Clinical trial NCT02712983
Conditions: Non-cystic Fibrosis Bronchiectasis
Keywords: Inhaled tobramycin tobramycin inhalation powder bronchiectasis pulmonary Pseudomonas aeruginosa infection dose-finding study
Sponsor: Novartis Pharmaceuticals
Start date: 2017-02-08; Completion date: 2019-03-20
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) arm 2: Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical arm 3: Cohort A (3 capsules o.d.): Inhaled placebo (PBO) arm 4: Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) arm 5: Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical arm 6: Cohort B (5 capsules o.d.): inhaled placebo (PBO) arm 7: Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) arm 8: Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical arm 9: Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)
Interventions: intervention 1: TIP intervention 2: TIP and placebo intervention 3: Placebo
Intervention descriptions: intervention 1: TIP dose regimen intervention 2: TIP and inhaled placebo dose regimen intervention 3: Inhaled placebo dose regimen

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
TBM100/Tobramycin Inhalation Powder
Clinical Trial Protocol CTBM100G2202 / NCT02712983
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
Document type:
Amended Protocol Version
EUDRACT number:
2015-003040-39
Version number:
v03 (Clean)
Clinical trial phase:
II
Release date:
21-Jun-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................10
Amendment 3 ....................................................................................................................13
Amendment rationale ........................................................................................................13
Changes to the protocol.....................................................................................................13
Amendment 2 ....................................................................................................................14
Amendment rationale ........................................................................................................14
Changes to the protocol.....................................................................................................16
Amendment 1 ....................................................................................................................17
Amendment rationale ........................................................................................................17
Changes to the protocol.....................................................................................................18
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................22
2
Study objectives and endpoints .........................................................................................22
2.1
Primary objectives .................................................................................................22
2.2
Secondary objectives .............................................................................................23
2.3
Exploratory objectives...........................................................................................23
2.4
Objectives and related endpoints...........................................................................24
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale for study design .....................................................................................26
3.3
Rationale for dose/regimen, route of administration and duration of treatment....27
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................28
3.6
Risks and benefits..................................................................................................28
4
Population..........................................................................................................................29
4.1
Inclusion criteria ....................................................................................................29
4.2
Exclusion criteria...................................................................................................30
5
Treatment...........................................................................................................................33
5.1
Study treatment......................................................................................................33


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5.1.1
Investigational and control drugs..........................................................33
5.1.2
Additional treatment..............................................................................33
5.2
Treatment arms......................................................................................................33
5.3
Treatment assignment and randomization.............................................................34
5.4
Treatment blinding.................................................................................................35
5.5
Treating the patient................................................................................................35
5.5.1
Patient numbering .................................................................................35
5.5.2
Dispensing the study drug.....................................................................36
5.5.3
Handling of study and additional treatment..........................................36
5.5.4
Instructions for prescribing and taking study treatment........................37
5.5.5
Permitted dose adjustments and interruptions of study treatment ........38
5.5.6
Rescue medication ................................................................................38
5.5.7
Concomitant medication .......................................................................38
5.5.8
Prohibited medication ...........................................................................40
5.5.9
Emergency breaking of assigned treatment code..................................41
5.6
Study Completion and Discontinuation.................................................................41
5.6.1
Study completion and post-study treatment..........................................41
5.6.2
Discontinuation of Study Treatment.....................................................41
5.6.3
Withdrawal of informed consent...........................................................43
5.6.4
Loss to follow-up ..................................................................................43
5.6.5
Early study termination by the sponsor.................................................44
6
Visit schedule and assessments .........................................................................................44
6.1
Information to be collected on screening failures..................................................50
6.2
Patient demographics/other baseline characteristics .............................................50
6.2.1
Chest CT-scan.......................................................................................51
6.3
Treatment exposure and compliance .....................................................................51
6.4
Efficacy..................................................................................................................51
6.4.1
Microbiological assessment ..................................................................52
53
6.4.3
Anti-pseudomonal antibiotic use...........................................................53
6.4.4
Pulmonary exacerbations ......................................................................53
6.4.5
Pulmonary function tests.......................................................................54
6.4.6
Health-related Quality of Life...............................................................54
57
6.4.8
Appropriateness of efficacy assessments..............................................58
6.5
Safety.....................................................................................................................58


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6.5.1
Physical examination ............................................................................58
6.5.2
Vital signs..............................................................................................58
6.5.3
Height and weight .................................................................................59
6.5.4
Laboratory evaluations..........................................................................59
6.5.5
Post-inhalation events ...........................................................................59
6.5.6
Bronchial hyperreactivity......................................................................60
6.5.7
Audiology..............................................................................................60
6.5.8
Pregnancy and assessments of fertility .................................................60
6.5.9
Adverse events of special interest.........................................................61
6.5.10
Hospitalizations for respiratory-related adverse events ........................61
6.5.11
Appropriateness of safety measurements..............................................61
6.6
Other assessments..................................................................................................61
6.6.1
Resource utilization...............................................................................61
6.6.2
Pharmacokinetics ..................................................................................61
62
63
6.6.5
Patient diaries........................................................................................64
7
Safety monitoring..............................................................................................................64
7.1
Adverse events.......................................................................................................64
7.2
Serious adverse events...........................................................................................65
7.2.1
Definition of SAE .................................................................................65
7.2.2
SAE reporting........................................................................................66
7.3
Liver safety monitoring .........................................................................................67
7.4
Renal safety monitoring.........................................................................................67
7.5
Reporting of study treatment errors including misuse/abuse ................................68
7.6
Pregnancy reporting...............................................................................................68
8
Data review and database management.............................................................................68
8.1
Site monitoring ......................................................................................................68
8.2
Data collection.......................................................................................................69
8.3
Database management and quality control............................................................69
8.4
Data Monitoring Committee..................................................................................70
8.5
Adjudication Committee........................................................................................70
9
Data analysis......................................................................................................................71
9.1
Analysis sets ..........................................................................................................71
9.2
Patient demographics and other baseline characteristics.......................................71
9.3
Treatments .............................................................................................................71


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9.4
Analysis of the primary variable(s) .......................................................................72
9.4.1
Variable(s).............................................................................................72
9.4.2
Statistical model, hypothesis, and method of analysis..........................72
9.4.3
Handling of missing values/censoring/discontinuations.......................72
9.4.4
Supportive analyses...............................................................................73
9.5
Analysis of secondary variables ............................................................................73
9.5.1
Efficacy variables..................................................................................73
9.5.2
Safety variables .....................................................................................76
9.5.3
Resource utilization...............................................................................77
9.5.4
Pharmacokinetics ..................................................................................77
77
77
9.5.7
PK/PD ...................................................................................................77
9.6
Interim analyses.....................................................................................................78
9.7
Sample size calculation..........................................................................................78
10 Ethical considerations........................................................................................................78
10.1
Regulatory and ethical compliance........................................................................78
10.2
Informed consent procedures.................................................................................79
10.3
Responsibilities of the investigator and IRB/IEC..................................................79
10.4
Publication of study protocol and results...............................................................80
11 Protocol adherence ............................................................................................................80
11.1
Protocol Amendments ...........................................................................................80
12 References .........................................................................................................................80
13 Appendix 1: Clinically notable laboratory values.............................................................83
14 Appendix 2: Specific Renal Alert Criteria and Actions....................................................84
15 Appendix 3: Sputum/blood collection logs .......................................................................85
16 Appendix 4: Instructions for use for the T-326 Inhaler.....................................................86
17 Appendix 5: Spirometry Guidance....................................................................................93
18 Appendix 6: QOL-B..........................................................................................................96
100
107
109
109
110
24 Appendix 12: Anti-pseudomonal medications................................................................110


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List of tables
Table 2-1
Primary objectives and related endpoints- Objectives..........................24
Table 5-1
Prohibited medications requiring study drug discontinuation ..............40
Table 6-1
Assessment schedule.............................................................................46
Table 14-1
Specific Renal Alert Criteria and Actions.............................................84
Table 15-1
Time schedule for sputum sampling for sputum pharmacokinetic 
assessments ...........................................................................................85
Table 15-2
Time schedule for blood sampling for serum pharmacokinetic 
assessments ...........................................................................................85
Table 15-3
Time schedule for blood sampling for serum pharmacokinetic 
assessments in PK sub-study.................................................................86
Table 24-1
Anti-pseudomonal medications...........................................................110
List of figures
Figure 3-1
Study design..........................................................................................26


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List of abbreviations
ACR
Albumin-creatinine-ratio
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BE
Bronchiectasis
b.i.d.
twice a day
BSI
Bronchiectasis Severity Index
BUN
Blood urea nitrogen
CF
Cystic Fibrosis
CFR
US Code of Federal Regulations 
CFU
Colony forming unit
Cmax
Maximum concentration
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CT
Computed Tomography
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
EDC
Electronic Data Capture
FAS
Full Analysis Set
GCP
eGFR
Good Clinical Practice
Estimated Glomerular Filtration Rate
HRQoL
Health-related quality of life
HR-CT
High resolution computerized tomography
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
i.v.
Intravenous
IRB
Institutional Review Board
ISC
Independent Study Coordinator
KDIGO
Kidney Disease Improving Global Outcomes
LFT
Liver function test 
MedDRA
Medical dictionary for regulatory activities 
MDRD
Modification of diet in renal disease
MIC
Minimum inhibitory concentration
NIRT
Novartis Interactive Response Technology
NTM
Nontuberculosis mycobacterial
OC/RDC
Oracle Clinical/Remote Data Capture 
o.d.
once a day
PCD
primary ciliary dyskinesia


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PCR
Protein-creatinine-ratio
p.o.
oral(ly)
PRO
patient reported outcome
PK
Pharmacokinetic
QOL-B
Quality of Life Questionnaire for Bronchiectasis
SAE
Serious Adverse Event
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
TIP
Tobramycin Inhalation Powder hard capsules 28 mg
TOBI
Tobramycin nebulizer solution 300 mg/mL
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects
with established disease and in those with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data.


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Protocol summary
Protocol number
CTBM100G2202
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
Brief title
Dose-finding study, to assess the efficacy, safety and tolerability of
tobramycin inhalation powder in patients with Non-CF Bronchiectasis and 
pulmonary P. aeruginosa infection
Sponsor and Clinical 
Phase
Novartis, Clinical phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this Phase II study is to support the selection of a safe and 
tolerable TIP dose, and regimen that exhibits effective bacterial reduction of 
P. aeruginosa in non-CF BE patients with P. aeruginosa colonization.
Primary Objectives

To evaluate the effect of different doses of TIP on the change in P. 
aeruginosa bacterial load in sputum as assessed by the change in 
colony forming units (CFUs) from baseline to Day 29 of treatment, each 
compared to placebo.

