
73.2  (17.49)
Forced expiratory flow from 25 to 75 % (FEF2575%) % predicted  
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 45 participants
24.7  (14.86)
1.Primary Outcome
Title Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs/SAEs Leading to Discontinuation of Study Drug and Deaths Over 12 Treatment Cycles
Hide Description An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Based on the severity, AEs were categorised into 3 types as mild, moderate and severe. Death was a fatal event leading to permanent cessations of all vital functions of the body.
Time Frame Baseline (start of study treatment in core study) to Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population, defined as all the participants who entered the extension study and received at least one dose of study drug within the extension.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: Participants
AEs 39
Mild AEs 10
Moderate AEs 18
Severe AEs 11
SAEs 19
Discontinued study drug due to AEs 2
Discontinued study drug due to SAEs 1
Deaths 1
2.Secondary Outcome
Title Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Over 12 Treatment Cycles
Hide Description FEV1 was defined as the volume of air expired in 1 second. FEV1 was assessed as a pulmonary function by using spirometry tests in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria. FEV1% predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant’s age, gender and height. Relative change in FEV1 % predicted from baseline to pre-dose day X = ((pre-dose day*FEV1% predicted – baseline FEV1% predicted) / baseline FEV1 % predicted) x 100.
Time Frame Baseline (start of study treatment in core study), Day 29, Day 85, Day 141, Day 197, Day 253, Day 309, Day 337, Day 365, Day 421, Day 477, Day 533, Day 589, Day 645, 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension safety population, defined as all the participants who entered the extension study and received at least one dose of study drug within the extension and had FEV1% values at both baseline and the post baseline time points. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Mean (Standard Deviation)
Unit of Measure: Percent change in FEV1 % predicted
Core cycle 1, Day 29 (n=44) 5.0  (20.36)
Core cycle 2, day 85 (n=45) 0.8  (19.51)
Core cycle 3, day 141 (n=45) 1.3  (15.32)
Core cycle 4, day 197 (n=44) 0.0  (17.34)
Core cycle 5, day 253 (n=43) -0.5  (17.91)
Core cycle 6, day 309 (n=45) -1.6  (14.19)
Core study completion, (n=43) -3.1  (19.72)
Extension Cycle 7, day 337(n=44) -5.2  (14.29)
Extension Cycle 7, day 365(n=44) -3.7  (14.84)
Extension Cycle 8, day 421(n=41) -6.1  (14.55)
Extension Cycle 9, day 477(n=42) -4.8  (14.03)
Extension Cycle 10, day 533(n=39) -7.5  (13.97)
Extension Cycle 11, day 589(n=38) -5.4  (19.49)
Extension Cycle 12, day 645(n=35) -7.5  (14.15)
Extension completion, (n=33) -9.3  (12.76)
3.Secondary Outcome
Title Absolute Change From Baseline in Pseudomonas Aeruginosa Sputum Density Over 12 Treatment Cycles
Hide Description Microbiological data was collected to understand the direct impact of the drug on the pathogens. Sputum samples were cultured for the presence of three Pseudomonas aeruginosa (P. aeruginosa) biotypes measured were mucoid, dry and small colony variant. Absolute change was determined using the formula = (Post-baseline value- baseline value). If no P. aeruginosa was isolated for a visit, log10 colony forming units (CFU) was imputed with log10 (19) for all biotypes.
Time Frame Baseline (start of study treatment in core study), Day 29, Day 85, Day 141, Day 197, Day 253, Day 309, Day 337, Day
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) twice daily (bid) via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Mean (Standard Deviation)
Unit of Measure: log 10 CFU/g
Core cycle 1, day 29 (n=42) -1.9  (2.83)
Core cycle 2, day 85 (n=43) -1.5  (1.60)
Core cycle 3, day 141 (n=44) -1.4  (2.00)
Core cycle 4, day 197 (n=41) -1.2  (1.80)
Core cycle 5, day 253 (n=40) -2.2  (2.26)
Core cycle 6, day 309 (n=39) -1.4  (2.02)
Core study completion, day 337 (n=42) -0.7  (2.38)
Extension cycle 7, day 337 (n=40) -0.7  (2.46)
Extension cycle 7, day 365 (n=41) -1.4  (2.18)
Extension cycle 8, day 421 (n=41) -1.1  (2.20)
Extension cycle 9, day 477 (n=39) -1.1  (2.33)
Extension cycle 10, day 533 (n=35) -0.8  (1.97)
Extension cycle 11, day 589 (n=36) -1.0  (2.38)
Extension cycle 12, day 645 (n=31) -0.6  (1.96)
Extension completion, day 673 (n=29) -1.0  (2.70)
4.Secondary Outcome
Title Tobramycin Minimum Inhibitory Concentration (MIC) 50 and MIC 90 Values for Pseudomonas Aeruginosa Over 12 Treatment Cycles
Hide Description MIC was defined as the lowest concentration of an antimicrobial agent required to inhibit the visible growth of a microorganism after overnight incubation. 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 (mucoid,dry and small colony variant biotypes).
