iBEST-1: Dose-finding Study to Assess the Efficacy, Safety and Tolerability of Tobramycin Inhalation Powder in Patients With Non-Cystic Fibrosis Bronchiectasis and Pulmonary P. Aeruginosa Infection

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02712983
• Collaborator: Queen's University Belfast, UK (Other), University Hospital Antwerp, BE (Other), University of Milan, IT (Other), Fundacion Clinic per a la Recerca Biomedica (Other), Erasmus Medical Center (Other), Papworth Hospital Cambridge, UK (Other), Royal Brompton Hospital Trust, UK (Other), University of Dundee (Other), University of Edinburgh (Other)
• Enrollment: 107
• Locations: 34
• Arms: 9
• Actual Duration (Months): 25.3
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to support the selection of a safe and tolerable tobramycin inhalation powder (TIP) dose, and regimen that exhibits effective bacterial reduction of P. aeruginosa in non-cystic fibrosis bronchiectasis (BE) patients with P. aeruginosa colonization.

Condition or Disease	Intervention/Treatment	Phase
Non-cystic Fibrosis Bronchiectasis	Drug: TIP; Drug: TIP and placebo; Drug: Placebo	Phase 2

Detailed Description

This was a blinded, randomized, dose and regimen finding trial utilizing a three treatment cohort design where active TIP and TIP/Placebo cyclical (3 capsules o.d [Cohort A], 5 capsules o.d. [Cohort B] or 4 capsules b.i.d. [Cohort C]) versus Placebo were administered for a total of 112 days.

Novartis decided to close the recruitment of new subjects into this study earlier than scheduled. Subjects who had a signed informed consent form and entered screening by 10-Sep-2018 still participated in the study. The latest possible randomization was on 08-Oct-2018. All subjects enrolled in the study (107 enrolled subjects out of 180 planned) continued as planned through to their last scheduled visit. The early recruitment halt of the study was not due to safety or lack of efficacy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 107 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Blinded, Parallel Group, Multi-center Dose-finding Study, to Assess the Efficacy, Safety and Tolerability of Different Doses of Tobramycin Inhalation Powder in Patients With Non-Cystic Fibrosis Bronchiectasis and Pulmonary P. Aeruginosa Infection
• Actual Study Start Date: Feb 8, 2017
• Actual Primary Completion Date: Mar 20, 2019
• Actual Study Completion Date: Mar 20, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A (3 capsules o.d.): TIP Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Drug: TIP; TIP dose regimen
Experimental: Cohort A (3 capsules o.d.): TIP/PBO Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Drug: TIP and placebo; TIP and inhaled placebo dose regimen
Placebo Comparator: Cohort A (3 capsules o.d.): PBO Cohort A (3 capsules o.d.): Inhaled placebo (PBO)	Drug: Placebo; Inhaled placebo dose regimen
Experimental: Cohort B (5 capsules o.d.): TIP Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Drug: TIP; TIP dose regimen
Experimental: Cohort B (5 capsules o.d.): TIP/PBO Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Drug: TIP and placebo; TIP and inhaled placebo dose regimen
Placebo Comparator: Cohort B (5 capsules o.d.): PBO Cohort B (5 capsules o.d.): inhaled placebo (PBO)	Drug: Placebo; Inhaled placebo dose regimen
Experimental: Cohort C (4 capsules b.i.d.): TIP Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Drug: TIP; TIP dose regimen
Experimental: Cohort C (4 capsules b.i.d.): TIP/PBO Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Drug: TIP and placebo; TIP and inhaled placebo dose regimen
Placebo Comparator: Cohort C (4 capsules b.i.d.): PBO Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)	Drug: Placebo; Inhaled placebo dose regimen

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs) [Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)]

   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. 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. Only values for all morphotypes presented.

Secondary Outcome Measures

1. Change From Baseline to Each Post-baseline Visit in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs) [Baseline (Visit 101/Day 1), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 (Day 113), End of Treatment (EOT), Visit 201 (Day 141), Visit 202 (Day 169)]

   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. 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. Only values for all morphotypes are presented.

2. Time to First Onset of Pulmonary Exacerbation by Exacerbation Category [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   The time to first onset of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. Participants were censored at the time of completion of study or early discontinuation if they did not have a pulmonary exacerbation during the study period.

3. Duration of Pulmonary Exacerbation by Exacerbation Category [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   The duration of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization.

4. Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   The exposure adjusted rate of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. The Exposure adjusted rate = (Number of pulmonary exacerbations reported during the study period) / (sum of study duration in days for all participants/ 365.25). Only descriptive analysis performed.

5. Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   Pulmonary exacerbations are defined as events requiring antibiotic therapy AND for which at least 3 of the following 6 symptoms, signs, or findings were present outside of normal variation: 1. Increased sputum volume, or change in viscosity/consistency or purulence for more than 24 hours; 2. Increased shortness of breath at rest or on exercise for more than 24 hours; 3. Increased cough for more than 24 hours; 4. Fever of ≥38° Celsius within the last 24 hours; 5. Increased malaise/fatigue/lethargy for more than 24 hours; 6. A reduction in forced expiratory volume in the first second of expiration (FEV1) or forced vital capacity (FVC) of least 10% from screening. Participants were categorized as: a) Overall, b) Category 1: treated with oral antibiotics only and c) Category 2: treated with parenteral Antibiotics and/or requiring hospitalization. Only descriptive analysis performed.

6. Percentage of Participants Who Permanently Discontinued Study Drug Due to Pulmonary Exacerbation [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   The percentage of participants who permanently discontinued study drug due to pulmonary exacerbation compared to placebo was analyzed.

7. Time to Permanent Study Drug Discontinuation Due to Pulmonary Exacerbation [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   The time to permanent study drug discontinuation due to Pulmonary exacerbation. Participants were censored at the time of last contact if they did not permanently discontinue study drug due to pulmonary exacerbation requiring during the study period. Only descriptive analysis performed.

8. Time to First Use (Overall, Oral, and Parenteral) of Anti-pseudomonal Antibiotics Usage [From Baseline (Visit 101/Day 1) up to approximately Day 173]

   The time to first use of anti-pseudomonal antibiotics administered compared to placebo was analyzed. Participants were censored at the time of last contact if they did not have anti-pseudomonal antibiotics over the entire study period.

9. Percentage of Participants Requiring Anti-pseudomonal Antibiotics [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

   The percentage of participants requiring anti-pseudomonal antibiotics compared to placebo was analyzed. Only descriptive analysis performed.

10. Duration of Anti-pseudomonal Antibiotics Usage [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

    The total number of days of new anti-pseudomonal antibiotic use compared to placebo was analyzed. Only descriptive analysis

11. Percentage of Participants Requiring Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

    The percentage of participants requiring hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.

12. Duration of Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

    The duration of hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.

13. Number of Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

    The number of hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Respiratory related adverse events were identified using the AEs captured under system organ class 'Respiratory, thoracic and mediastinal disorders' and 'Infections and infestations'.

14. Time to First Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]

    Time to first hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Participants were censored at the time of last contact if they did not have a hospitalization due to serious respiratory-related adverse events over the entire study period.

15. Serum Tobramycin Concentration [Baseline (Visit 101/Day 1), Visit 102 (Day 8) and Visits 103 (Day 29): 0-1 hours and 1-2 hours post-dose.]

    The serum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in serum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Serum specimens for PK tobramycin concentration were assessed at Visit 101 (Day 1/start of treatment) 0 to 1 and 1 to 2 hours post-dose and Visit 102 (Day 8) 0 to 1 and 1 to 2 hours post-dose. Prior to protocol amendment #2, PK samples were assessed on Visits 103 (Day 29) rather than Visit 102. Only descriptive analysis performed.

16. Sputum Tobramycin Concentration [Baseline (Visit 101/Day 1): 0-1 hours and 1-2 hours post-dose; Visit 102 (Day 8):0-2 hours and 5-6 hours post-dose; Visits 103 (Day 29): 5 to 6 hours post-dose, Visit 104 (Day 57) and Visit 105 (Day 85): 3-4 hours post-dose.]