To assess the safety and tolerability with different doses of TIP and 
different regimens during the treatment epoch and during the follow-up 
epoch for each, as compared to placebo.
Secondary Objectives

To assess the effect of different doses of TIP and different regimens on 
the frequency of pulmonary exacerbations 

To assess the efficacy profile of different doses of TIP and different 
regimens, as measured by the use of anti-pseudomonal antibiotics 

To assess the time to first hospitalization

To assess the pharmacokinetic concentrations of tobramycin in serum 
and in sputum from different doses of TIP and different regimens.

To assess the antimicrobial efficacy of TIP over the entire study 
duration, as measured by the absolute change in P. aeruginosa colony 
forming units (CFU) in sputum from baseline to each post-baseline 
treatment visit and during the follow-up visits.

To evaluate the safety profile of TIP in terms of clinical laboratory 
results.

To evaluate the impact of treatment with TIP on the Quality of Life 
Questionnaire for Bronchiectasis (QOL-B) by measuring change from 
baseline to all post-baseline visits. 
Study design
This is a blinded, randomized, dose and regimen finding trial utilizing a 3 
treatment cohort design where active TIP doses or placebo in addition to 
the local standard care within each cohort are delivered once or twice daily. 
Approximately 180 eligible patients will be randomized to one out of the 3 
cohorts. The patients within each cohort will be randomized to blinded TIP
(TIP continuous regimen or TIP/placebo cyclical regimen cohorts) or 
placebo. Total duration of the study is expected to be up to 196 days.
Population
The study population will consist of approximately 180 male and female BE 
patients ≥18 years old with clinical diagnosis of non-CF bronchiectasis 


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confirmed radiologically by CT scan, a history of exacerbations and who 
had a history of positive culture for P. aeruginosa in sputum.  
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 parenteral antibiotic treatment within 12 
months prior to screening.

FEV1 ≥ 30% predicted at screening (Visit 1).

P. 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 (revised per amendment 02).

Patients with active pulmonary tuberculosis. 

Patients currently receiving treatment for nontuberculous mycobacterial 
(NTM) pulmonary disease.

Patients who are receiving inhaled anti-pseudomonal antibiotic within 
28 days prior to study drug administration (Visit 101).
Study treatment

Tobramycin inhalation powder (TIP) drug-device combination product 
consisting of tobramycin dry powder for inhalation in capsules (TBM100 
28 mg inhalation powder hard capsule) administered by the T-326 
Inhaler.

Matching placebo capsules to tobramycin inhalation powder 
administered by the T-326 Inhaler.
Key efficacy 
assessments

P. aeruginosa: CFU (sputum) or semi-quantitative culture data (deep-
throat cough swabs for non-sputum producing patients)

Other potentially pathogenic micro-organisms 

MICs of tobramycin and other selected antibiotics for P. aeruginosa
isolates 

Anti-pseudomonal antibiotic use 

Pulmonary exacerbations and related signs and symptoms

Pulmonary function by using spirometry


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
Patient reported outcomes
Key safety 
assessments

Adverse events, Serious adverse events

Physical examination and vital signs

Clinical chemistry, Hematology

Urinalysis and dipstick

Post-inhalation events 

Bronchial hyperreactivity measured by change in FEV1% predicted 
post-inhalation 

Audiology (will be performed at selected sites and in patients with 
hearing events)

Serum pregnancy (females of child bearing potential)

Adverse events of special interest 

Hospitalizations for respiratory-related AE
Other assessments

Resource utilization

Pharmacokinetics
Data analysis
The primary efficacy objective is to evaluate the effect of different daily 
doses of TIP on the change in P. aeruginosa bacterial load in sputum as 
assessed by the change in colony forming units (CFUs) from baseline to 
Day 29 of treatment, each compared to placebo.
The comparisons of different TIP daily doses (combining TIP continuous or
TIP/placebo cyclical regimens within a cohort) versus placebo will be 
evaluated by testing the following null hypothesis (H0) versus the 
alternative hypothesis (Ha):
H0: TIP treatment group is equal to placebo group in bacterial load in 
sputum at Day 29
Ha: TIP treatment group is not equal to placebo group in bacterial load in 
sputum at Day 29
The primary efficacy endpoint will be analyzed using the analysis of 
covariance (ANCOVA) model. The model will contain treatment, cohort, 
baseline CFU, and baseline macrolide use. Pairwise comparisons of TIP 
dosing groups will be conducted versus placebo. To control the family-wise 
type-I error rate (three dose levels vs. placebo) at the two-sided 5% 
significance level, the step-wise Dunnett procedure will be used.
The estimated adjusted treatment difference (TIP – placebo) will be 
displayed along with the associated standard error, 2-sided 95% 
confidence interval (CI), and p-value (2-sided).
Key words
Inhaled tobramycin; tobramycin inhalation powder; bronchiectasis; 
pulmonary Pseudomonas aeruginosa infection; dose-finding study


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Amendment 3
Amendment rationale
The purpose of this protocol amendment is to revise:
Exclusion criterion 33b: To clarify the assessment of total abstinence as highly effective 
contraception method. Total abstinence has to be in line with the preferred and usual lifestyle 
of the subject. For consistency with the “Recommendations related to contraception and 
pregnancy testing” of the Clinical Trials Facilitation Group the wording has been reverted to 
the initial protocol wording.
In addition, this amendment includes the definition of personal data and modified withdrawal 
of study consent definition in accordance with the European Economic Area General Data 
Protection Regulation requirements.
This amendment also includes the following changes in planned statistical analysis:

removing the cohort from the models due to confounding with treatment, 

including the multiple imputation technique as a sensitivity analysis and,

dropping some exploratory analyses due to small sample size as outlined below.  
Changes to the protocol
Glossary of terms

Definition of personal data added and definition of withdrawal of consent modified.
4.2 Exclusion criteria 

Exclusion criterion 33b revised, as described above.
5.6.3 Withdrawal of informed consent.

Section revised, as described above.
Section 9: 

Cohort is removed in the models for statistical analysis of primary and secondary variables 
due to confounding with treatment.

Section 9.1. Information has been added to clarify that patients who are mistakenly
randomized or who have not taken double blind study drug will be excluded from the full 
analysis set (FAS).

Section 9.4.3 refers to a sensitivity analysis to account for patients who require treatment
with anti-pseudomonal drugs for exacerbation: it was previously planned to exclude
patient data from the start day of systemic anti-pseudomonal treatment for the relevant
efficacy endpoints. This analysis will not be performed. Alternatively, for the primary
endpoint only, multiple imputation will be implemented, as multiple imputation 
technique is more robust.


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
Section 9.5.1.2 states that the proportion of patients with at least one pulmonary
exacerbation, and the proportion of patients who permanently discontinue study drug 
due to pulmonary exacerbation will be analyzed using both logistic regression and time 
to event analysis. However, due to small sample size, these two endpoints will be 
evaluated using time to event analysis only. The
annual
rate
of
pulmonary
exacerbations will be summarized only overall and not by exacerbations category due 
to small sample size.

Section 9.5.1.3 refers to the use of anti-pseudomonal antibiotics. As anti-pseudomonal 
antibiotics used for treatment of pulmonary exacerbations are often used in combination, 
dose cannot be defined consistently. Therefore,the total amount (in doses) of anti-
pseudomonal antibiotics used to treat pulmonary exacerbation during the treatment epoch 
and the study period will not be analyzed.
Summary of previous amendments 
Amendment 2
Amendment rationale
The purpose of this protocol amendment is to revise the following enrolment criteria: 

Exclusion criterion 9a: The criterion was revised to reduce the number of disease-free 
survival years from 5 to 2 in patients with a history of cancer. Based on the 
tobramycin safety profile, there is no increased risk of cancer expected due to study 
medication.

Exclusion criterion 10a: The exclusion criterion was revised to clarify that patients 
with clinically significant (in the opinion of the investigator) hearing loss that 
interferes with patients’ daily activities (such as normal conversations) or chronic 
tinnitus should not be enrolled. The use of a hearing device is reflective of a clinically 
significant hearing loss; hence patients using hearing aids at screening are not eligible. 
Ototoxicity, manifested as both auditory toxicity (hearing loss) and vestibular toxicity, 
has been reported with parenteral aminoglycosides. Hearing loss and tinnitus were 
reported by patients in clinical trials with tobramycin inhalation powder. 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.

Exclusion criterion 18a: The renal exclusion criterion was updated with focus on the 
estimated glomerular filtration rate (eGFR, as per MDRD) and proteinuria, which are 
specific indicators to characterize the patient’s renal function. Serum creatinine and 
blood urea nitrogen (BUN) have been removed as they are subject to significant 
diurnal variation based on the patients’ hydration status and dependent on the meal 
composition taken. The mention of creatinine clearance is redundant as eGFR is 
measured. 


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
Exclusion criterion 21a: Patients with primary ciliary dyskinesia (PCD) were 
previously excluded from study participation because these patients frequently have 
hearing impairment secondary to chronic sinusitis and repeated otitis media episodes. 
The exclusion criterion was revised so that PCD patients may be enrolled, provided 
their hearing threshold at screening audiometry is 25dB or lower at frequencies 
0.5-4 kHz.

Exclusion criterion 33a: The criterion was revised to clarify the assessment of 
abstinence as highly effective contraception method.
The window for re-screening was revised to allow re-screening once for any patient until 
enrolment is completed. Bronchiectasis patients with P.aeruginosa infections may have 
several exacerbations a year. Therefore, patients who had an exacerbation during the 
screening period are now allowed to be re-screened twice until enrolment is completed.
Furthermore, the renal alert criteria and follow-up actions and the discontinuation criteria 
were amended in order to focus on the relevant renal function markers. To improve the renal 
function monitoring distinction is made between renal findings and confirmed renal events.
Instructions for study treatment interruption/discontinuation have been clarified to distinguish 
events that mandate permanent study drug discontinuation as per protocol from those that are 
at investigators’ discretion.

Study treatment must be discontinued in patients who have a serum creatinine increase 
of 50% or more compared to baseline, as confirmed according to Appendix 2 Specific 
Renal Alert Criteria and Actions. The threshold of 50% is aligned with the definition 
of Stage 1 Acute Kidney Injury/Risk for Acute Kidney Injury in the KDIGO guideline 
(2012).

Serum creatinine increase of up to 50% can reasonably be the result of patients’ 
hydration status. Patients with serum creatinine increase of 25 – <50% will be 
monitored according to Appendix 2, which now includes also eGFR measurement as 
follow up action in patients with serum creatinine increase. Investigators should 
consider study treatment interruption or discontinuation based on clinical judgement. 

In patients with proteinuria ≥ 3+ urine microscopy, albumin-creatinine-ratio (ACR) 
and protein-creatinine-ratio (PCR) will be determined. Patients with confirmed 
proteinuria ≥ 3+ must discontinue study treatment. 