Time Frame Baseline (start of study treatment in core study), Day 29, Day 85, Day 141, Day 197, Day 253, Day 309, Day 337, Day 365, Day 421, Day 477, Day 533, Day 589, Day 645, 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population, who had microbiological data at specified time points. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: micrograms/milliliters
Core cycle, Baseline- MIC 50 (n=45) 2
Core cycle 1, day 29- MIC 50 (n=41) 2
Core cycle 2, day 85- MIC 50 (n=40) 2
Core cycle 3, day 141- MIC 50 (n=43) 2
Core cycle 4, day 197- MIC 50 (n=40) 2
Core cycle 5, day 253- MIC 50 (n=36) 2
Core cycle 6, day 309- MIC 50 (n=37) 4
Core study completion, Day 337- MIC 50 (n=40) 2
Extension cycle 7, day 337- MIC 50 (n=38) 2
Extension cycle 7, day 365- MIC 50 (n=38) 2
Extension cycle 8, day 421- MIC 50 (n=39) 2
Extension cycle 9, day 477- MIC 50 (n=39) 4
Extension cycle 10, day 533- MIC 50 (n=35) 2
Extension cycle 11, day 589- MIC 50 (n=36) 2
Extension cycle 12, day 645- MIC 50 (n=32) 2
Extension completion, Day 673 - MIC 50 (n=29) 2
Core cycle, Baseline- MIC 90 (n=45) 32
Core cycle 1, day 29- MIC 90 (n=41) 256
Core cycle 2, day 85- MIC 90 (n=40) 256
Core cycle 3, day 141- MIC 90 (n=43) 512
Core cycle 4, day 197- MIC 90 (n=40) 128
Core cycle 5, day 253- MIC 90 (n=36) 256
Core cycle 6, day 309- MIC 90 (n=37) 512
Core study completion, Day 337- MIC 90 (n=40) 512
Extension cycle 7, day 337- MIC 90 (n=38) 512
Extension cycle 7, day 365- MIC 90 (n=38) 128
Extension cycle 8, day 421- MIC 90 (n=39) 128
Extension cycle 9, day 477- MIC 90 (n=39) 512
Extension cycle 10, day 533- MIC 90 (n=35) 256
Extension cycle 11, day 589- MIC 90 (n=36) 512
Extension cycle 12, day 645- MIC 90 (n=32) 512
Extension completion, Day 673 - MIC 90 (n=29) 512
5.Secondary Outcome
Title Percentage of Participants Who Used New Anti-pseudomonal Antibiotics Over 12 Treatment Cycles
Hide Description The rate of anti-pseudomonal antibiotics use were determined from the collection of concomitant medication during the study.
Time Frame Baseline of core study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: Percentage of participants
77.8
6.Secondary Outcome
Title Total Number of Days of New Anti-pseudomonal Antibiotics Use Over 12 Treatment Cycles
Hide Description The total number of days with usage of new anti-pseudomonal antibiotic were determined.
Time Frame Baseline of core study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (Full Range)
Unit of Measure: Days
Overall route (n=35)
59.0
(15 to 252)
Oral use (n=31)
42.0
(11 to 175)
i.v use (n=25)
32.0
(7 to 252)
Inhaled use (n=1)
9.0
(9.0 to 9.0)
7.Secondary Outcome
Title Time to Use of New Anti-pseudomonal Antibiotics Over 12 Treatment Cycles
Hide Description Time to first usage of anti-pseudomonal antibiotic was determined using Kaplan Meier estimate. Participants without an event were censored at the date of the last available post-baseline measurement.
Time Frame Baseline of core study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: Days
202.0
(89.0 to 336.0)
8.Secondary Outcome
Title The Percentage of the Participants Hospitalized Due to Serious Respiratory-related AEs Were Determined During the Study.
Hide Description The percentage of the participants hospitalized due to serious respiratory-related AEs were determined during the study.
Time Frame Baseline of core study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: Percentage of participants
40.0
9.Secondary Outcome
Title Number of Hospitalization Days Due to Respiratory Related Serious Adverse Events (SAEs) Over 12 Treatment Cycles
Hide Description The total number of hospitalization days due to serious respiratory-related adverse events was analyzed using Kaplan-Meier estimate.