    The sputum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in sputum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Only descriptive analysis performed.

17. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

18. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

19. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

20. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

21. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

22. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

23. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

24. Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]

    The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed.

• Male and female patients of ≥ 18 years of age at screening (Visit 1).

• Proven diagnosis of non-CF BE as documented by computed tomography or high-resolution computed tomography

• At least 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation requiring intravenous antibiotic treatment within 12 months prior to screening.

• FEV1 ≥ 30% predicted at screening (Visit 1).

• 1. aeruginosa, must be documented in a respiratory sample at least 1 time within 12 months and also present in the expectorated sputum culture at Visit 1.

Key Exclusion Criteria:

• Patients with a history of cystic fibrosis.

• Patients with a primary diagnosis of bronchial asthma.

• Patients with a primary diagnosis of COPD associated with at least a 20 pack year smoking history.

• Any significant medical condition that is either recently diagnosed or was not stable during the last 3 months, other than pulmonary exacerbations, and that in the opinion of the investigator makes participation in the trial against the patients' best interests.

• Clinically significant (in the opinion of the investigator) hearing loss that interferes with patients' daily activities (such as normal conversations) or chronic tinnitus. Patients with a past history of clinically significant hearing loss in the opinion of the investigator may be eligible only if their hearing threshold at screening audiometry is 25dB or lower at frequencies 0.5-4 kHz. The use of a hearing device is reflective of a clinically significant hearing loss; hence patients using hearing aids at screening are not eligible.

• Patients with active pulmonary tuberculosis.

• Patients currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease.

• Patients who are regularly receiving inhaled anti-pseudomonal antibiotic (during the study inhaled anti-pseudomonal antibiotics are not allowed other than the study drug).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bruxelles		Belgium	1070
2	Novartis Investigative Site	Leuven		Belgium	3000
3	Novartis Investigative Site	Nice	Cedex1	France	06001
4	Novartis Investigative Site	Montpellier cedex 5	Herault	France	34059
5	Novartis Investigative Site	Grenoble		France	38043
6	Novartis Investigative Site	Toulouse		France	31059
7	Novartis Investigative Site	Essen	North Rhine-Westphalia	Germany	45239
8	Novartis Investigative Site	Berlin		Germany	14059
9	Novartis Investigative Site	Frankfurt		Germany	60596
10	Novartis Investigative Site	Hannover		Germany	30625
11	Novartis Investigative Site	Leipzig		Germany	04357
12	Novartis Investigative Site	Monza	MB	Italy	20900
13	Novartis Investigative Site	Pisa	PI	Italy	56124
14	Novartis Investigative Site	Pordenone	PN	Italy	33170
15	Novartis Investigative Site	Milan		Italy	20112
16	Novartis Investigative Site	Pavia		Italy	27100
17	Novartis Investigative Site	Scafati		Italy	84018
18	Novartis Investigative Site	Barcelona	Cataluna	Spain	08035
19	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
20	Novartis Investigative Site	Barcelona	Catalunya	Spain	08041
21	Novartis Investigative Site	Valencia	Comunitat Valencia	Spain	46014
22	Novartis Investigative Site	Baracaldo - Vizcaya		Spain	48903
23	Novartis Investigative Site	Barcelona		Spain	08003
24	Novartis Investigative Site	Valencia		Spain	46009
25	Novartis Investigative Site	Valladolid		Spain	47003
26	Novartis Investigative Site	Cambridge	Cambridgeshire	United Kingdom	CB23 3RE
27	Novartis Investigative Site	Dundee	Perthshire	United Kingdom	DD1 9SY
28	Novartis Investigative Site	Birmingham		United Kingdom	B15 2TH
29	Novartis Investigative Site	Edinburgh		United Kingdom	ED16 4SA
30	Novartis Investigative Site	Lancaster		United Kingdom	LA1 4RP
31	Novartis Investigative Site	Leeds		United Kingdom	LS9 7TF
32	Novartis Investigative Site	London		United Kingdom	SW 6NP
33	Novartis Investigative Site	Newcastle upon Tyne		United Kingdom	NE7 7DN
34	Novartis Investigative Site	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Queen's University Belfast, UK
• University Hospital Antwerp, BE
• University of Milan, IT
• Fundacion Clinic per a la Recerca Biomedica
• Erasmus Medical Center
• Papworth Hospital Cambridge, UK
• Royal Brompton Hospital Trust, UK
• University of Dundee
• University of Edinburgh

Investigators

• Study Director: Novartis Pharma, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jun 21, 2018
• Statistical Analysis Plan - May 21, 2019

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02712983
• Other Study ID Numbers: CTBM100G2202; 2015-003040-39
• First Posted: Mar 18, 2016
• Last Update Posted: Aug 25, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Inhaled tobramycin; tobramycin inhalation powder; bronchiectasis; pulmonary Pseudomonas aeruginosa infection; dose-finding study
• Additional relevant MeSH terms: Infections; Respiratory Aspiration; Bronchiectasis; Fibrosis

Study Results

Participant Flow

Recruitment Details	A total of 107 subjects were enrolled in the trial from 6 countries (Belgium [2 sites], France [4 sites], Germany [5 sites], Italy [6 sites], Spain [8 sites] and United Kingdom [9 sites]).
Pre-assignment Detail	This study planned to recruit approximately 180 subjects to one of the 3 cohorts in a ratio of 1:1:1. The subjects within each cohort were randomized to blinded TIP or placebo with the following randomization scheme: TIP:TIP/Placebo cyclical:Placebo, in a 2:2:1 ratio.

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort A (3 Capsules o.d.): PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort A (3 capsules o.d.): Inhaled placebo (PBO)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): inhaled placebo (PBO)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)
Period Title: Treatment Phase
STARTED	14	13	7	15	14	7	15	15	7
Pharmacokinetic Analysis Set	14	13	0	15	14	0	15	14	0
COMPLETED	9	12	6	7	10	7	6	6	5
NOT COMPLETED	5	1	1	8	4	0	9	9	2
Period Title: Treatment Phase
STARTED	0	1	0	1	2	1	2	3	0
COMPLETED	0	0	0	0	0	0	0	0	0
NOT COMPLETED	0	1	0	1	2	1	2	3	0

Baseline Characteristics

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort A (3 Capsules o.d.): PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): PBO	Total
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort A (3 capsules o.d.): Inhaled placebo (PBO)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): inhaled placebo (PBO)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)	Total of all reporting groups
Overall Participants	14	13	7	15	14	7	15	15	7	107
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.4 (12.66)	57.5 (11.83)	61.3 (7.45)	64.3 (17.86)	62.4 (16.71)	69.1 (13.21)	66.1 (12.23)	60.8 (12.94)	71.3 (10.39)	63.4 (13.64)
Sex: Female, Male (Count of Participants)
Female	9 64.3%	10 76.9%	3 42.9%	10 66.7%	7 50%	6 85.7%	9 60%	8 53.3%	4 57.1%	66 61.7%
Male	5 35.7%	3 23.1%	4 57.1%	5 33.3%	7 50%	1 14.3%	6 40%	7 46.7%	3 42.9%	41 38.3%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	12 85.7%	11 84.6%	7 100%	13 86.7%	11 78.6%	5 71.4%	15 100%	15 100%	7 100%	96 89.7%
Asian	1 7.1%	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%	0 0%	2 1.9%
Pacific Islander	0 0%	0 0%	0 0%	1 6.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.9%
Other	1 7.1%	2 15.4%	0 0%	1 6.7%	3 21.4%	1 14.3%	0 0%	0 0%	0 0%	8 7.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)
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. 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. Only values for all morphotypes presented.
Time Frame	Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only the participants who had microbiological data at specified time points were included.