BUN has been removed from the discontinuation criteria because it is not specific 
enough to determine renal failure. 
The pharmacokinetics (PK) sampling scheme was revised in order to maximize the number of 
samples for tobramycin exposure in particular in patients who are on alternating TIP/placebo 
treatment. Changing PK sampling from Day 29 to Day 8 is acceptable to assess the exposure.
This is based on the short estimated terminal half-life of tobramycin in serum after inhalation 
of a single 112 mg dose of TIP which was approximately 3 hours (Ting 2014).  
Additional minor clarifications were included, as summarized below in Changes to the 
protocol.


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Changes to the protocol
3.1 Study design
Any patient can be re-screened once until enrollment has completed. Patients who had an 
exacerbation during the screening phase can be re-screened twice until recruitment has been 
completed.
4.2 Exclusion criteria

Exclusion criterion 9a. was amended to allow patients with a history of cancer (excluding 
lung cancer) and 2 years or more disease-free survival time to be included.

Exclusion criterion 10a. was amended to clarify that patients with clinically significant (in 
the opinion of the investigator) hearing loss that interferes with patients’ daily activities 
(such as normal conversations) or chronic tinnitus are not to be enrolled. 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.

Exclusion criterion 18a. was amended to remove serum creatinine and serum urea (BUN) 
from the panel of renal values relevant for enrolment. 

Exclusion criterion 21a. was revised: Patients with primary ciliary dyskinesia (PCD) may 
be enrolled, if their hearing threshold at screening audiometry is 25dB or lower at 
frequencies 0.5-4 kHz.

Exclusion criterion 33a. was revised to clarify that women of child-bearing potential may 
participate in the study if the investigator assesses their abstinence compliance.
5.4 Section was amended to include unblinding requests from the Novartis study-independent 
safety review team.
5.5.7 Concomitant medication
Section was revised to clarify that short-term (maximum of 28 consecutive days) treatment 
with corticosteroids in case of an Adverse Event is permitted. 
5.5.8 Prohibited medication
Section was revised to clarify that long-term treatment (more than 28 days) with 
corticosteroids >15mg/day is prohibited.
5.6.2 Discontinuation of Study Treatment
The discontinuation criteria were amended based on above rationale and aligned with 
Section 14 Appendix 2 Specific Renal Alert Criteria and Actions.
Table 6-1 Assessment schedule
A note was added to clarify that visits should occur on the designated day, or as close to it as 
possible, consistent with Section 6 Visit schedule and assessments.
The schedule was amended to account for changes in PK sampling and requirement for 
audiology assessments in patients with a past history of hearing loss or PCD according to the 
above rationale.
6.4.1 Microbiological assessment


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The section was revised to clarify different options of obtaining sputum samples or swabs.
6.5.7 Audiology
The section was revised in alignment with exclusion criterion 10a.
6.6.2 Pharmacokinetics
The pharmacokinetics sampling scheme was aligned with the tobramycin exposure.
7.4 Renal safety monitoring
The section was revised to be aligned with Section 5.6.2 Discontinuation of Study Treatment 
and Section 14 Appendix 2
Section 14 Appendix 2
Specific Renal Alert Criteria and Actions were amended according to the above rationale and 
in alignment with Section 5.6.2 Discontinuation of Study Treatment.
Section 15 Appendix 3: Sputum/blood collection logs
The section was revised according to the amended PK collection schedule.
IECs
A copy of this amended protocol will be sent to the Independent Ethics Committee (IECs) and 
Health Authorities as appropriate.
The changes described in this amended protocol require IEC approval prior to implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 1
Amendment rationale
The purpose of this protocol amendment is to clarify specific elements in the protocol. First, 
the timing of the Data Monitoring Committee (DMC) interim review is removed, as this is 
detailed in the DMC charter. 
Furthermore, the amendment clarifies that for the signs and symptoms characterizing the 
pulmonary exacerbations and which are required to last for more than 24 hours, additional 
information regarding duration will be collected to document if the reported signs and 
symptoms are present for more than 48 hours. The additional information is collected in line 
with the recently published consensus definition of pulmonary exacerbations for clinical 
research (Hill et al 2017).
In addition, thresholds and criteria for renal event monitoring are revised in accordance with 
the updated Novartis renal safety guideline and the safety profile of Tobramycin Inhalation 
Powder (TIP) obtained from clinical and post-marketing experience in cystic fibrosis (CF) 
patients. Based on the review of the most recent data cumulatively (until 30-June-2017), there 
is no evidence to suggest a causal relationship between use of TIP and the potential risk of 


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nephrotoxicity. The risk for nephrotoxicity is expected to be very low considering the 
systemic levels of tobramycin after TIP administration (Cmax is 1.02 ± 0.53 μg/mL) compared 
to the maximum systemic levels recommended for avoidance of the toxicity associated with 
intravenous tobramycin therapy (Cmax greater than 12 μg/mL) (Sweetman 2011). The revised 
renal safety alert criteria have been designed to facilitate the early detection of a renal event.
Moreover, corrections on minor inconsistencies or clarifications are incorporated in this 
protocol amendment.
Changes to the protocol

Section 4.1 Inclusion criteria: In inclusion criterion 4 ‘intravenous’ has been replaced 
with ‘parenteral’ anti-pseudomonal antibiotic treatment. For consistency ‘intravenous’ 
has been replaced with ‘parenteral’ anti-pseudomonal antibiotics in sections 2.2 
secondary objectives, 5.5.7 Concomitant medication and 9.5.1.3 Anti-pseudomonal 
antibiotics.

Section 4.2 Exclusion criteria: exclusion criterion 26 has been clarified, in line with 
exclusion criterion 27.

Table 6-1 and Section 6.4.6 Exit Interviews: The footnote on exit interviews is 
updated considering the timing of conduct of exit interviews.   

Section 6.4.4 Pulmonary exacerbations: additional time point of 48 hours is added to 
collect the presence of exacerbation symptoms, signs and findings lasting for more 
than48 hours. Furthermore, the protocol definition has been aligned to reflect the data 
collection in the Case Report Forms (‘fever’).

Section 6.4.6 Health-related Quality of Life: The instructions were previously based 
on paper questionnaires and have been aligned with the electronic data collection used 
in this study.

Section 6.5.4.3 Urinalysis: The assessments have been revised according to the 
updated renal event monitoring.

Section 6.5.7 Audiology: The audiology assessment time window at visit 2 and 
following visits has been clarified.

Section 7.4 Renal safety monitoring: Renal Alert criteria have been revised for 
consistency between sections 7.4 and Appendix 2 and in line with the revised Novartis 
guidelines. Thresholds and criteria for renal event monitoring are revised as follows: 

Confirmed serum creatinine increase ≥ 25% from pretreatment baseline

New dipstick proteinuria ≥ 3+ 

Hematuria ≥ 3+ on urine dipstick 
In the event that any of the above is met, the renal markers will be repeated and the 
protein-creatinine ratio (PCR) and the albumin-creatinine-ratio (ACR) will be 
determined.


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
Section 8.4 Data Monitoring Committee: The timing of the DMC review has been 
removed and referred to DMC charter for more details.

Appendix 2: Revised Specific Renal Alert Criteria and Actions as indicated above.
IECs
A copy of this amended protocol will be sent to the Independent Ethics Committee (IECs) and 
Health Authorities as appropriate.


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1
Introduction
1.1
Background 
Bronchiectasis (BE) is defined as the irreversible dilatation of bronchi with destruction of 
elastic and muscular components of their walls. The gold standard method for diagnosis is via 
high resolution computerized tomography (HR-CT) scan. Bronchiectasis is frequently 
idiopathic in origin, or may be a result of a number of post-infectious causes, congenital 
diseases (e.g., immunodeficiency, primary ciliary dyskinesia, cystic fibrosis), inflammatory 
diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) or anatomic obstruction, all 
of which predispose to a cycle of chronic infection and inflammation, and airways damage.
BE is often associated with bacterial infections that may be linked to higher morbidity. The 
cystic fibrosis population, who demonstrate significant bronchiectatic changes as a result of 
chronic lung infection and inflammation, experience a significant morbidity and mortality 
related to chronic Pseudomonas (P.) aeruginosa infection. The presence of bacterial 
colonization/infection in non–cystic fibrosis bronchiectasis (non–CF BE) has been associated 
with predictors of morbidity, such as exacerbations, and hospital admissions (Chalmers and 
Hill 2012). The pathogens most frequently associated with non-CF BE are: Haemophilus 
influenzae (30-47%), Streptococcus pneumoniae (7-11%), Pseudomonas aeruginosa (12-
31%), Staphylococcus aureus (4-7%), and Moraxella catarrhalis (2-20%) (O’Donnell 2008). 
Wilson et al (2013) have published other potentially pathogenic microorganisms (PPMs) such 
as Klebsiella spp (7%) and Proteus spp (6%). However, the link between a specific bacterial 
colonization and exacerbation is often difficult to demonstrate. Several studies tried to 
identify the predictors of morbidity in non-CF BE patients. Among them colonization with P. 
aeruginosa may play a key role (Ho et al 1998, Angrill et al 2002, Loebinger et al 2009). 
Non-CF BE prevalence is not well defined; in a US cohort using a claims database (with the 
cohort definition having a combination of diagnostic criteria) estimates range from 4.2 cases 
per 100,000 persons aged 18-34 years up to 272 cases per 100,000 in those over 75 years 
(Weycker et al 2005) with a mean age of 61 years. Most subjects (68%) were women and 
common comorbidities included COPD (30.1%), ischemic heart disease (12.6%), malignant 
neoplasms (11.4%), diabetes mellitus (8.9%), and heart failure (8.1%).
At present, no specific treatment standards are available; some “best practice” 
recommendations have been developed such as the British Thoracic Society guidelines 
(Pasteur et al 2010); there are also review papers based mainly on the experience from CF. In 
stable lung disease (with or without chronic infection) the treatment aim is to reduce 
symptoms, limit exacerbations, preserve lung function and improve health-related quality of 
life (HRQoL). Antibiotic treatment is primarily recommended to treat exacerbations. Data on 
long-term treatment with antibiotics are sparse and evidence for clinical benefits remains 
limited: inhaled continuous therapy with gentamicin over 12 months was successful, however 
treatment effect was lost after 3 months off-treatment (Murray et al 2011). Recently Haworth 
et al (2014) have shown that 6 months therapy with inhaled colistin was successful, but only 
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A few pilot studies using inhaled tobramycin nebulised solution have been performed in non-
CF BE patients, with variable treatment success rates (Barker et al 2000, Scheinberg and 
Shore 2005, Drobnic et al 2005). Other exploratory studies have assessed inhalation treatment 
as follow-up after intravenous (i.v.) therapy (Orriols et al 1999) or add-on treatment to oral 
ciprofloxacin during acute exacerbations (Bilton et al 2006); trends in improvements of 
clinical and/or microbiological outcomes have been noted in the arms with inhaled 
tobramycin. Eradication of P. aeruginosa infection has been noted in some of these studies, 
varying from less than 20% up to 40% (Barker et al 2000, Scheinberg and Shore 2005). 
Tolerability in these studies was noted to be lower than that seen with TOBI (tobramycin 
nebulised solution) registration trials in CF patients.