Time Frame Baseline of core study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (Full Range)
Unit of Measure: Days
17.0
(4 to 129)
10.Secondary Outcome
Title Time to First Hospitalization Due to Respiratory Related Serious Adverse Events (SAEs) Over 12 Treatment Cycles
Hide Description The day of first hospitalization due to serious respiratory-related adverse events was analysed using Kaplan Meier estimate.
Time Frame Baseline of core study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(NA to NA)
[1]
Here, value is not applicable due to insufficient number of events.
11.Secondary Outcome
Title Acute Relative Change From Pre-dose to 30-minute Post-dose in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Over 12 Treatment Cycles
Hide Description FEV1 was defined as the volume of air expired in 1 second. FEV1 was assessed as a pulmonary function by using spirometry tests in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria. Relative change in FEV1 % predicted was calculated by using the formula = 100 *(30-min post-dose value - pre-dose value) / pre-dose value.
Time Frame Baseline (start of study treatment in core study), Day 29, Day 85, Day 141, Day 197, Day 253, Day 309, Day 337, Day 365, Day 421, Day 477, Day 533, Day 589, Day 645, 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Mean (Standard Deviation)
Unit of Measure: Percent change in FEV1 % predicted
Core cycle 1, day 1 (n=44) -4.9  (6.72)
Core cycle 1, day 29 (n=41) -3.5  (4.25)
Core cycle 2, day 85 (n=39) -3.5  (6.19)
Core cycle 3, day 141 (n=42) -2.6  (6.06)
Core cycle 4, day 197 (n=40) -3.2  (5.41)
Core cycle 5, day 253 (n=41) -3.8  (5.47)
Core cycle 6, day 309 (n=39) -2.5  (5.94)
Extension cycle 7, day 365(n=37) -0.1  (7.79)
Extension cycle 8, day 421(n=36) -3.7  (5.10)
Extension cycle 9, day 477(n=37) -3.5  (4.78)
Extension cycle 10, day 533(n=36) -1.0  (12.54)
Extension cycle 11, day 589(n=35) -3.3  (6.73)
Extension cycle 12, day 645(n=30) -3.1  (4.01)
12.Secondary Outcome
Title Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted Over 6 Treatment Cycles in Extension Study
Hide Description FEV1 was defined as the volume of air expired in 1 second. FEV1 was assessed as a pulmonary function by using spirometry tests in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria. FEV1% predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant’s age, gender and height. Relative change in FEV1 % predicted from baseline to pre-dose day X = ((pre-dose day*FEV1% predicted – baseline FEV1% predicted) / baseline FEV1 % predicted) x 100.
Time Frame Baseline (start of study treatment in extension study), Day 365, Day 421, Day 477, Day 533, Day 589, Day 645, 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
Extension safety population, defined as all the participants who entered the extension study and received at least one dose of study drug within the extension and had FEV1% values at both baseline and the post baseline time points. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Mean (Standard Deviation)
Unit of Measure: Percent change in FEV1 % predicted
Extension Cycle 7, day 365(n=44) 4.0  (16.93)
Extension Cycle 8, day 421(n=41) 2.4  (13.71)
Extension Cycle 9, day 477(n=42) 2.4  (16.18)
Extension Cycle 10, day 533(n=39) -1.4  (13.75)
Extension Cycle 11, day 589(n=38) 0.3  (14.76)
Extension Cycle 12, day 645(n=35) -0.6  (13.95)
Extension completion, (n=33) -3.5  (10.74)
13.Secondary Outcome
Title Absolute Change From Baseline in Pseudomonas Aeruginosa Density Over 6 Treatment Cycles in Extension Study
Hide Description Microbiological data was collected to understand the direct impact of the drug on the pathogens. Sputum samples were cultured for the presence of three Pseudomonas aeruginosa (P. aeruginosa) biotypes measured were mucoid, dry and small colony variant. If no P. aeruginosa was isolated for a visit, log10 colony forming units (CFU) was imputed with log10 (19) for all biotypes. Absolute change was calculated by using the formula = (Value at actual time point - start of extension value).
Time Frame Baseline (start of study treatment in extension study), Day 365, Day 421, Day 477, Day 533, Day 589, Day 645, 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population, who had microbiological data at specified time points. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Mean (Standard Deviation)
Unit of Measure: log10 CFU
Extension Cycle 7, day 365(n=38) -0.7  (2.77)
Extension Cycle 8, day 421(n=39) -0.2  (2.60)
Extension Cycle 9, day 477(n=39) -0.2  (2.51)
Extension Cycle 10, day 533(n=35) 0.2  (2.89)
Extension Cycle 11, day 589(n=36) 0.0  (2.49)
Extension Cycle 12, day 645(n=32) 0.4  (2.75)
Extension completion, (n=29) 0.3  (2.48)
14.Secondary Outcome
Title Percentage of Participants Who Used New Anti-pseudomonal Antibiotics in Extension Study
Hide Description The rate of anti-pseudomonal antibiotics use were determined from the collection of concomitant medication during the study.