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Baseline	6.80 (1.202)	7.67 (1.507)	6.10 (2.419)	6.98 (1.804)	6.79 (0.908)	5.73 (1.885)	6.57 (1.625)	6.74 (1.892)	7.09 (2.012)
Change from BL at Day 8	-2.82 (1.440)	-3.23 (2.204)	-2.04 (2.274)	-3.98 (1.865)	-4.54 (1.283)	-3.47 (1.583)	-3.30 (1.937)	-3.58 (1.878)	-0.72 (1.765)
Change from BL at Day 29	-2.61 (2.600)	-2.80 (2.823)	-1.56 (2.885)	-3.57 (2.218)	-4.36 (1.101)	-2.58 (2.871)	-2.98 (2.474)	-2.96 (2.618)	0.05 (1.518)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 8 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -3.62 to -1.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.60
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 8 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -3.30 to -0.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 8 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.20 to -0.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.63
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 8 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 95%; -4.38 to -2.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.56
	Estimation Comments
Other Statistical Analysis		LS Mean Diff (SE) vs pooled placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 8 Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -5.06 to -2.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.55
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 8 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -4.57 to -2.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.61
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 8: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -3.66 to -1.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.44
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 8: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -3.79 to -2.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.43
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 29 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -4.28 to -1.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 29 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -4.03 to -0.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.84
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 29 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -4.04 to -0.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.88
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 29 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -5.16 to -1.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.83
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 29 Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -6.13 to -3.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 29 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -4.68 to -1.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.79
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 29: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -4.43 to -2.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.61
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 29: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -4.19 to -1.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.61
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Each Post-baseline Visit in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)
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. 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. Only values for all morphotypes are presented.
Time Frame	Baseline (Visit 101/Day 1), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 (Day 113), End of Treatment (EOT), Visit 201 (Day 141), Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only the participants who had microbiological data at specified time points were included.

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Baseline (BL)	6.80 (1.202)	7.67 (1.507)	6.10 (2.419)	6.98 (1.804)	6.79 (0.908)	5.73 (1.885)	6.57 (1.625)	6.74 (1.892)	7.09 (2.012)
Change from BL at Day 57	-1.72 (3.066)	-0.72 (2.677)	-0.90 (1.894)	-1.62 (2.804)	-3.53 (2.220)	-0.49 (2.305)	-2.25 (2.646)	-0.96 (2.576)	0.20 (1.408)
Change from BL at Day 85	-2.47 (2.446)	-2.94 (2.492)	-2.81 (3.653)	-3.88 (2.470)	-3.08 (1.624)	-2.00 (2.951)	-2.76 (2.446)	-3.01 (2.641)	-0.36 (2.238)
Change from BL at Day 113	-2.94 (1.977)	-1.03 (2.002)	-1.82 (2.331)	-1.99 (3.020)	-3.17 (2.378)	-1.54 (3.534)	-2.79 (2.141)	-1.50 (2.707)	-0.20 (1.513)
Change from BL at EOT	-2.49 (1.896)	-1.08 (1.907)	-0.84 (1.766)	-1.86 (2.607)	-2.60 (2.531)	-1.29 (3.300)	-2.01 (2.192)	-1.42 (2.650)	-0.34 (1.445)
Change from BL at Day 141	-0.90 (2.113)	-0.82 (2.117)	0.10 (1.551)	-2.17 (2.863)	-0.92 (2.385)	-0.87 (3.640)	-0.68 (2.067)	-1.34 (2.793)	-0.06 (2.191)
Change from BL at Day 169	-0.62 (2.324)	-1.19 (1.885)	0.46 (1.651)	-1.27 (2.684)	0.62 (1.038)	1.33 (4.219)	0.03 (1.882)	-0.51 (3.036)	0.62 (2.694)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 57 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -3.82 to -0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.87
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 57 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -2.21 to 1.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.88
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 57 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.87 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 57 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -3.34 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.88
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 57 Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.9
	Confidence Interval	(2-Sided) 95%; -5.50 to -2.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.82
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 57 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -3.26 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.92
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 57: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -3.98 to -1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.68
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 57: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -2.50 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.67
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 85 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -4.00 to -0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.90
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 85 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -3.81 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 85 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -4.96 to -0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.11
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 85 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.6
	Confidence Interval	(2-Sided) 95%; -5.44 to -1.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.93
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 85 Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -4.90 to -1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.96
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 85 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -4.66 to -0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.03
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 85: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -4.11 to -1.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.74
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 85: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -4.12 to -1.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.72
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 113 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -4.55 to -1.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.87
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 113 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -1.61 to 1.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.83
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 113 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -4.93 to -0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.16
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 113 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.62 to -0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.84
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 113 Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95%; -4.94 to -1.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.91
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 113 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -4.37 to -0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.98
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 113: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -4.24 to -1.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.70
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 113: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -2.73 to -0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.65
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	EoT Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -3.64 to -0.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.73
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	EoT Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.61 to 1.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	EoT Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -2.81 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	EoT Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -3.14 to -0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.73
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	EoT Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -3.89 to -0.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.73
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	EoT Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -3.12 to -0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.73
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	EoT: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -3.08 to -0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.56
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	EoT: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -2.25 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.56
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 141 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -2.63 to 0.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.91
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 141 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -1.83 to 1.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.95
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 141 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -2.03 to 2.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.11
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 141 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -3.68 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.92
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 141 Cohort C (4 capsules b.i.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -2.78 to 1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.96
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 141 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -3.36 to 0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.06
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 141: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.97 to 0.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.74
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 141: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -2.45 to 0.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.73
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 169 Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -3.24 to 0.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.96
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 169 Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -3.05 to 0.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Day 169 Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -2.73 to 1.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.09
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Day 169 Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -4.22 to -0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.03
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Day 169 Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -2.48 to 2.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.14
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Day 169 Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -2.33 to 2.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.12
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Day 169: Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -2.24 to 0.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Day 169: Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -2.61 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.75
	Estimation Comments

3. Secondary Outcome

Title	Time to First Onset of Pulmonary Exacerbation by Exacerbation Category
Description	The time to first onset of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. Participants were censored at the time of completion of study or early discontinuation if they did not have a pulmonary exacerbation during the study period.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Overall	NA	NA	NA	NA	NA	NA	NA	NA	173.00
Oral	NA	NA	NA	NA	NA	NA	NA	NA	173.00
Parenteral	NA	NA	NA	NA	NA	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Overall Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.14 to 3.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.18 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Overall Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.42 to 3.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.20 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Overall Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.21 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95%; 0.44 to 3.62
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Overall Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.44 to 2.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Overall Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Oral Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.08 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Oral Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.25 to 2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Oral Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.25 to 3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Oral Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.19 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Oral Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.02 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Oral Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.16 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Oral Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.13 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Oral Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Parenteral Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	10.71
	Confidence Interval	(2-Sided) 95%; 1.10 to 104.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Parenteral Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	4.62
	Confidence Interval	(2-Sided) 95%; 0.41 to 52.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Parenteral Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.23
	Confidence Interval	(2-Sided) 95%; 0.28 to 37.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Parenteral Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 0.10 to 25.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Parenteral Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	11.30
	Confidence Interval	(2-Sided) 95%; 1.09 to 117.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Parenteral Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	4.30
	Confidence Interval	(2-Sided) 95%; 0.50 to 37.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

4. Secondary Outcome

Title	Duration of Pulmonary Exacerbation by Exacerbation Category
Description	The duration of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Overall	15.7 (6.22)	18.0 (8.26)	20.2 (6.37)	10.3 (5.12)	25.5 (27.09)	14.8 (6.73)	19.0 (12.64)	15.2 (7.39)	14.5 (5.61)
Oral	19.5 (12.02)	15.4 (4.24)	19.3 (3.20)	8.3 (4.16)	14.0 (NA)	16.3 (5.51)	18.6 (5.77)	14.0 (5.24)	15.6 (5.75)
Parenteral	15.0 (5.52)	22.0 (12.73)	16.0 (NA)	66.0 (NA)	16.8 (4.86)	23.1 (18.73)	16.6 (4.22)	10.0 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Overall Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	9.8
	Confidence Interval	(2-Sided) 95%; -27.15 to 46.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.15
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	19.8
	Confidence Interval	(2-Sided) 95%; -22.63 to 62.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.81
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Overall Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	8.0
	Confidence Interval	(2-Sided) 95%; -31.32 to 47.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.29
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	12.7
	Confidence Interval	(2-Sided) 95%; -26.49 to 51.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 19.24
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Overall Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	46.5
	Confidence Interval	(2-Sided) 95%; 3.37 to 89.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.17
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -34.21 to 40.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.37
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Overall Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	21.4
	Confidence Interval	(2-Sided) 95%; -8.03 to 50.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.46
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Overall Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Diff (SE) vs pooled placebo
	Estimated Value	11.9
	Confidence Interval	(2-Sided) 95%; -17.52 to 41.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 14.44
	Estimation Comments	ANCOVA model includes treatment as a fixed-effect factor and number of pulmonary exacerbations in the 12 months prior to screening as a covariate.