Barker et al (2000): n= 74 patients double blind study TOBI 300 mg/5mL b.i.d. (37 
patients) vs. placebo (37 patients), 4 weeks on/2 weeks off drug. Efficacy: significant 
microbiologic effect demonstrated – P. aeruginosa density reduction 4.54 log10 CFU/g 
sputum, P<0.01; P. aeruginosa eradicated in 35% of TOBI patients, more TOBI patients 
evaluated as having “improved” medical condition (investigators judgment). Safety: 
subset of patients appeared to have drug-related adverse events –increased cough, dyspnea, 
increased sputum, chest pain, wheezing.

Scheinberg and Shore (2005): n=41 Open label; 3 cycles of 2 weeks on/2 weeks off 
nebulized TOBI 300 mg/5mL b.i.d.: 40 day follow-up. Result: microbiological benefit 
(decreased P. aeruginosa density) in addition to an improvement in pulmonary symptom 
scores.

Orriols et al (1999): n=17 open label; nebulized ceftazidime 1000 mg + nebulized 
tobramycin solution 100 mg b.i.d. for 12 months vs. no inhaled antibiotics. Results: fewer 
hospitalizations, no improvement in pulmonary function (spirometry & arterial blood gas 
analysis).

Drobnic et al (2005): n=30 double-blind, cross over; 300 mg/5mL nebulized TOBI b.i.d. 
or placebo, two 6 months treatment periods with 1 month wash out. Results: number of 
admissions and days of admissions reduced, decreased Pa density. No difference in 
exacerbation rate, pulmonary function and quality of life. No bacterial resistance.

Bilton et al (2006): n=53 double-blind, randomized; ciprofloxacin oral plus either 300 
mg/5mL nebulized TOBI b.i.d. or placebo, 2 weeks treatment, clinical outcome 
assessment at day 21. Results: consistent microbiological response but no statistical 
significant difference in clinical efficacy. 
Tobramycin inhalation powder (TIP™) has been developed for the suppressive management 
of pulmonary infection due to P. aeruginosa in CF subjects aged 6 years and older. TIP is 
supplied in hard capsules at 28 mg dosage strength, to be administered via the T-326 dry 
powder inhaler. Phase III clinical studies have shown efficacy and safety comparable to 
nebulized tobramycin (TOBI) but with faster administration time and improved portability 
(Konstan et al 2011b). Bronchiectasis is a major component of the CF lung disease.
TIP is intended to be developed for the treatment of chronic lung infection with P. aeruginosa
in symptomatic bronchiectasis patients, as documented by CT-structural changes. Given the 
benefits of inhaled tobramycin in CF patients and based on the preliminary results from pilot 
studies in BE patients with TOBI and also with inhaled gentamicin (Murray et al 2011), TIP is 
expected to show a reduction in bacterial load in BE patients which could translate into 


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reduction of clinical symptoms, reduction in rates of exacerbation and reduction in use of 
systemic antibiotics.
The pharmacokinetics of parenteral tobramycin do not differ significantly in CF patients 
compared with patients without CF when subject age, fat-free mass, sex and renal function are 
taken into consideration (Hennig et al 2013). 
Based on the known concentration-dependent killing of bacteria and a post-administration 
antibiotic effect of aminoglycosides, once daily (o.d.) parenteral administration of tobramycin 
is well accepted (Smyth et al 2005). Concentration-dependent killing means that the 
bactericidal action of aminoglycosides is related to the peak concentration of antibiotic 
achieved. Greater bactericidal effect occurs at concentrations exceeding the minimum 
inhibitory concentration (MIC). The post-administration antibiotic effect is a phenomenon in 
which the bactericidal action of the aminoglycoside continues even after the antibiotic has 
been cleared and its concentration has fallen below the MIC. These pharmacological 
properties suggest that aminoglycosides can be administered o.d. Therefore in this study a 
once-daily regimen will be evaluated and compared to b.i.d regimen.
This study has been developed and will be executed as part of the iABC (inhaled Antibiotics 
in Bronchiectasis and Cystic Fibrosis) project. iABC, as an IMI (Innovative Medicines 
Initiative) project, 
 
 The scope of 
the iABC project is to advance the development of two inhaled antibiotics (one of them being 
TIP) for patients with CF and BE. Novartis retains the role of the sponsor and as such is 
responsible for the regulatory and pharmacovigilance activities, including clinical trial
conduct. 
1.2
Purpose 
The purpose of this Phase II study is to support the selection of a safe and tolerable TIP daily 
dose, frequency of administration and regimen that exhibits effective bacterial reduction of P.
aeruginosa in non-CF BE patients with a history of exacerbations and who had at least one 
positive culture of P. aeruginosa in sputum in the last 12 months, and a positive culture at 
screening for P. aeruginosa. Data from this study will be used to provide guidance on the 
dose selection and frequency of administration for subsequent 
 studies. 
2
Study objectives and endpoints
2.1
Primary objectives

To evaluate the effect of different doses of TIP administered o.d. and one b.i.d. dose on 
the change in P. aeruginosa bacterial load in sputum as assessed by the change in colony 
forming units (CFUs) from baseline to Day 29 of treatment, each compared to placebo.

To assess the safety and tolerability with different doses of TIP administered o.d. and b.i.d. 
and different regimens (TIP and TIP/placebo cyclical) during the treatment epoch (112 
days) and during the follow-up epoch (56 days) for each as compared to placebo.


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2.2
Secondary objectives

To assess the effect of different doses of TIP administered o.d. and one b.i.d. dose and 
different regimens (TIP and TIP/placebo cyclical) on the frequency, rate (by patient-
months), severity and time to onset of pulmonary exacerbations at the end of the treatment 
epoch and over the entire study, each compared to placebo. 

To assess the efficacy profile of different doses of TIP administered o.d. and one b.i.d.
dose and different regimens (TIP and TIP/placebo cyclical), as measured by the time to 
first use, proportion of patients requiring anti-pseudomonal antibiotics (overall, oral, 
parenteral) and the duration of treatment of anti-pseudomonal antibiotics, each compared 
to placebo. 

To assess the time to first hospitalization, proportion of patients requiring hospitalization 
and the duration of hospitalization due to serious respiratory-related AEs (other than those 
regularly scheduled hospitalization that were planned prior to study start).

To assess the pharmacokinetic concentrations of tobramycin in serum and in sputum from 
different doses of TIP administered o.d. and one b.i.d. dose and different regimens (TIP 
and TIP/placebo cyclical).

To assess the antimicrobial efficacy of TIP over the entire study duration, as measured by 
the absolute change in P. aeruginosa colony forming units (CFU) in sputum from baseline 
to each post-baseline treatment visit and during the follow-up visits.

To evaluate the safety profile of TIP in terms of clinical laboratory results.

To evaluate the safety profile of TIP in terms of audiology findings throughout the 
treatment epoch (subgroup of all patients that are in enrolled at sites that are adequately 
equipped and trained to perform audiologic assessments).

To evaluate the safety profile of TIP in terms of acute change in forced expiratory volume 
at 1 second (FEV1) % predicted values from pre-dose to 30±15 minutes after completion 
of study drug administration at the clinical site at visits during the treatment epoch.

To evaluate the impact of treatment with TIP on the Respiratory Symptom Scale Quality 
of Life Questionnaire for Bronchiectasis (QOL-B) by measuring change from baseline to 
all post-baseline visits. 
2.3
Exploratory objectives
 


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
To explore the characteristics of the post-inhalational events at all visits during the 
treatment epoch.

To explore the impact of healthcare resource utilization of TIP treatment.
2.4
Objectives and related endpoints
Table 2-1
Primary objectives and related endpoints- Objectives 
OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure
Statistical
Analysis Section
Primary
To evaluate the effect of 
different doses of TIP 
administered o.d. and one
b.i.d. dose on the change in 
P. aeruginosa bacterial load 
in sputum as assessed by 
the change in colony 
forming units (CFUs) from 
baseline to Day 29 of 
treatment, each compared 
to placebo.
Title: P. aeruginosa density in sputum 
Unit of Measure: CFUs per mL
Description: Quantitative measurement for P. 
aeruginosa in pre-dose sputum samples 
measured by central lab as summarized in 
Section 6.4.1.
Time Frame: baseline, Day 29
Section 9.4
To assess the safety and 
tolerability with different 
Title: Safety and tolerability
Section 9.5.2


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure
Statistical
Analysis Section
doses of TIP administered 
o.d.and one b.i.d. and 
different regimens (TIP and 
TIP/placebo cyclical) during 
the treatment epoch (112 
days) and during the follow-
up epoch (56 days) for 
each as compared to 
placebo.
Unit of Measure: percentage of adverse events
Description: Rate and severity of local adverse 
events
Time Frame: baseline and post-baseline visits
3
Investigational plan
3.1
Study design
This is a blinded, randomized, dose and regimen finding trial utilizing a 3 treatment cohort 
design where active TIP doses or placebo in addition to the local standard care within each 
cohort are delivered once or twice daily. Approximately 180 eligible patients will be 
randomized to one out of the 3 cohorts in a ratio of 1:1:1. The patients within each cohort will 
be randomized to blinded TIP or placebo with the following randomization scheme: TIP: 
TIP/placebo cyclical: placebo, in a 2:2:1 ratio. In total, the study has nine treatment arms 
distributed among the 3 cohorts (see Section 5.1). Total duration of the study is expected to be 
up to 196 days with a total of 9 visits, consisting of up to 28 days for the screening epoch; 
after randomization a 112-day treatment epoch with 6 clinic visits, followed by a 56-day 
follow-up epoch with 2 clinic visits. Patients will be assessed for safety, tolerability and 
efficacy (see Assessment Schedule Table 6-1).
At an initial screening visit (Visit 1), informed consent will be obtained before any study 
related assessment or procedures are performed, inclusion/exclusion criteria will be assessed 
and current medications reviewed. All patients signing informed consent must be registered in 
the Interactive Response Technology (IRT).  The patients will commence a flexible 7-28 day 
screening epoch where all screening assessments will be performed and the presence of 
pulmonary bacterial colonization with P. aeruginosa based on sputum culture will be done. 
Patients who are otherwise eligible may be re-tested for P. aeruginosa in the sputum and/or 
laboratory evaluations during the screening epoch. Any patient can be re-screened once until 
enrollment has completed. Patients who had an exacerbation during the screening phase can 
be re-screened twice until recruitment has been completed. The P. aeruginosa bacterial load 
estimation will be done by quantitative identification using standard culture methods (Patel et 
al 2002). 
. At 
the completion of the baseline assessments on Day 1 (Visit 2), all patients who meet the 
eligibility criteria will be randomized to one of the three treatment cohorts and enter the 112-
day treatment epoch on the same day. The randomization by cohort and treatment arm will be 
stratified by use of macrolides. After Visit 101 (Day 1), the patients will attend a visit after 7 
days of treatment (Day 8, Visit 102).  The next visit is planned on Day 29 (Visit 103), and 
monthly thereafter (Day 57 Visit 104 to Day 113, end of treatment Visit 106). Following the 
treatment epoch, patients will enter the 56-day follow-up epoch (no study medication, but 