Time Frame Baseline of extension study, Day 673 (end of extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: Percentage of participants
68.9
15.Secondary Outcome
Title Total Number of Days of New Anti-pseudomonal Antibiotics Use in Extension Study
Hide Description The total number of days with usage of new anti-pseudomonal antibiotic were determined.
Time Frame Baseline of extension study, Day 673 (end of extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (Full Range)
Unit of Measure: Days
Overall route (n=31)
33.0
(1 to 252)
Oral use (n=23)
28.0
(1 to 44)
i.v use (n=20)
16.0
(7 to 252)
Inhaled use (n=1)
9.0
(9 to 9)
16.Secondary Outcome
Title Time to Use of New Anti-pseudomonal Antibiotics in Extension Study
Hide Description Time to first usage of anti-pseudomonal antibiotic was determined using Kaplan Meier estimate. Participants without an event were censored at the date of the last available post-baseline measurement.
Time Frame Baseline of extension study, Day 673 (end of extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: Days
139
(86 to 271)
17.Secondary Outcome
Title Percentage of Participants Hospitalized Due to Respiratory Related Serious Adverse Events (SAEs) in Extension Study
Hide Description The percentage of the participants hospitalized due to serious respiratory-related AEs were determined during the extension study.
Time Frame Baseline of extension study, Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: Percentage of participants
35.6
18.Secondary Outcome
Title Number of Hospitalization Days Due to Respiratory Related Serious Adverse Events (SAEs) in Extension Study
Hide Description The total number of hospitalisation days due to serious respiratory-related adverse events was analysed using Kaplan-Meier estimate.
Time Frame Baseline of extension study, Day 673 (end of extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (Full Range)
Unit of Measure: Days
16.0
(5 to 64)
19.Secondary Outcome
Title Time to First Hospitalization Due to Respiratory Related Serious Adverse Events (SAEs) in Extension Study
Hide Description The day of first hospitalization due to serious respiratory related adverse events was analysed using Kaplan Meier estimate.
Time Frame Baseline of extension study, Day 673 (end of extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(NA to NA)
[1]
Here, value is not applicable due to insufficient number of events.
20.Secondary Outcome
Title Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs/SAEs Leading to Discontinuation of Study Drug and Deaths Over 6 Treatment Cycles in Extension Study
Hide Description An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalisation, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Death was a fatal event leading to permanent cessations of all vital functions of the body.
Time Frame Baseline (start of study treatment in extension study) to Day 673 (end of the extension study)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed in extension safety population, defined as all the participants who entered the extension study and received at least one dose of study drug within the extension.
Arm/Group Title Tobramycin Inhalation Powder
Hide Arm/Group Description:
Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid).The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy.
Overall Number of Participants Analyzed 45
Measure Type: Number
Unit of Measure: Number of participants
AEs 36
SAEs 16
Discontinued study drug due to AEs 1
Discontinued study drug due to SAEs 0
Deaths 1
Time Frame Baseline (start of study treatment in extension study) to Day 673 (end of the extension study)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Core Extension Overall
Hide Arm/Group Description Eligible participants were assigned to four capsules of TIP at 28 mg 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 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose = 224 mg tobramycin (112 mg b.i.d.). These 56 days represented 1 cycle of therapy during core study. Participants inhaled four capsules of tobramycin inhalation powder (28 mg) bid via the T-326 inhaler device, for 28 days (treatment phase in each cycle). Each treatment phase therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each) with the total daily dose of 224 mg tobramycin (112 mg bid). The treatment phase was followed by 28 days of no study treatment (off treatment in each cycle). These 56 days represented 1 cycle of therapy. All participants who inhaled tobramycin inhalation powder during both core and extension study.