5. Secondary Outcome

Title	Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period
Description	The exposure adjusted rate of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. The Exposure adjusted rate = (Number of pulmonary exacerbations reported during the study period) / (sum of study duration in days for all participants/ 365.25). Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Overall	1.71	1.39	1.29	1.20	0.66	1.46	1.21	1.35	1.41
Oral	0.34	1.22	0.86	0.85	0.16	0.55	0.42	0.88	1.19
Parenteral	0.85	0.43	0.34	0.16	0.73	0.48	0.35	0.11

6. Secondary Outcome

Title	Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category
Description	Pulmonary exacerbations are defined as events requiring antibiotic therapy AND for which at least 3 of the following 6 symptoms, signs, or findings were present outside of normal variation: 1. Increased sputum volume, or change in viscosity/consistency or purulence for more than 24 hours; 2. Increased shortness of breath at rest or on exercise for more than 24 hours; 3. Increased cough for more than 24 hours; 4. Fever of ≥38° Celsius within the last 24 hours; 5. Increased malaise/fatigue/lethargy for more than 24 hours; 6. A reduction in forced expiratory volume in the first second of expiration (FEV1) or forced vital capacity (FVC) of least 10% from screening. Participants were categorized as: a) Overall, b) Category 1: treated with oral antibiotics only and c) Category 2: treated with parenteral Antibiotics and/or requiring hospitalization. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
No of participants with no events	8 57.1%	9 69.2%	10 142.9%	9 60%	11 78.6%	9 128.6%	29 193.3%	27 180%	11 157.1%
No. of participants with 1 event	3 21.4%	1 7.7%	4 57.1%	3 20%	4 28.6%	4 57.1%	11 73.3%	8 53.3%	7 100%
No. of participants with 2 events	2 14.3%	2 15.4%	1 14.3%	2 13.3%	0 0%	2 28.6%	3 20%	6 40%	3 42.9%
No. of participants with 3 events	1 7.1%	1 7.7%	0 0%	0 0%	0 0%	0 0%	1 6.7%	1 6.7%	0 0%
No of participants with no events	12 85.7%	9 69.2%	12 171.4%	10 66.7%	14 100%	12 171.4%	38 253.3%	31 206.7%	13 185.7%
No. of participants with 1 event	2 14.3%	2 15.4%	2 28.6%	3 20%	1 7.1%	3 42.9%	5 33.3%	8 53.3%	5 71.4%
No. of participants with 2 events	0 0%	1 7.7%	1 14.3%	1 6.7%	0 0%	0 0%	1 6.7%	2 13.3%	3 42.9%
No. of participants with 3 events	0 0%	1 7.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.7%	0 0%
No of participants with no events	10 71.4%	13 100%	13 185.7%	12 80%	14 100%	11 157.1%	37 246.7%	36 240%	20 285.7%
No. of participants with 1 event	3 21.4%	0 0%	2 28.6%	2 13.3%	1 7.1%	4 57.1%	6 40%	6 40%	1 14.3%
No. of participants with 2 events	1 7.1%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.7%	0 0%	0 0%
No. of participants with 3 events	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Percentage of Participants Who Permanently Discontinued Study Drug Due to Pulmonary Exacerbation
Description	The percentage of participants who permanently discontinued study drug due to pulmonary exacerbation compared to placebo was analyzed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Count of Participants [Participants]	2 14.3%	0 0%	1 14.3%	0 0%	0 0%	2 28.6%	41 273.3%	40 266.7%	0 0%

8. Secondary Outcome

Title	Time to Permanent Study Drug Discontinuation Due to Pulmonary Exacerbation
Description	The time to permanent study drug discontinuation due to Pulmonary exacerbation. Participants were censored at the time of last contact if they did not permanently discontinue study drug due to pulmonary exacerbation requiring during the study period. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Median (95% Confidence Interval) [Days]	NA	NA	NA	NA	NA	NA	NA	NA	NA

9. Secondary Outcome

Title	Time to First Use (Overall, Oral, and Parenteral) of Anti-pseudomonal Antibiotics Usage
Description	The time to first use of anti-pseudomonal antibiotics administered compared to placebo was analyzed. Participants were censored at the time of last contact if they did not have anti-pseudomonal antibiotics over the entire study period.
Time Frame	From Baseline (Visit 101/Day 1) up to approximately Day 173

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only the participants who required antipseudomonal antibiotics were included.

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Overall	122.00	NA	116.00	161.00	NA	NA	NA	NA	141.00
Oral	NA	NA	NA	NA	NA	NA	NA	NA	173.00
Parenteral	NA	NA	NA	NA	NA	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Overall Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.51 to 3.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.15 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Overall Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.44 to 3.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.32 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Overall Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.10 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Overall Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.43 to 2.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Overall Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.37 to 1.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Overall Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Oral Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.30 to 2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Oral Cohort A: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.20 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Oral Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.40 to 3.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Oral Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.31 to 2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Oral Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.06 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Oral Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.45 to 3.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Oral Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.27 to 1.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP/PBO, Pooled PBO
	Comments	Oral Pooled TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.40 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Parenteral Cohort A: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.72
	Confidence Interval	(2-Sided) 95%; 0.84 to 16.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Parenteral Cohort B: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; 0.22 to 8.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Parenteral Cohort B: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 95%; 0.46 to 10.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Parenteral Cohort C: TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.05 to 4.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Parenteral Cohort C: TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.56
	Confidence Interval	(2-Sided) 95%; 0.53 to 12.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Paremteral Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.33 to 5.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

10. Secondary Outcome

Title	Percentage of Participants Requiring Anti-pseudomonal Antibiotics
Description	The percentage of participants requiring anti-pseudomonal antibiotics compared to placebo was analyzed. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Any anti-pseudomonal antibiotic use?=Yes	8 57.1%	4 30.8%	6 85.7%	7 46.7%	3 21.4%	7 100%	17 113.3%	18 120%	12 171.4%
Any anti-pseudomonal antibiotic use?=No	6 42.9%	9 69.2%	9 128.6%	7 46.7%	12 85.7%	8 114.3%	27 180%	24 160%	9 128.6%
Any anti-pseudomonal antibiotic use?=Yes	5 35.7%	4 30.8%	5 71.4%	6 40%	2 14.3%	6 85.7%	12 80%	16 106.7%	10 142.9%
Any anti-pseudomonal antibiotic use?=No	9 64.3%	9 69.2%	10 142.9%	8 53.3%	13 92.9%	9 128.6%	32 213.3%	26 173.3%	11 157.1%
Any anti-pseudomonal antibiotic use?=Yes	5 35.7%	0 0%	2 28.6%	4 26.7%	1 7.1%	4 57.1%	8 53.3%	8 53.3%	3 42.9%
Any anti-pseudomonal antibiotic use?=No	9 64.3%	13 100%	13 185.7%	10 66.7%	14 100%	11 157.1%	36 240%	34 226.7%	18 257.1%

11. Secondary Outcome

Title	Duration of Anti-pseudomonal Antibiotics Usage
Description	The total number of days of new anti-pseudomonal antibiotic use compared to placebo was analyzed. Only descriptive analysis
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Overall	18.4 (10.39)	20.0 (12.03)	19.2 (14.84)	25.7 (13.21)	15.3 (10.07)	15.7 (10.90)	18.1 (11.43)	20.6 (12.24)	14.6 (8.27)
Oral	14.2 (7.79)	19.8 (12.34)	15.0 (7.42)	14.0 (10.92)	20.0 (8.49)	10.8 (6.24)	15.5 (7.29)	14.3 (9.79)	13.7 (7.41)
Parenteral	15.0 (10.02)	20.0 (14.14)	23.8 (15.20)	6.0 (NA)	11.3 (2.75)	15.1 (10.23)	17.5 (12.12)	12.7 (7.64)