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baseline standard care according to the local guidelines) and attend two follow-up epoch visits 
(Visits 201 and 202). 
Figure 3-1
Study design 
3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.
This study is designed to find a dose and regimen 
 in non-CF BE 
patients with pulmonary P. aeruginosa infections. A parallel study design with three treatment 
cohorts is used to investigate three different TIP doses and regimens versus placebo. 
The study will implement a within-cohort blinding approach. If the study were blinded across 
all arms, all of the subjects in the study would need to inhale the maximal dose of 10 capsules 
every day to maintain the blind in a double-blind double dummy design (5 morning + 5 
evening). In previous double-blind studies in CF patients (EVOLVE and EDIT) it has been 
noted that tolerability of placebo was overall similar with that of TIP, being most likely driven 
by the amount of powder inhaled and its oro-pharyngeal deposition (Konstan et al 2011a, 
Konstan et al 2011b). In order to assess tolerability (defined by the rate of local AEs) related 
to the dose, within-cohort blinding is planned in this study. For each dose level, the patients 
will be randomized as follows: TIP:TIP/placebo cyclical: placebo in a 2:2:1 ratio. This 
randomization scheme will allow the analysis of tolerability across treatment arms within the 
same cohort for those patients on active study drug without bias from an open design, and will 
also permit comparison of efficacy outcomes to a pooled placebo group. The randomization 
scheme has been chosen to ensure that a total of 36 patients are randomized into the three 
cohorts to receive placebo (12 placebo patients per cohort) and also the number of patients 
between TIP/placebo cyclical and TIP are evenly distributed 24 patients per treatment arm. It 
______________________________________________________________
Day-28 
to -7
Day 1
Day 29
Day 57
Day 85 
Day 113
Day 141
Day 169
Day 8
End of 112-day 
Treatment Epoch
Study Completion
Baseline/
Randomization
Double-blind within treatment arm for Cohorts A, B, C
Screening
Epoch 
Cohort A:  3 capsules OD
Cohort B: 5 capsules OD
56-day Follow-up 
Epoch 
TIP 112 days (n=24)
TIP 112 days (n=24)
Placebo 112 days (n=12)
Cohort C: 4 capsules BID
TIP 112 days (n=24)
Placebo 112 days (n=12)
Placebo 112 days (n=12)
TIP (28 days TIP + Placebo 28 days) for 2 cycles (n=24)
TIP (28 days TIP + Placebo 28 days) for 2 cycles (n=24) 
TIP (28 days TIP + Placebo 28 days) for 2 cycles (n=24) 


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is not expected that the amount of placebo powder administered will influence efficacy 
measurements, therefore the placebo patients will be pooled (12 patients per dose, in total 36 
patients on placebo for the efficacy endpoint). Patients from both TIP and TIP/placebo 
cyclical treatment arms will be pooled within the same cohort for the primary endpoint 
measurement at Day 29, as they both receive the same active treatment during the first 28 
days. For further details about the analysis, see Section 9.4.
From the pilot studies in BE patients with the nebulized tobramycin solution it has been 
suggested that tolerability might be lower in BE patients compared to in CF patients, because 
of coughing, dyspnea or wheezing. The current design is able to assess the tolerability of 
different doses and regimens of TIP in this new indication. 
The number of arms and regimens were selected on the basis of the dose rationale below.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The planned doses to be administered in this study are 84 mg (3 capsules), 140 mg (5 capsules) 
once daily each and 112 mg (4 capsules) twice daily to identify the TIP dose that exhibits 
effective bacterial reduction in non-CF BE patients who had one positive sputum cultures in 
the last 12 months and a positive culture at screening. 
 
 
 The 112 mg twice daily dose has been established as the safe and effective 
dose for the treatment of patients with CF (Konstan et al 2011a, Konstan et al 2011b) and is 
used as reference dose in this study. The dose regimens selected for this study are chosen 
based on the early pilot studies with TOBI suggesting that BE patients may tolerate inhaled 
therapy less well than CF patients. Further, in the TPI001 study (Geller et al 2007), the 
sputum concentrations measured in CF patients after single doses of 3 capsules and 4 capsules  
provided similar tobramycin sputum concentrations with the ranges of Cmax largely 
overlapping, the mean slightly above 1000 µg/g sputum. The concentrations achieved for o.d. 
doses of 3 and 4 capsules of TIP in TPI001 study (Geller et al 2007) have largely exceeded 
the tobramycin MIC, including the MICs for highly resistant P. aeruginosa strains and hence 
were chosen for this study. The 5 capsule o.d. dose was chosen to evaluate whether it offers 
superior safety and efficacy compared to the approved 4 capsule b.i.d. dose. One capsule dose 
was considered, but not retained, because in the TPI001 study the tobramycin Cmax was 258 
µg/g sputum, which is close to the upper end of the tobramycin MIC range that is seen in 
some patients, creating a risk for selection of resistant strains.
Additionally, it is well established that the efficacy of tobramycin, an aminoglycoside, is 
driven by a concentration-dependent bactericidal effect (Maglio et al 2002, Scaglione and 
Paraboni 2006); therefore it is suited to once daily dosing, which would substantially enhance 
patient compliance. The use of tobramycin once daily intravenously in cystic fibrosis patients 
has been shown to be safe and effective (Smyth et al 2005, Whitehead et al 2002).
The treatment duration of 16 weeks (followed by 8 weeks follow-up) is chosen to test efficacy 
and safety beyond 4 weeks of treatment. Indeed, there is precedent from the TIP studies in the 
CF indication, that 4 weeks of treatment are sufficient to achieve bacterial suppression in the 
lungs (Konstan et al 2011a, Konstan et al 2011b). However based on the TOBI pilot study in 


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BE (Barker et al 2000) it is assumed that a duration of 4 weeks of treatment is too short to 
translate into improvement in clinical outcomes (reduction of exacerbations, use of i.v. 
antibiotics). A duration of 112 days allows to test two full cycles (28 days on-/ 28days off-
therapy) of cyclical dosing. With regards to the cyclical regimen (TIP/placebo cyclical 
treatment arms), it is thought that a single cycle is not sufficient to detect a clinical effect. For 
example, in ORBIT-2, using inhaled dual-release ciprofloxacin for inhalation (Serisier et al 
2013), the trends in exacerbation were only observed after the second treatment period. 
Clinical evidence in bronchiectasis is increasing to suggest that a continuous regimen also 
might be appropriate. Long-term studies in BE with continuous therapies (Murray et al 2011, 
Haworth et al 2014), have shown improvements in exacerbations and patient reported 
outcome (PROs). Murray et al (2011) (12 months daily inhaled gentamicin in BE patients, 
followed by 3 months off-treatment period) have shown a reduction in exacerbations 
(gentamicin group: 33.3% vs. saline: 80%). Notably, the treatment effect was lost after 3 
months follow-up. Authors have seen no emergence of resistance. Haworth et al (2014) in a 
double-blind placebo controlled study, 6-months daily therapy with colistin in BE patients, 
have shown in the overall population trends in favor of the therapy were shown, but which did 
not reach statistical significance (p=0.11). However, in the adherent patients, the delay in time 
to exacerbation was statistically significant (p=0.038). Therefore it is proposed to also test a 
continuous treatment regimen for 16 weeks, a duration that may allow to detection of trends in 
improving clinical outcomes and PROs, as compared to placebo. Further, 8 weeks of follow-
up will inform about the persistence of the clinical effects. Smith et al (1989) suggested that 
twelve weeks of continuous inhaled tobramycin treatment in CF patients led to increase in 
MIC. Recent studies of 12-months' and 6-months', respectively, duration (Murray et al 2011
and Haworth et al 2014) in BE patients, did not observe an increase in resistance that 
translated into a loss in clinical efficacy. Therefore, during the proposed phase II study, 
tobramycin MIC will be closely monitored at every visit and the microbiology data will be 
interpreted in the context of change in clinical response. 
 
3.4
Rationale for choice of comparator
Placebo is chosen as comparator since no approved active comparator is available for the 
indication under study. It is considered necessary to include placebo in order to determine 
which doses and frequency of regimen offer an efficacy benefit in terms of reduction of 
bacterial load. Both patients and investigators remain blinded to the assignment to active or 
placebo within the cohort. The subjects would be aware of the number of capsules and the 
frequency of daily administration of active and placebo that they have been assigned to but 
have no knowledge of whether they were allocated to active or placebo. 
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable. 
3.6
Risks and benefits 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria. 
All patients will be closely supervised in this study. Systemic antibiotic treatment is allowed, 


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upon investigator's decision, as needed depending on the patient’s condition (see Section 5.5.7
Concomitant treatment).
Tobramycin is an aminoglycoside that is active against Gram-negative bacteria including 
P. aeruginosa and has been used parenterally for many years for the treatment of Gram-
negative PPMs (including P. aeruginosa) in pulmonary infections, including BE. Its efficacy 
and safety profile is well-established. TOBI® (tobramycin inhalation solution, or TIS) has 
become the gold standard inhaled antipseudomonal treatment in CF since its launch in 1998. 
TIP was developed for use in the same CF population as TIS. The approved TIP dose for CF 
provides comparable sputum and serum pharmacokinetic exposures to the approved TIS dose 
with respect to tobramycin and has comparable safety and efficacy profiles. TIP is approved 
for use in CF 
 at the dose 112 mg (i.e. 4 capsules of 28 
mg each) twice daily. The pharmacokinetics of parenteral tobramycin do not differ 
significantly in CF patients compared with patients without CF when subject age, fat-free 
mass, sex and renal function are taken into consideration (Hennig 2013). Therefore the 
systemic exposure in BE is not expected to differ from the CF patients. Based on the serum 
pharmacokinetic data from previous studies of TIP in CF patients, a dose of 5 capsules is not 
expected to exceed the maximum threshold of 12 µg/ml for Cmax and 2 µg/ml for Ctrough. 
Increased variability can be expected in subjects treated with 5 capsules compared to 3 
capsules of TIP. To assess the pharmacokinetic properties of tobramycin from TIP in BE 
patients and to develop a PK model, tobramycin concentrations in serum and sputum will be 
measured.
The safety and tolerability profile of TIP in BE patients is not yet established. The highest 
daily dose planned to be tested in this study is the dose that has been demonstrated to be safe 
and effective in CF patients. The phase II study will define a dose that is effective in 
suppressing clinically relevant bacterial pathogens which is also safe and well tolerated. Renal 
and oto-toxicity will be monitored.
4
Population
The study population will consist of approximately 180 male and female BE patients ≥18 
years old with clinical diagnosis of non-CF bronchiectasis confirmed radiologically by CT 
scan, a history of exacerbations requiring systemic antibiotic administration and who had one 
positive culture for P. aeruginosa in sputum in the last 12 months and a P. aeruginosa
positive culture at screening. Patients also should have an FEV1 of at least 30% predicted. It is 
anticipated that approximately 260 patients will need to be screened in order to randomize 
approximately 180 patients across 3 cohorts of the study with a cohort randomization ratio of 
1:1:1 and within each cohort a ratio of 2:2:1 for TIP:TIP/placebo cyclical:placebo 
randomization. Patients will be stratified by use of macrolides.
4.1
Inclusion criteria
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed. 
2. Male and female patients of ≥ 18 years of age at screening (Visit 1).