All-Cause Mortality
Core Extension Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Core Extension Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   12/45 (26.67%)   16/45 (35.56%)   19/45 (42.22%) 
Cardiac disorders       
Cardiac failure  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Cardiogenic shock  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Gastrointestinal disorders       
Distal intestinal obstruction syndrome  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Infections and infestations       
Bronchopneumonia  1  1/45 (2.22%)  0/45 (0.00%)  1/45 (2.22%) 
Infective pulmonary exacerbation of cystic fibrosis  1  11/45 (24.44%)  14/45 (31.11%)  17/45 (37.78%) 
Influenza  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Pneumonia  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Investigations       
Forced expiratory volume decreased  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Metabolism and nutrition disorders       
Hyperamylasaemia  1  1/45 (2.22%)  0/45 (0.00%)  1/45 (2.22%) 
Nervous system disorders       
Syncope  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Reproductive system and breast disorders       
Ovarian cyst  1  1/45 (2.22%)  0/45 (0.00%)  1/45 (2.22%) 
Prostatitis  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea exertional  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Haemoptysis  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Respiratory acidosis  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Respiratory failure  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Vascular disorders       
Haemodynamic instability  1  0/45 (0.00%)  1/45 (2.22%)  1/45 (2.22%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Core Extension Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   33/45 (73.33%)   32/45 (71.11%)   36/45 (80.00%) 
Gastrointestinal disorders       
Abdominal pain  1  4/45 (8.89%)  4/45 (8.89%)  7/45 (15.56%) 
Constipation  1  0/45 (0.00%)  3/45 (6.67%)  3/45 (6.67%) 
Diarrhoea  1  5/45 (11.11%)  5/45 (11.11%)  8/45 (17.78%) 
Dyspepsia  1  0/45 (0.00%)  2/45 (4.44%)  2/45 (4.44%) 
Nausea  1  2/45 (4.44%)  1/45 (2.22%)  2/45 (4.44%) 
Vomiting  1  2/45 (4.44%)  1/45 (2.22%)  3/45 (6.67%) 
General disorders       
Chest discomfort  1  1/45 (2.22%)  2/45 (4.44%)  2/45 (4.44%) 
Fatigue  1  2/45 (4.44%)  3/45 (6.67%)  4/45 (8.89%) 
Pyrexia  1  3/45 (6.67%)  2/45 (4.44%)  4/45 (8.89%) 
Infections and infestations       
Bacterial disease carrier  1  1/45 (2.22%)  3/45 (6.67%)  3/45 (6.67%) 
Ear infection  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Infective pulmonary exacerbation of cystic fibrosis  1  18/45 (40.00%)  16/45 (35.56%)  25/45 (55.56%) 
Nasopharyngitis  1  9/45 (20.00%)  9/45 (20.00%)  13/45 (28.89%) 
Pharyngitis  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Rhinitis  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Sinusitis  1  1/45 (2.22%)  3/45 (6.67%)  4/45 (8.89%) 
Upper respiratory tract infection  1  2/45 (4.44%)  2/45 (4.44%)  4/45 (8.89%) 
Urinary tract infection  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Investigations       
Forced expiratory volume decreased  1  4/45 (8.89%)  5/45 (11.11%)  8/45 (17.78%) 
Pulmonary function test decreased  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Staphylococcus test positive  1  3/45 (6.67%)  0/45 (0.00%)  3/45 (6.67%) 
Metabolism and nutrition disorders       
Hyperglycaemia  1  0/45 (0.00%)  2/45 (4.44%)  2/45 (4.44%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  1/45 (2.22%)  1/45 (2.22%)  2/45 (4.44%) 
Musculoskeletal chest pain  1  1/45 (2.22%)  1/45 (2.22%)  2/45 (4.44%) 
Nervous system disorders       
Headache  1  4/45 (8.89%)  4/45 (8.89%)  6/45 (13.33%) 
Reproductive system and breast disorders       
Dysmenorrhoea  1  1/45 (2.22%)  1/45 (2.22%)  2/45 (4.44%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1  8/45 (17.78%)  8/45 (17.78%)  11/45 (24.44%) 
Dysphonia  1  4/45 (8.89%)  1/45 (2.22%)  4/45 (8.89%) 
Haemoptysis  1  8/45 (17.78%)  10/45 (22.22%)  12/45 (26.67%) 
Oropharyngeal pain  1  6/45 (13.33%)  3/45 (6.67%)  9/45 (20.00%) 
Productive cough  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Rhinorrhoea  1  0/45 (0.00%)  3/45 (6.67%)  3/45 (6.67%) 
Sputum increased  1  7/45 (15.56%)  5/45 (11.11%)  10/45 (22.22%) 
Wheezing  1  1/45 (2.22%)  1/45 (2.22%)  2/45 (4.44%) 
Vascular disorders       
Hypertension  1  2/45 (4.44%)  0/45 (0.00%)  2/45 (4.44%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
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Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01775137     History of Changes
Other Study ID Numbers: CTBM100C2401E1
First Submitted: January 22, 2013
First Posted: January 24, 2013
Results First Submitted: July 28, 2015
Results First Posted: November 6, 2015
Last Update Posted: November 6, 2015