12. Secondary Outcome

Title	Percentage of Participants Requiring Hospitalization Due to Serious Respiratory-related Adverse Events
Description	The percentage of participants requiring hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
No of participants with 0 event	10 71.4%	13 100%	13 185.7%	12 80%	14 100%	11 157.1%	37 246.7%	36 240%	19 271.4%
No. of participants with 1 event	3 21.4%	0 0%	2 28.6%	1 6.7%	0 0%	4 57.1%	5 33.3%	5 33.3%	2 28.6%
No. of participants with 2 events	0 0%	0 0%	0 0%	0 0%	1 7.1%	0 0%	1 6.7%	0 0%	0 0%
No. of participants with > 2 events	1 7.1%	0 0%	0 0%	1 6.7%	0 0%	0 0%	1 6.7%	1 6.7%	0 0%

13. Secondary Outcome

Title	Duration of Hospitalization Due to Serious Respiratory-related Adverse Events
Description	The duration of hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Only the participants with at least one hospitalization are included in the analysis

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	4	0	2	2	1	4	7	6	2
Mean (Standard Deviation) [Days]	15.2 (5.19)	22.0 (12.73)	12.2 (6.06)	11.0 (NA)	19.0 (5.23)	16.2 (7.05)	15.2 (6.44)	10.5 (0.71)

14. Secondary Outcome

Title	Number of Hospitalization Due to Serious Respiratory-related Adverse Events
Description	The number of hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Respiratory related adverse events were identified using the AEs captured under system organ class 'Respiratory, thoracic and mediastinal disorders' and 'Infections and infestations'.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Number [Hospitalization]	6	0	2	5	2	4	10	9	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Cohort A (3 capsules o.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	5.62
	Confidence Interval	(2-Sided) 95%; 0.83 to 38.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized linear model assuming the negative binomial distribution including treatment and baseline macrolide use as class-effect factors. The log exposure to study in years is included as an offset variable in the model.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Cohort B (5 capsules o.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95%; 0.21 to 19.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized linear model assuming the negative binomial distribution including treatment and baseline macrolide use as class-effect factors. The log exposure to study in years is included as an offset variable in the model.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Cohort B (5 capsules o.d.): TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	3.05
	Confidence Interval	(2-Sided) 95%; 0.43 to 21.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized linear model assuming the negative binomial distribution including treatment and baseline macrolide use as class-effect factors. The log exposure to study in years is included as an offset variable in the model.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Cohort C (4 capsules b.i.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	1.84
	Confidence Interval	(2-Sided) 95%; 0.19 to 17.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized linear model assuming the negative binomial distribution including treatment and baseline macrolide use as class-effect factors. The log exposure to study in years is included as an offset variable in the model.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Cohort C (4 capsules b.i.d.): TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	3.41
	Confidence Interval	(2-Sided) 95%; 0.47 to 25.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized linear model assuming the negative binomial distribution including treatment and baseline macrolide use as class-effect factors. The log exposure to study in years is included as an offset variable in the model.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	2.74
	Confidence Interval	(2-Sided) 95%; 0.47 to 16.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Generalized linear model assuming the negative binomial distribution including treatment and baseline macrolide use as class-effect factors. The log exposure to study in years is included as an offset variable in the model.

15. Secondary Outcome

Title	Time to First Hospitalization Due to Serious Respiratory-related Adverse Events
Description	Time to first hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Participants were censored at the time of last contact if they did not have a hospitalization due to serious respiratory-related adverse events over the entire study period.
Time Frame	Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	44	42	21
Median (95% Confidence Interval) [Day]	NA	NA	NA	NA	NA	NA	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort A (3 Capsules o.d.): TIP, Pooled PBO
	Comments	Cohort A (3 capsules o.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	4.50
	Confidence Interval	(2-Sided) 95%; 0.77 to 26.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP, Pooled PBO
	Comments	Cohort B (5 capsules o.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95%; 0.28 to 14.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort B (5 Capsules o.d.): TIP/PBO, Pooled PBO
	Comments	Cohort B (5 capsules o.d.): TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 0.20 to 11.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP, Pooled PBO
	Comments	Cohort C (4 capsules b.i.d.): TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.06 to 7.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort C (4 Capsules b.i.d.): TIP/PBO, Pooled PBO
	Comments	Cohort C (4 capsules b.i.d.): TIP/PBO, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.81
	Confidence Interval	(2-Sided) 95%; 0.62 to 23.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pooled TIP, Pooled PBO
	Comments	Pooled TIP, Pooled PBO
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95%; 0.35 to 9.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on Cox proportional hazards model with treatment as fixed effect and number of pulmonary exacerbations in the 12 months prior to screening as a covariate, stratified by baseline macrolide use.

16. Secondary Outcome

Title	Serum Tobramycin Concentration
Description	The serum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in serum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Serum specimens for PK tobramycin concentration were assessed at Visit 101 (Day 1/start of treatment) 0 to 1 and 1 to 2 hours post-dose and Visit 102 (Day 8) 0 to 1 and 1 to 2 hours post-dose. Prior to protocol amendment #2, PK samples were assessed on Visits 103 (Day 29) rather than Visit 102. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1), Visit 102 (Day 8) and Visits 103 (Day 29): 0-1 hours and 1-2 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. Prior to protocol amendment #2, PK samples were assessed on Visit 103 (Day 29) rather than Visit 102 (Day 8).

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical
Measure Participants	14	13	15	14	15	15
Visit 101 (Day 1)/0-1 hr post dose	0.256 (0.144)	0.479 (0.47)	0.4 (0.259)	0.441 (0.273)	0.59 (0.37)	0.321 (0.21)
Visit 101 (Day 1)/1-2 hr post dose	0.481 (0.287)	0.571 (0.349)	0.517 (0.392)	0.624 (0.322)	0.64 (0.338)	0.476 (0.295)
Visit 102 (Day 8)/0-1 hr post dose	0 (NA)	1.81 (NA)	0.258 (NA)	1.4 (NA)	0.489 (0.257)
Visit 102 (Day 8)/1-2 hr post dose	0.18 (NA)	1.67 (NA)	0.588 (NA)	1.48 (NA)	0.447 (NA)
Visit 103 (Day 29)/0-1 hr post dose	0.607 (0.455)	0.0718 (0.0498)	1.23 (1.08)	0.103 (0.0983)	1.05 (0.603)	0.339 (0.274)
Visit 103 (Day 29)/1-2 hr post dose	0.768 (0.477)	0.0818 (0.0972)	1.37 (0.647)	0.104 (0.096)	1.05 (0.622)	0.307 (0.24)

17. Secondary Outcome

Title	Sputum Tobramycin Concentration
Description	The sputum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in sputum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Only descriptive analysis performed.
Time Frame	Baseline (Visit 101/Day 1): 0-1 hours and 1-2 hours post-dose; Visit 102 (Day 8):0-2 hours and 5-6 hours post-dose; Visits 103 (Day 29): 5 to 6 hours post-dose, Visit 104 (Day 57) and Visit 105 (Day 85): 3-4 hours post-dose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set. Prior to protocol amendment #2, Sputum specimens for PK assessments were collected at Visit 103 (Day 29) 5 to 6 hours rather than Visit 102 (Day 8) 0 to 2 and 5 to 6 hours and on Visit 105 (Day 85) 3 to 4 hours rather than Visit 104 (Day 57) 3 to 4 hours.