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3. Proven diagnosis of non-CF BE as documented by computed tomography or high-
resolution computed tomography and as assessed by the investigator. 
4. At least 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation 
requiring parenteral antibiotic treatment within 12 months prior to screening.
5. FEV1 ≥ 30% predicted at screening (Visit 1).
6. A stable regimen of local standard treatment for BE (treatments unchanged for 28 days 
prior to randomization).
7. P. aeruginosa, must be documented in a respiratory sample (expectorated sputum, deep-
throat cough swab, oro-pharyngeal swab, broncho-alveolar lavage) at least 1 time within 
12 months (at least 28 days prior to Visit 1) and also present in the expectorated sputum 
culture at Visit 1.
8. Must be known sputum producers with a history of daily expectoration. 
9. Able to use the T-326 Inhaler as instructed in the protocol in the opinion of the 
investigator. 
10. Clinically stable pulmonary status in the opinion of the investigator.
11. Patients performing daily airway clearance.
4.2
Exclusion criteria
Patients/subjects fulfilling any of the following criteria are not eligible for inclusion in this 
study. No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients/subjects.
1. Patients with a history of cystic fibrosis.
2. Patients with a primary diagnosis of bronchial asthma.
3. Patients with a primary diagnosis of COPD associated with at least a 20 pack year 
smoking history.
4. Current smokers at Visit 1 or not stopped smoking within 4 weeks prior Visit 1.
5. Signs and symptoms of acute pulmonary or non-pulmonary conditions.
6. 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.
7. History of local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics 
(other than bronchial hyperreactivity).
8. Any patient with lung cancer or a history of lung cancer.
9a. Any patient with active cancer or a history of cancer with less than 2 years disease-free 
survival time (whether or not there is evidence of local recurrence or metastases). 
Localized basal cell carcinoma (without metastases) of the skin is acceptable. Patients 
with a history of cancer (excluding lung cancer) and 2 years or more disease-free survival 
time may be included.
10a.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 


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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. 
11. Patients whose body mass index is less than 15 or greater than 40 kg/m2.
12. Patients requiring long-term oxygen therapy for chronic hypoxemia. This is typically 
patients requiring oxygen therapy >15 h per day delivered by home oxygen cylinder or 
concentrator.
13. Patients who have had a pulmonary exacerbation requiring systemic glucocorticosteroid 
treatment and/or antibiotics in the 4 weeks prior to Visit 1. In the event of an exacerbation 
occurring during the screening epoch, the patient must discontinue from the study. The 
patient may be rescreened once the inclusion/exclusion criteria have been met.
14. Patients with active pulmonary tuberculosis. 
15. Patients currently receiving treatment for nontuberculous mycobacterial (NTM) 
pulmonary disease.
16. Patients with one or more positive cultures in the last 12 months for Mycobacterium. 
avium complex, M. abscessus complex, M. kansasii, M. malmoense, M. xenopi, M. simiae
or M. chelonae, unless all subsequent NTM cultures (at least two) are negative and in the 
opinion of the investigator the patient does not meet ATS criteria for NTM-pulmonary 
disease. 
17. Hemoptysis of more than 60 mL at any time within 30 days prior to study drug 
administration (Visit 101).
18a.Estimated glomerular filtration rate (eGFR) of 50 mL/min/1.73m2 or less, or an abnormal 
urinalysis defined as 2+ or greater proteinuria at screening (Visit 1).
19. Patients with clinically significant laboratory abnormalities (not associated with the study 
indication) at screening (Visit 1).
20. Patients with primary immunodeficiency receiving immunoglobulin therapy.
21a. Patients with primary ciliary dyskinesia (PCD) may be eligible if their hearing threshold 
at screening audiometry is 25dB or lower at frequencies 0.5-4 kHz.
22. Patients with active allergic bronchopulmonary aspergillosis.
23. Patients with an organ and bone marrow transplant/graft versus host disease.
24. Patients with haematological malignancies.
25. Patients with other clinically significant conditions (not associated with the study 
indication) at screening which might interfere with the assessment of this study.
26. Patients who are receiving inhaled anti-pseudomonal antibiotic within 28 days prior to 
study drug administration (Visit 101).
27. Any use of systemic anti-pseudomonal antibiotics within 28 days prior to study drug 
administration (Visit 101).
28. Use of loop diuretics, i.v. urea, i.v. mannitol within 7 days prior to study drug 
administration (Visit 101).
29. Patients receiving any medication that may influence the response to treatment. Prohibited 
medications: immunomodulators (cyclosporine, tacrolimus, anti-TNF alpha, 
steroids >15mg/day, alpha 1 antitrypsine, methotrexate, azathioprine, immune globulins 
(IV or subcutaneous), Prolastin, anti-cytokines).


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30. Initiation of treatment with chronic macrolide therapy within 28 days prior to study drug 
administration (subjects may be taking chronic macrolide therapy at the time of 
enrollment into the study, but they must have initiated treatment more than 28 days prior 
to Visit 101, study drug administration).
31. Use of any other investigational drug within 30 days prior to screening (Visit 1) or 5 half-
lives, whichever is longer.
32. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
33b.Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 1 day after stopping of study medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). 

Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment is she considered not of child bearing 
potential.
34. Patients unable to successfully use a dry powder inhaler device or perform spirometry 
measurements.
35. Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic Patient Diary.
36. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study such as:


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
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
TIP is a drug-device combination product consisting of tobramycin dry powder for inhalation 
in capsules (TBM100 28 mg inhalation powder hard capsule) administered by the T-326 
Inhaler. The test product consists of capsules of TIP at 28 mg dosage strength. The matching 
placebo is provided in hard capsules containing placebo particles consisting of DSPC (1,2-
distearoyl-sn-glycero-3-phosphocholine) and calcium chloride (CaCl2). Three different dose 
regimens for the test product and placebo are investigated in this study. 
A dose will always consist of sequential inhalation of the content of the number of prescribed 
capsules.
5.1.2
Additional treatment
No additional treatment beyond investigational treatment is requested for this trial. Patients 
will be allowed standard of care, as defined locally.
5.2
Treatment arms
Patients will be randomized to the following three cohorts in a ratio of 1:1:1. Blinding will be 
done within each cohort. Patients will be further randomized within each cohort to one of the 
three treatment arms: TIP, TIP/placebo cyclical, or placebo with a randomization ratio of 
2:2:1. 
Cohort A:

TIP: Three capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T-326 
Inhaler, for 112 days (on treatment). The total daily dose and each treatment therefore 
consists of 84 mg tobramycin (3 capsules of 28 mg each),

TIP/placebo cyclical: patients will take same doses, i.e. 3 capsules o.d., by alternating TIP 
28-days with placebo 28-days for two cycles for a total of 112 days.

Placebo: The reference product consists of placebo capsules (DSPC/CaCl2). The dose 
regimen for the reference product is three capsules blinded, inhaled o.d. via the T-326 
Inhaler, for 112 days (on treatment).


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Cohort B:

TIP: Five capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T-326 
Inhaler, for 112 days (on treatment). The total daily dose and each treatment therefore 
consists of 140 mg tobramycin (5 capsules of 28 mg each).

TIP/placebo cyclical: patients will take same doses, i.e. 5 capsules o.d., by alternating TIP 
28-days with placebo 28-days for two cycles for a total of 112 days.

Placebo: The reference product consists of placebo capsules. The dose regimen for the 
reference product is five capsules blinded, inhaled o.d. via the T-326 Inhaler, for 112 days 
(on treatment).
Cohort C:

TIP: Four capsules of blinded TIP at 28 mg dosage strength, inhaled b.i.d. in the morning 
and in the evening via the T-326 Inhaler, for 112 days of treatment. Each dose therefore 
consists of 112 mg tobramycin (4 capsules of 28 mg each), the total daily dose 
corresponds to 224 mg tobramycin (112 mg b.i.d.),

TIP/placebo cyclical: patients will take same doses, i.e. 4 capsules b.i.d., by alternating 
TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Placebo: The reference product consists of placebo capsules. The dose regimen for the 
reference product is four capsules blinded, inhaled b.i.d. via the T-326 Inhaler, for 112 
days (on treatment).
The treatment epoch is followed by a 56-day follow-up epoch (no study treatment).
5.3
Treatment assignment and randomization 
At Visit 101 (see Table 6-1), all eligible patients/subjects will be randomized via Novartis 
Interactive Response Technology (NIRT) to one of the treatment arms with the randomization 
stratum (use of macrolides as part of their standard of care therapy). The investigator or 
his/her delegate will contact the NIRT after confirming that the patient fulfills all the 
inclusion/exclusion criteria. The NIRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of investigational treatment to be dispensed to the patient. The 
randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Novartis IRT (NIRT) provider using a validated 
system that automates the random assignment of patient numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization by cohort and treatment arm will be stratified by use of macrolides.
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group.


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5.4
Treatment blinding 
The study will implement a within-cohort blinding approach (for details see Section 3.2).
Patients/subjects, investigator staff, persons performing the assessments, and data analysts 
will remain blind to the identity of the treatment from the time of randomization until 
database lock, using the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study.

The identity of the treatments within-cohort will be concealed by the use of study drug
that are all identical in packaging, labeling, schedule of administration, appearance, taste, 
and odor.
The randomization codes associated with patients/subjects from whom PK samples are taken 
will be disclosed to PK bioanalysts who will keep PK results confidential until database lock.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9), request 
from the Novartis study-independent safety review team, request from the Data Monitoring 
Committee if needed for the safety interim analysis (Section 8.4) or as an outcome of their 
evaluation and at the conclusion of the study. Health authorities will be granted access to 
unblinded data if needed. Any patient whose treatment code has been broken inadvertently or 
for any non-emergency reason will be discontinued from treatment.
Each center shall identify individuals(s) called Independent Study Coordinators (ISC) 
responsible for dispensing study drug to the patient, assisting and supervising the patient with 
the first inhalation at the site during Visit 101, and supervising the patient whilst inhaling 
study drug at Visits 102 thru 106 (last inhalation). The ISC are independent of the study team 
in that they do not perform any patient assessments or study activities. The ISCs must not 
discuss the characteristics of the trial drug with the patients, the investigator(s) or any study 
staff responsible for evaluating patients, or Novartis personnel involved in conducting, 
monitoring, or analyzing data in this trial.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed of the site 
number assigned by Novartis and a sequential number assigned by the IRT. Once assigned to 
a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the investigator or his/her staff will contact the IRT 
and provide the requested identifying information for the patient to register them into the IRT. 
The site must select the eCRF book with a matching Subject Number from the EDC system to 
enter data. 


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If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being randomized will be entered on the Screening 
epoch Study Disposition CRF.
5.5.2
Dispensing the study drug 
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance specific for each dose level. Active and placebo packaging will be matching for 
each dose level.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 9 treatment arms. Investigator staff will 
identify the investigational treatment package(s) to dispense to the patient by contacting the 
IRT and obtaining the medication number(s). Immediately before dispensing the package to 
the patient, the ISC or appropriate independent investigator staff will detach the outer part of 
the label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique subject number. 
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Quality 
Assurance per the procedure provided by the Field Monitor.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and empty blisters from Visit 102, through Visit 
106 or at the time of discontinuation of study treatment (TD). 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.


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5.5.4
Instructions for prescribing and taking study treatment 
The study drug (TIP or placebo) will be dispensed by the ISC at Visit 101 (start of treatment) 
and Visit 103 through Visit 106. Each patient will receive a kit of investigational treatment 
containing the medication for 28 days of treatment. For dosing visits 103, 104 and 105 study 
drug administered during the visit should be taken from the newly dispensed kit. At Visit 106, 
the study drug administered during the visit should be taken from the kit dispensed at Visit 
105. Each kit contains five weekly boxes with each weekly box containing an inhaler and the 
required number of blister cards for one week dosing. The content of the fifth weekly box 
serves as a reserve in case a reserve inhaler is needed and provides supply until the next 
scheduled visit.  Instructions for use for the T-326 Inhaler are given in Appendix 4 and will be 
handed out to the patient at Visit 101. Use of the reserve supply will be recorded on the 
appropriate CRF. 
Patients will be provided with medication as described in Section 5.2.
The ISC will train the patient and assist and supervise the patient with the first inhalation at 
the site during Visit 101 by using instructions for use of T-326 Inhaler, describing in detail 
how to handle the drug-device combination. The ISC will also assist and supervise the 
patient’s inhalation of the study drug at Visit 102 (Day 8) through Visit 106 (Day 113) or at 
the study treatment discontinuation visit (TD) if applicable. Detailed instructions for use are 
included in Appendix 4. In summary, each capsule containing the study medication has to be 
removed one at a time from the blister card, inserted into the T-326 Inhaler, the inhaler 
actuated and the study drug inhaled according to instructions. Patients are instructed to 
perform two inhalations and breath-hold maneuvers for each capsule by default, then verify 
that the capsule has been emptied completely and inhale again as necessary.
The last administration of study medication will be in the morning at Visit 106 (Day 113). 
Administration of any short-acting bronchodilator should occur 15 to 90 minutes prior to the 
spirometric assessments. Any other inhaled medications should have been taken prior to 
administration of study drug and any chest physiotherapeutic measures shall have been 
completed previously. If applicable, any long-acting bronchodilator prescribed to the patient 
should have been taken within the last 12 hours prior to the spirometric assessments; 
otherwise a short-acting bronchodilator shall be taken as described above. Also, the 
examinations which should be performed before study drug inhalation defined in Table 6-1
need to be completed prior to study drug administration. To ensure a robust and valid 
assessment of FEV1 at each assessment it is important that these are done consistently at a 
similar time of day (to account for diurnal effects) and following consistent use (or not) of 
prior bronchodilator therapy. 
All dosages prescribed and dispensed to the patient must be recorded on the Dosage 
Administration Record CRF.
All kits of investigational treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.


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If any faults or complaints are identified with the device, these should be returned to Novartis 
with a completed Device Return Form. The forms will be supplied to each investigator site by 
the Field Monitor.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study drug dose adjustments are not permitted.
The patients with pulmonary exacerbations will continue in the study as scheduled once they 
have recovered and discontinued antibiotics administered for the exacerbation. If the patient 
continues in the study after the interruption of the study drug treatment, the schedule of 
visit/treatment cycle should be aligned with the original visit schedule. 
Any interruption of the inhalation of study drug treatment must be recorded on the Dosage 
Administration Record CRF.
5.5.6
Rescue medication
Rescue medication for pulmonary exacerbations (including systemic antibiotics) and for 
bronchospasm is allowed. For concomitant treatments permitted see Section 5.5.7. Use of 
rescue medication must be recorded on the Concomitant medications/Significant non-drug 
therapies CRF.
5.5.7
Concomitant medication 
If a patient experiences a pulmonary exacerbation and/or worsening of the disease condition, 
he/she will be treated as deemed appropriate by the investigator. Following treatment for the 
pulmonary exacerbation and/or worsening of the disease condition, the patient will be 
expected to continue in the study as scheduled provided, in the opinion of the investigator, 
he/she can be safely returned to their pre-pulmonary exacerbation concomitant medications. 
In addition, if the patient requires any prohibited treatment listed in Table 5-1, then he/she 
should be withdrawn from the study medication.
The following treatments are permitted between Visit 101 and the completion of the 
study/termination visit and should be accurately documented in the CRF:

Antibiotics (parenteral or by mouth) are allowed for the treatment of pulmonary 
exacerbations as dictated by the patient’s condition.

Inhalation of study medication must be interrupted during i.v. aminoglycoside therapy. 
A window of 12 hours is recommended between stop of the study medication and 
initiation of i.v. aminoglycosides. Patients should restart inhalation of study 
medication within 24 hours after completing the i.v. treatment in order to complete 
the 112-day treatment epoch as close as possible to their initial study schedule, 
following completion of the course of i.v. aminoglycoside therapy.

Inhalation of study medication may continue upon physician’s decision, if the 
antibiotics used are other than aminoglycosides.

Pre-planned systemic antibiotics in the absence of an AE (prophylaxis of pulmonary 
exacerbation) are permitted only during the follow-up epoch.


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
Short term treatment (of a maximum of 28 consecutive days) with corticosteroids for the 
treatment of pulmonary exacerbations or other adverse events

Macrolides (anti-inflammatory regimen):

Patients should have been initiated on oral chronic macrolide therapy (i.e. macrolides 
prescribed for more than 14 days) more than 28 days prior to study drug 
administration (Visit 101) and should remain on treatment through the 
completion/termination visit. 

Bronchodilators:

Patients should have been kept on the same regimen more than 28 days prior to the 
first study drug administration (Visit 101) through the completion/termination visit. If 
patients are on short-acting bronchodilators, they should be consistently used prior to 
each assessment and inhaled 15 to 90 minutes prior to any spirometric assessments. 
Long-acting bronchodilators should be inhaled at least 12 hours prior to any
spirometric assessments.

To ensure a robust and valid assessment of FEV1 at each visit, it is recommended that 
these are done consistently at a similar time of day (to account for diurnal effects) and 
following consistent use (or not) of prior bronchodilator therapy. 

Inhaled corticosteroids:

Patients should have been initiated on therapy more than 28 days prior to study drug 
administration (Visit 101) and should remain on an unaltered regimen through the 
completion/termination visit.

Use of oxygen is allowed for acute events, such as exacerbation. Long-term oxygen 
therapy for chronic hypoxemia over >15 h per day is not allowed.
Selected information for all antibiotics and macrolides, corticosteroids and bronchodilators 
administered within 12 months prior to screening will be recorded in the CRF.
Caution for concomitant use
Based on the interaction profile for tobramycin following intravenous and aerosolized 
administration, concurrent and/or sequential use of TIP with other drugs with neurotoxic, 
nephrotoxic, or ototoxic potential should be avoided.
Other medicinal products that have been reported to increase the potential toxicity of 
parenterally administered aminoglycosides include:

amphotericin B, cefalothin, polymyxins (risk of increased nephrotoxicity);

platinum compounds (risk of increased nephrotoxicity and ototoxicity);

anticholinesterases, botulinum toxin (neuromuscular effects).
If the patient’s condition/disease requires medications (including those listed above) which 
may potentially affect the systemic tobramycin levels (even the study drug is tobramycin
inhalation powder), continuation of inhalation of study medication is at the investigator’s
discretion.

If inhalation of study medication is continued during the following drug therapy, patients


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will continue with the study schedule for the remainder of the study; however, therapeutic
drug monitoring is strongly recommended.

If inhalation of study medication is interrupted during the following drug therapy (either
as a routine measure or due to elevated serum tobramycin levels), patients should restart
inhalation of study medication in order to complete the 112-day treatment epoch as close 
as possible to their initial study schedule. 
Caution should be exercised when prescribing TIP to patients with known or suspected 
neuromuscular disorders such as myasthenia gravis or Parkinson’s disease. Aminoglycosides 
may aggravate muscle weakness because of a potential curare-like effect on neuromuscular 
function.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of the study 
treatment administration (Visit 101). If a prohibited medication is taken between start of study 
treatment administration and end of the treatment epoch, study drug must be discontinued.  If 
taken during the follow-up epoch, the prohibited medication should be stopped as soon as 
possible. Use of the prohibited medication should be documented in the appropriate section of 
the CRF.
Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in 
serum and tissue. TIP should not be administered concomitantly with ethacrynic acid, 
furosemide, urea, or intravenous mannitol.
Table 5-1
Prohibited medications requiring study drug discontinuation
Medication
Inhaled antibiotics except as per protocol
loop diuretics*
urea (intravenous)*
mannitol (intravenous)*
Cyclosporine
Tacrolimus
anti-TNF alpha
long-term treatment with corticosteroids >15mg/day (more than 28 days)
alpha 1 antitrypsine replacement therapy (Prolastin)
Methotrexate
Azathioprine
immune globulins (IV or subcutaneous)
anti-cytokines
Any other investigational treatments
Long-term oxygen therapy >15h per day
* Potential for nephrotoxicity


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5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis (or CRO) monitor for the site and the Study Team that 
the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
Study drug must be discontinued after emergency unblinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken.
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol. Completion of the study will be when the last patient has 
completed Visit 202.
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up. This care may include resuming of their standard of care 
treatment as deemed by their physician.
5.6.2
Discontinuation of Study Treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish 

Non-compliance of the patient with study procedures or investigator instructions, as per 
the investigator’s judgment 


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
Emergence of AEs when worsened from baseline (Visit 2) or any newly occurring 
development of AEs with regards to the following:

If a patient is found to have a 20-dB or greater decrease in auditory acuity at one or 
more frequencies in 1 or both ears due to sensorineural deficit, the patient will be 
withdrawn from treatment and monitored until auditory acuity values return to the 
most recent pre-dose value (either at screening or baseline) or until study closure, 
whichever occurs first, i.e. the patient must be withdrawn from study treatment but 
should continue in the study. In case no pre-dose value is available for comparison, 
discontinuation of the study treatment and withdrawal of the patient from the study 
should be based on the investigator’s best medical judgment. 