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical
Measure Participants	14	13	15	14	15	15
Visit 101 (Day 1)/0-1 hr post dose	1750 (2160)	637 (608)	2640 (2680)	2020 (2360)	2820 (2250)	2060 (1840)
Visit 101 (Day 1)/1-2 hr post dose	1100 (2480)	204 (445)	1650 (2340)	1100 (2310)	631 (441)	610 (463)
Visit 102 (Day 8)/0-2 hr post dose	1440 (1470)	2390 (2730)	2460 (761)	4290 (3730)	1980 (2060)	2290 (1560)
Visit 102 (Day 8)/5-6 hr post dose	32.4 (NA)	4460 (NA)	1200 (51.6)
Visit 103 (Day 29)/5-6 hr post dose	389 (554)	136 (258)	915 (1450)	16.3 (28.6)	620 (513)	134 (175)
Visit 104 (Day 57)/3-4 hr post dose	198 (138)	0 (NA)	96.4 (NA)	4540 (NA)	0 (0)
Visit 105 (Day 85)/3-4 hr post dose	791 (883)	45.7 (75.8)	101 (100)	61 (108)	2810 (2200)	121 (166)

18. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	43	42	21
Baseline (BL)	51.33 (38.33)	60.5 (28.60)	45.8 (19.98)	50.5 (33.04)	46.2 (30.29)	53.8 (26.72)	47.6 (29.41)	54.8 (29.10)	49.8 (27.97)
Change from BL at Day 8	5.6 (18.83)	-2.8 (14.35)	-6.7 (22.02)	-2.9 (18.06)	0.9 (11.51)	3.1 (14.44)	0.2 (17.83)	-0.7 (15.62)	-7.4 (17.76)
Change from BL at Day 29	-2.1 (24.40)	-7.2 (16.44)	-5.3 (27.90)	-2.6 (8.41)	-0.4 (16.23)	-6.2 (27.48)	-2.3 (22.04)	-5.3 (19.05)	-1.1 (17.68)
Change from BL at EoT	-6.7 (18.66)	-6.1 (18.53)	-19.4 (23.00)	-6.7 (23.39)	-5.8 (31.36)	-9.8 (30.43)	-10.2 (25.44)	-7.6 (24.47)	0.4 (20.30)
Change from BL at Day 169	5.5 (25.27)	-3.3 (18.09)	0.0 (22.44)	-1.3 (16.27)	-3.9 (26.43)	7.3 (22.54)	0.4 (24.43)	0.6 (19.04)	-4.8 (16.77)

19. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	43	42	21
Baseline (BL)	63.1 (24.28)	67.2 (14.26)	53.3 (21.68)	64.3 (29.77)	57.8 (26.86)	67.6 (24.67)	57.8 (24.11)	66.3 (23.46)	63.9 (19.79)
Change from BL at Day 8	5.6 (14.36)	-2.2 (19.76)	2.2 (20.17)	-1.4 (13.88)	3.6 (17.43)	-4.2 (20.95)	3.8 (17.01)	-2.7 (18.03)	-1.4 (14.67)
Change from BL at Day 29	1.5 (19.66)	-1.1 (18.17)	2.0 (21.33)	-1.0 (14.87)	-0.9 (19.82)	-4.5 (23.88)	0.7 (19.65)	-2.3 (19.06)	1.8 (16.00)
Change from BL at EoT	-0.5 (23.95)	-5.0 (24.47)	-0.4 (23.79)	-9.0 (25.30)	0.9 (20.30)	-4.0 (24.27)	0.0 (22.01)	-6.0 (24.17)	1.0 (19.70)
Change from BL at Day 169	10.3 (16.96)	-7.2 (17.17)	10.7 (13.41)	-2.7 (21.82)	-6.1 (15.94)	6.7 (16.92)	4.4 (17.13)	-1.5 (18.99)	-4.4 (15.51)

20. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	42	42	21
Baseline (BL)	56.4 (22.89)	47.9 (17.21)	52.4 (21.54)	44.4 (26.51)	47.4 (25.36)	51.9 (18.63)	51.9 (23.11)	48.1 (20.92)	46.2 (25.46)
Change from BL at Day 8	6.8 (18.45)	1.9 (24.54)	-6.1 (31.18)	4.8 (17.27)	5.2 (20.52)	2.2 (11.27)	2.6 (23.43)	3.0 (17.57)	-2.9 (16.08)
Change from BL at Day 29	-4.3 (30.95)	4.6 (15.23)	-9.9 (28.57)	3.4 (18.36)	-0.7 (24.66)	-5.6 (23.77)	-4.2 (27.39)	80.6 (19.74)	1.8 (19.69)
Change from BL at EoT	-5.6 (25.26)	2.8 (24.22)	-12.1 (26.04)	3.2 (28.05)	-0.7 (29.24)	2.2 (30.35)	-5.6 (26.77)	2.7 (27.19)	-1.2 (23.97)
Change from BL at Day 169	8.1 (20.55)	3.7 (22.89)	3.7 (24.22)	2.2 (21.47)	-2.8 (22.78)	1.1 (19.21)	2.8 (22.22)	2.4 (20.69)	-2.5 (20.36)

21. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	42	42	21
Baseline (BL)	79.5 (14.28)	71.2 (18.51)	77.4 (17.73)	74.4 (29.50)	71.1 (18.86)	76.1 (23.54)	75.8 (17.15)	74.0 (23.87)	79.6 (16.96)
Change from BL at Day 8	2.6 (11.48)	-4.2 (12.05)	-0.8 (13.67)	2.4 (11.52)	4.4 (18.33)	4.4 (6.19)	2.4 (14.80)	1.2 (10.47)	-1.4 (11.87)
Change from BL at Day 29	1.9 (11.36)	-4.9 (12.03)	2.8 (13.18)	3.8 (16.53)	5.6 (13.24)	-1.2 (14.93)	3.6 (12.35)	-0.6 (14.73)	-1.9 (12.31)
Change from BL at EoT	1.3 (17.63)	-8.3 (22.19)	-9.1 (18.43)	2.4 (32.26)	1.1 (15.06)	-3.3 (14.36)	-1.7 (17.12)	-2.8 (23.76)	-2.3 (15.60)
Change from BL at Day 169	6.1 (21.44)	-6.9 (15.00)	7.4 (17.40)	5.0 (18.51)	0.0 (7.11)	6.7 (21.45)	4.2 (15.98)	1.0 (18.78)	3.9 (13.85)

22. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	43	42	21
Baseline (BL)	66.2 (19.21)	51.3 (22.53)	36.5 (21.18)	63.5 (26.17)	48.5 (19.95)	55.7 (26.80)	49.7 (23.13)	56.9 (25.22)	51.9 (25.24)
Change from BL at Day 8	3.0 (13.49)	2.1 (23.61)	29.6 (23.67)	-2.6 (12.49)	-0.7 (21.91)	8.5 (15.66)	9.6 (23.78)	2.8 (17.67)	5.0 (14.18)
Change from BL at Day 29	4.9 (15.51)	-2.5 (26.05)	22.8 (18.14)	-1.5 (24.50)	2.6 (23.95)	4.8 (19.89)	8.7 (21.19)	0.4 (23.07)	-1.2 (15.72)
Change from BL at EoT	3.0 (21.71)	2.1 (26.14)	17.8 (27.89)	-5.6 (26.73)	1.5 (30.10)	5.7 (15.38)	6.9 (27.25)	0.8 (22.95)	-0.6 (18.04)
Change from BL at Day 169	3.3 (24.27)	-5.1 (20.41)	25.3 (21.73)	-4.2 (28.43)	-4.2 (25.42)	11.9 (21.91)	7.2 (26.36)	0.5 (24.15)	-0.5 (19.37)

23. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	38	33	21
Baseline (BL)	67.7 (25.56)	68.9 (26.09)	64.3 (29.29)	73.1 (18.63)	56.4 (27.76)	54.5 (27.42)	62.6 (27.39)	65.7 (24.75)	64.6 (30.69)
Change from BL at Day 8	-2.2 (19.46)	-8.6 (29.28)	0.0 (15.71)	-9.3 (17.62)	4.3 (14.01)	4.0 (7.49)	1.0 (16.04)	-4.5 (19.73)	-2.6 (19.33)
Change from BL at Day 29	-9.1 (28.03)	-8.3 (27.70)	8.3 (30.14)	-10.0 (22.50)	1.9 (13.26)	-3.7 (25.46)	-0.4 (24.26)	-7.4 (24.27)	-5.1 (25.91)
Change from BL at EoT	-7.1 (21.81)	-8.6 (31.32)	-10.1 (16.07)	-14.8 (23.37)	6.8 (26.66)	1.0 (9.23)	-2.9 (22.92)	-7.6 (22.83)	-3.0 (30.13)
Change from BL at Day 169	1.4 (26.19)	-3.7 (31.92)	0.0 (13.28)	-4.2 (24.44)	0.0 (17.37)	12.7 (11.88)	0.4 (18.72)	0.9 (25.15)	-5.1 (18.16)

24. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	43	42	21
Baseline (BL)	41.0 (17.83)	35.3 (19.29)	33.1 (20.26)	41.1 (27.83)	39.4 (21.70)	40.0 (20.70)	37.7 (19.91)	38.9 (22.52)	41.7 (16.67)
Change from BL at Day 8	7.1 (23.28)	4.9 (20.24)	10.0 (11.87)	-2.4 (13.25)	5.6 (13.24)	5.6 (15.96)	7.4 (16.52)	2.6 (16.50)	0.0 (16.43)
Change from BL at Day 29	7.1 (26.54)	4.9 (20.24)	12.8 (16.26)	3.8 (19.73)	-1.1 (18.06)	-1.8 (26.19)	5.3 (21.19)	2.1 (22.02)	3.1 (14.49)
Change from BL at EoT	-3.2 (25.35)	0.7 (17.93)	-2.5 (15.28)	-3.6 (23.51)	1.1 (23.12)	-0.6 (23.46)	-1.4 (21.43)	-1.2 (21.53)	1.6 (16.67)
Change from BL at Day 169	10.6 (13.99)	0.0 (21.32)	14.4 (19.72)	6.7 (17.91)	-1.4 (11.70)	9.2 (14.93)	7.4 (16.30)	4.9 (18.31)	0.9 (19.57)

25. Secondary Outcome

Title	Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms
Description	The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
Time Frame	Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Cohort A (3 Capsules o.d.): TIP	Cohort A (3 Capsules o.d.): TIP/PBO	Cohort B (5 Capsules o.d.): TIP	Cohort B (5 Capsules o.d.): TIP/PBO	Cohort C (4 Capsules b.i.d.): TIP	Cohort C (4 Capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)	Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)	Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical	Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.	Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.	Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.
Measure Participants	14	13	15	14	15	15	43	42	21
Baseline (BL)	56.0 (13.05)	53.8 (18.12)	56.8 (17.63)	55.9 (21.69)	52.3 (22.39)	61.9 (13.31)	55.0 (17.98)	57.4 (17.83)	53.8 (14.42)
Change from BL at Day 8	10.3 (6.83)	6.5 (14.66)	13.9 (16.12)	3.3 (9.99)	9.8 (12.30)	-0.6 (16.20)	11.2 (12.05)	2.8 (13.85)	1.0 (12.09)
Change from BL at Day 29	7.0 (11.94)	0.6 (19.97)	6.3 (24.57)	3.6 (14.69)	6.9 (22.57)	-5.7 (25.58)	6.8 (19.65)	-0.7 (20.58)	2.3 (13.48)
Change from BL at EoT	-0.4 (11.21)	4.1 (15.65)	1.9 (18.52)	-0.6 (20.73)	6.7 (16.52)	-6.5 (26.18)	2.9 (15.58)	-1.4 (21.59)	4.0 (12.12)
Change from BL at Day 169	7.1 (11.76)	0.9 (16.42)	10.7 (8.63)	-2.7 (24.33)	5.6 (16.53)	10.7 (12.52)	7.6 (12.76)	2.8 (18.57)	1.6 (19.98)

Adverse Events

Time Frame	Adverse events were collected from first dose of study drug treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 134 days.
Adverse Event Reporting Description	Any sign or symptom that occurs during study treatment plus the 30 days post treatment.
Arm/Group Title	Cohort A (3 Capsules o.d.): TIP		Cohort A (3 Capsules o.d.): TIP/PBO		Cohort A (3 Capsules o.d.): PBO		Cohort B (5 Capsules o.d.): TIP		Cohort B (5 Capsules o.d.): TIP/PBO		Cohort B (5 Capsules o.d.): PBO		Cohort C:4 Capsules b.i.d. TIP		Cohort C (4 Capsules b.i.d.): TIP/PBO		Cohort C (4 Capsules b.i.d.): PBO
Arm/Group Description	Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)		Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical		Cohort A (3 capsules o.d.): Inhaled placebo (PBO)		Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)		Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical		Cohort B (5 capsules o.d.): inhaled placebo (PBO)		Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)		Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical		Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)
All Cause Mortality
	Cohort A (3 Capsules o.d.): TIP		Cohort A (3 Capsules o.d.): TIP/PBO		Cohort A (3 Capsules o.d.): PBO		Cohort B (5 Capsules o.d.): TIP		Cohort B (5 Capsules o.d.): TIP/PBO		Cohort B (5 Capsules o.d.): PBO		Cohort C:4 Capsules b.i.d. TIP		Cohort C (4 Capsules b.i.d.): TIP/PBO		Cohort C (4 Capsules b.i.d.): PBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Serious Adverse Events
	Cohort A (3 Capsules o.d.): TIP		Cohort A (3 Capsules o.d.): TIP/PBO		Cohort A (3 Capsules o.d.): PBO		Cohort B (5 Capsules o.d.): TIP		Cohort B (5 Capsules o.d.): TIP/PBO		Cohort B (5 Capsules o.d.): PBO		Cohort C:4 Capsules b.i.d. TIP		Cohort C (4 Capsules b.i.d.): TIP/PBO		Cohort C (4 Capsules b.i.d.): PBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		2/13 (15.4%)		0/7 (0%)		4/15 (26.7%)		3/14 (21.4%)		2/7 (28.6%)		2/15 (13.3%)		4/15 (26.7%)		1/7 (14.3%)
Cardiac disorders
Acute myocardial infarction	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Atrial fibrillation	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Gastrointestinal disorders
Intestinal obstruction	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
General disorders
Asthenia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Hepatobiliary disorders
Bile duct stone	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Cholecystitis acute	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Infections and infestations
Bacterial disease carrier	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Infective exacerbation of bronchiectasis	3/14 (21.4%)		0/13 (0%)		0/7 (0%)		2/15 (13.3%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		3/15 (20%)		0/7 (0%)
Pneumonia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Investigations
Blood creatinine abnormal	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Glomerular filtration rate decreased	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Nervous system disorders
Syncope	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Dyspnoea	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Haemoptysis	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Respiratory failure	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Vascular disorders
Orthostatic hypotension	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A (3 Capsules o.d.): TIP		Cohort A (3 Capsules o.d.): TIP/PBO		Cohort A (3 Capsules o.d.): PBO		Cohort B (5 Capsules o.d.): TIP		Cohort B (5 Capsules o.d.): TIP/PBO		Cohort B (5 Capsules o.d.): PBO		Cohort C:4 Capsules b.i.d. TIP		Cohort C (4 Capsules b.i.d.): TIP/PBO		Cohort C (4 Capsules b.i.d.): PBO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/14 (85.7%)		12/13 (92.3%)		6/7 (85.7%)		10/15 (66.7%)		10/14 (71.4%)		7/7 (100%)		13/15 (86.7%)		14/15 (93.3%)		5/7 (71.4%)
Blood and lymphatic system disorders
Anaemia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Eosinophilia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Iron deficiency anaemia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Thrombocytopenia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Ear and labyrinth disorders
Cerumen impaction	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Deafness	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Eustachian tube dysfunction	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Middle ear effusion	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Tinnitus	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Eye disorders
Eye pain	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Gastrointestinal disorders
Abdominal pain	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Abdominal pain upper	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Aerophagia	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Cheilitis	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Constipation	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Dental caries	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Diarrhoea	0/14 (0%)		3/13 (23.1%)		2/7 (28.6%)		1/15 (6.7%)		1/14 (7.1%)		0/7 (0%)		2/15 (13.3%)		0/15 (0%)		0/7 (0%)
Dry mouth	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		2/14 (14.3%)		1/7 (14.3%)		1/15 (6.7%)		0/15 (0%)		1/7 (14.3%)
Dyspepsia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Gastric polyps	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Gastrointestinal disorder	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Glossodynia	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Inguinal hernia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Lip swelling	0/14 (0%)		1/13 (7.7%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Mouth ulceration	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Nausea	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Oral pain	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Paraesthesia oral	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Rectal haemorrhage	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Vomiting	1/14 (7.1%)		1/13 (7.7%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
General disorders
Asthenia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Chest discomfort	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		1/14 (7.1%)		1/7 (14.3%)		2/15 (13.3%)		0/15 (0%)		0/7 (0%)
Chest pain	1/14 (7.1%)		2/13 (15.4%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		2/15 (13.3%)		0/7 (0%)
Discomfort	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		2/15 (13.3%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Exercise tolerance decreased	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Fatigue	1/14 (7.1%)		2/13 (15.4%)		0/7 (0%)		1/15 (6.7%)		3/14 (21.4%)		2/7 (28.6%)		2/15 (13.3%)		0/15 (0%)		1/7 (14.3%)
Influenza like illness	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Oedema peripheral	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Peripheral swelling	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Pyrexia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		2/15 (13.3%)		0/15 (0%)		0/7 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Hepatotoxicity	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Immune system disorders
Food allergy	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Infections and infestations
Bronchitis	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Candida infection	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Cystitis	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Ear infection	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Gastroenteritis viral	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Herpes simplex	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Hordeolum	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Infective exacerbation of bronchiectasis	4/14 (28.6%)		4/13 (30.8%)		6/7 (85.7%)		3/15 (20%)		5/14 (35.7%)		2/7 (28.6%)		4/15 (26.7%)		5/15 (33.3%)		2/7 (28.6%)
Influenza	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		1/7 (14.3%)
Joint abscess	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Labyrinthitis	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Lower respiratory tract infection	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Nasopharyngitis	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		1/15 (6.7%)		2/14 (14.3%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Oral candidiasis	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		1/7 (14.3%)		0/15 (0%)		1/15 (6.7%)		1/7 (14.3%)
Oral fungal infection	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Oral herpes	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Respiratory tract infection viral	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Rhinitis	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Sinusitis	0/14 (0%)		1/13 (7.7%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Sputum purulent	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Tooth infection	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Upper respiratory tract infection	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Urinary tract infection	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		2/15 (13.3%)		0/7 (0%)
Viral infection	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Viral upper respiratory tract infection	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Vulvovaginal candidiasis	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Airway complication of anaesthesia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Arthropod bite	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Fall	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Hypobarism	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Ligament sprain	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Procedural pain	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Road traffic accident	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Investigations
Blood cholesterol increased	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Blood creatine phosphokinase increased	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Blood creatinine increased	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		1/15 (6.7%)		1/14 (7.1%)		0/7 (0%)		6/15 (40%)		1/15 (6.7%)		0/7 (0%)
Blood electrolytes decreased	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Blood urea increased	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
C-reactive protein increased	1/14 (7.1%)		0/13 (0%)		1/7 (14.3%)		2/15 (13.3%)		0/14 (0%)		0/7 (0%)		2/15 (13.3%)		0/15 (0%)		0/7 (0%)
Eosinophil count abnormal	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Forced expiratory volume decreased	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Forced vital capacity decreased	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Gamma-glutamyltransferase increased	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Glomerular filtration rate decreased	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		1/14 (7.1%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Haemoglobin decreased	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Liver function test abnormal	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Neutrophil count increased	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Protein urine present	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Sputum abnormal	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Urine albumin/creatinine ratio increased	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Urine protein/creatinine ratio increased	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		2/15 (13.3%)		0/15 (0%)		0/7 (0%)
Weight decreased	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
White blood cell count increased	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Acidosis	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Decreased appetite	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Hyperglycaemia	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Hyponatraemia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Type 2 diabetes mellitus	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Joint contracture	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Joint swelling	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Limb discomfort	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Muscle contracture	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Muscle spasms	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		2/15 (13.3%)		0/15 (0%)		1/7 (14.3%)
Muscle tightness	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Musculoskeletal chest pain	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		1/15 (6.7%)		1/15 (6.7%)		1/7 (14.3%)
Myalgia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Pain in extremity	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		2/7 (28.6%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Periarthritis	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Nervous system disorders
Ageusia	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Anosmia	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Dizziness	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Headache	2/14 (14.3%)		4/13 (30.8%)		0/7 (0%)		1/15 (6.7%)		2/14 (14.3%)		1/7 (14.3%)		2/15 (13.3%)		0/15 (0%)		0/7 (0%)
Hypoaesthesia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Migraine	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Muscle spasticity	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Paraesthesia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Sciatica	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Tremor	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Psychiatric disorders
Anxiety	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Renal and urinary disorders
Calculus urinary	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Glycosuria	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Haematuria	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Proteinuria	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Renal cyst	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Renal failure	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Renal impairment	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Urinary incontinence	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Prostatitis	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Bronchiectasis	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Bronchospasm	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		3/15 (20%)		0/7 (0%)
Cough	2/14 (14.3%)		3/13 (23.1%)		1/7 (14.3%)		4/15 (26.7%)		2/14 (14.3%)		1/7 (14.3%)		2/15 (13.3%)		2/15 (13.3%)		3/7 (42.9%)
Dry throat	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		3/15 (20%)		0/15 (0%)		0/7 (0%)
Dysphonia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		2/15 (13.3%)		0/7 (0%)
Dyspnoea	2/14 (14.3%)		2/13 (15.4%)		1/7 (14.3%)		3/15 (20%)		2/14 (14.3%)		2/7 (28.6%)		4/15 (26.7%)		2/15 (13.3%)		0/7 (0%)
Dyspnoea exertional	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		1/7 (14.3%)
Dyspnoea paroxysmal nocturnal	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Epistaxis	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Haemoptysis	1/14 (7.1%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		2/14 (14.3%)		3/7 (42.9%)		0/15 (0%)		2/15 (13.3%)		1/7 (14.3%)
Increased bronchial secretion	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		1/15 (6.7%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Increased viscosity of bronchial secretion	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Nasal discomfort	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Oropharyngeal pain	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		2/14 (14.3%)		1/7 (14.3%)		2/15 (13.3%)		0/15 (0%)		1/7 (14.3%)
Pulmonary pain	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Rales	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Respiratory symptom	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Rhinorrhoea	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		1/7 (14.3%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Sputum discoloured	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Sputum increased	3/14 (21.4%)		1/13 (7.7%)		1/7 (14.3%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		3/15 (20%)		1/7 (14.3%)
Throat irritation	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Wheezing	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		1/7 (14.3%)		1/15 (6.7%)		2/15 (13.3%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Alopecia	0/14 (0%)		1/13 (7.7%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Dermatitis allergic	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Night sweats	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Rash	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		1/14 (7.1%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Rash papular	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		1/15 (6.7%)		0/15 (0%)		0/7 (0%)
Skin exfoliation	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Swelling face	0/14 (0%)		0/13 (0%)		1/7 (14.3%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		0/15 (0%)		0/7 (0%)
Urticaria	0/14 (0%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Vascular disorders
Hot flush	1/14 (7.1%)		0/13 (0%)		0/7 (0%)		0/15 (0%)		0/14 (0%)		0/7 (0%)		0/15 (0%)		1/15 (6.7%)		0/7 (0%)
Hypertension	0/14 (0%)		0/13 (0%)		0/7 (0%)		1/15 (6.7%)		0/14 (0%)		1/7 (14.3%)		0/15 (0%)		0/15 (0%)		0/7 (0%)

Limitations/Caveats

Novartis decided to close the recruitment of new subjects into this study earlier than scheduled. The early recruitment halt of the study was not due to safety or lack of efficacy.

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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 (ie, data from all sites) in the clinical trial.