Any of the following laboratory abnormalities when worsened from baseline (Visit 101) 
or are a newly occurring AE:

Proteinuria ≥3+, as confirmed according to Section 14, Appendix 2 Specific Renal 
Alert Criteria and Actions

Serum creatinine increase ≥50% compared to baseline, as confirmed according to 
Section 14, Appendix 2 Specific Renal Alert Criteria and Actions

Estimated glomerular filtration rate (GFR) of ≤50 mL/min/1.73m2

Pregnancy (see Section 6.5.8 and Section 7.6)

Use of any of the prohibited medications detailed in Table 5-1 and Section 5.5.8.

Any situation in which study participation might result in a safety risk to the patient.
Any renal finding needs to be followed up according to Section 14 Appendix 2 Specific Renal 
Alert Criteria and Actions, which lists additional laboratory abnormalities that may require 
study treatment discontinuation based on clinical judgement. Confirmed renal events need to 
be followed up and documented according to Section 14 Appendix 2.
Patients who interrupted study medication based on the investigator’s decision should 
continue in the study, as per the visits and assessment schedule (see Section 5.5.5) -
interruption of study treatment does not necessarily mandate withdrawal from the study.
Patients who discontinue study medication should NOT be considered withdrawn from the 
study. The patient should return to the clinic as soon as possible, after discontinuation of study 
drug, for a study treatment discontinuation visit and then enter the 2-month follow-up epoch. 
Treatment discontinuation visit assessments detailed in the “treatment discontinuation visit” 
(TD) in Table 6-1 should be completed and recorded in the CRF. If they fail to return for 
these assessments for unknown reasons, every effort should be made to contact them as 
specified in Section 5.6.4. The investigator must determine the primary reason for the 
patient’s premature discontinuation of study treatment and record this information on the 
Dosage Administration CRF.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits: 

new / concomitant treatments

adverse events/Serious Adverse Events


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If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone contact should preferably be done according to the study visit schedule.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 

Does not want to participate in the study any longer, and 

Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in 
assessment table (Table 6-1.)
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
All biological samples not yet analyzed at the time of withdrawal will no longer be used, 
unless permitted by applicable law. They will be stored according to applicable legal 
requirements.
The investigator must also contact the IRT to register the patient’s withdrawal from the study.
Patients who prematurely discontinue study treatment or withdraw from the study will not be 
replaced.
5.6.4
Loss to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.


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5.6.5
Early study termination by the sponsor 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
The study will consist of a screening epoch, a 112-day treatment epoch and a 56-day follow-
up epoch after the last treatment.
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible.
All data obtained for these assessments must be supported in the patients’ source 
documentation. Visit 2 (baseline) and Visit 101 are performed on the same day (Day 1). 
Patients are required to complete specific ‘baseline assessments (Inclusion/Exclusion criteria) 
as part of Visit 2 prior to being randomized and moving into the treatment epoch (Visit 101).
Missed or rescheduled visits should not lead to automatic discontinuation. 
Patients/subjects who prematurely discontinue the study for any reason should be scheduled 
for a visit as soon as possible, at which time all of the assessments listed for the final visit will 
be performed. At this final visit, all dispensed investigational product should be reconciled 
and the adverse event and concomitant medications reconciled on the CRF.
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last administration of study treatment. 
The PRO questionnaires should always be completed before any other assessments at a study 
visit. The following assessments should be performed prior to dosing for applicable visits:

Physical examination

Vital signs

Body weight

Serum specimen for Safety Laboratory

Serum pregnancy test

Urine pregnancy test

Urinalysis

Sputum specimens (2 separate specimens)  for central analysis

Pre-dose serum specimen for PK sub-study (if applicable)

Audiology at Visit 2

Pre-dose spirometry


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Table 6-1
Assessment schedule
Visits should occur on the designated day, or as close to it as possible.
Epoch
Screen
Treatment
Follow-up
Visit
1
2*
101*
102
103
104
105
106 or
TD 
201
202 or 
PSD
Day
-28 to -7
1
1
8
29
57
85
113 
141
169
Obtain informed consent
X
Contact IRT
S
S
S
S
S
S
S
S
Randomization via NIRT
S
Demographics
X
Relevant Medical history
X
BE-related Medical History 
X
Smoking history
X
Pulmonary exacerbations history
X
Inclusion/exclusion criteria check
X
X
Physical examination b
S
[S]a
S
S
S
S
S
Vital signs b
X
X
X
X
Height
X
Body weight b
X
X
X
X
ECG
S
Collection of most recent available digital CT-scan
X
Serum specimen for safety laboratory assessment 
(standard: hematology, serum chemistry) 
 
X
X
X
X
X
X
X
X
X
Urinalysis (standard) b
X
X
X
X
X
X
X
X
X
Serum pregnancy test b, d
X
X
Urine pregnancy test b, d
X
X
Sputum specimen analyzed locally for P. aeruginosa
S


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Epoch
Screen
Treatment
Follow-up
Visit
1
2*
101*
102
103
104
105
106 or
TD 
201
202 or 
PSD
Day
-28 to -7
1
1
8
29
57
85
113 
141
169
Pre-dose sputum specimens (2 separate specimens)  for 
central analysis (microbiology, 
 
)
X
X
X
X
X
X
X
X
Serum specimen for PK tobramycin 
concentration f
0-1 hour post-dose
X
X
1-2 hour post-dose
X
X
Sputum specimen for tobramycin 
PK concentration g
0-1 hour post-dose
X
1-2 hour post-dose
X
3-4 hour post-dose
X
5-6 hour post-dose
X
Serum specimen for PK sub-study h
Pre-dose
X
X
0-1 hour post-dose
X
X
1-2 hour post-dose
X
X
3-4 hour post-dose
X
X
5-6 hour post-dose
X
X
Audiology i
Xp
Xb
X
X
X
X
Xj
Xj
Spirometry k
Routine
X
X
X
Pre-& 30±15 min 
post dose 
X
X
X
X
X
X
QOL-B, 
X
X
X
X
X
X
X
X
Inhalation Device Training m
S
Dispense study drug via IRT
S
S
S
S


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Epoch
Screen
Treatment
Follow-up
Visit
1
2*
101*
102
103
104
105
106 or
TD 
201
202 or 
PSD
Day
-28 to -7
1
1
8
29
57
85
113 
141
169
Administer study drug at site n
X
X
X
X
X
X
Study drug accountability
S
S
S
S
S
Review Concomitant medication
X
X
X
X
X
X
X
X
X
Patient electronic 
diary (e-diary)
Issue patient e-diary
S
Download and review patient e-diary
S
S
S
S
S
Collect  patient e-diary
S
AE/SAE recordings (including pulmonary exacerbations)
X
X
X
X
X
X
X
X
X
X
Record Respiratory-related Hospitalizations 
X
X
X
X
X
X
X
X
X
Review Surgery and Procedures
X
X
X
X
X
X
X
X
X
Record Post inhalation events 
X
X
X
X
X
X
Complete Study Disposition page (Screening)
X
Complete Study disposition page (End of Treatment)
X
Complete Study disposition page (Follow-Up)
X
Conduct QOL-B exit interview (subset of patients) o
X
TD = Study treatment discontinuation; PSD = Premature subject/patient discontinuation
X = assessment to be recorded on clinical data base
S = these assessments are source documentation only and will not be entered into the CRF
* Visit 2 (baseline) and Visit 101 are performed on the same day (Day 1). Patients are required to complete specific ‘baseline assessments (Inclusion/Exclusion criteria) 
prior to being randomized and moving into the treatment epoch (Visit 101).
a The physical exam will be repeated at Visit 2 only if findings at previous visit are abnormal and clinically significant.
b To be performed prior to dosing. 
d Obtain only for females of child-bearing potential. 
e Pre-dose sputum specimens (2 separate specimens) will be collected from each patient for central analysis (one each for microbiology 
 
). If a patient is unable to expectorate, one induced sputum specimen will be taken at baseline. For all post-baseline visits, a deep-throat cough 
swab can be collected from non-sputum producing patients for microbiology.


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f All subjects will have post-dose serum specimens collected during specified time windows. The time interval is measured from the completion of study drug
administration.  There must be a minimum of one hour difference between consecutive sampling points. Samples may be obtained from a peripheral site by phlebotomy 
or through a temporary i.v. site, but not through an existing central access or catheter. A patient who discontinues early and is on study medication will be asked to 
provide an extra serum specimen at the treatment discontinuation visit.
g All patients will have post-dose sputum specimens collected for PK testing  during specified time windows. The time interval is measured from the completion of study 
drug administration. In patients who are not able to spontaneously produce sputum, one specimen of induced sputum post-dose per specified interval will be collected. No 
induced sputum sample for PK will be collected at baseline in patients who had induced sputum pre-dose for microbiology assessments. A patient who discontinues early 
and is on study medication will be asked to provide an extra sputum specimen at the treatment discontinuation visit.
h Subjects in the serum PK sub-study will have a pre-dose serum specimen collected prior to administration of study drug. A patient who discontinues early and is on 
study medication will be asked to provide a pre-dose serum specimen at the treatment discontinuation visit. 
i Audiological assessments will be conducted at selected study sites or in patients with oto-toxic events. Auditory acuity will be measured at frequencies from 250 to 
8000Hz using a standard dual-channel audiometer. Audiology can be performed within 3 days of the assigned visit.
j If  audiology is normal up to and including the end of the treatment epoch (Visit 106), audiological examination is not needed at Visits 201 and 202.
k Spirometric measurements shall be conducted at approximately the same time of day to minimize effects of diurnal variability in lung function. 
l  PROs to be completed for whom a validated version in a language well understood by the patient is available. 
 
 1. QOL-B, 
 
m Identical training regardless of treatment arm.
n   The ISC will assist subjects in conducting the first study drug inhalation (Visit 101), while the inhalation of the study drug at Visits 102, 103, 104,105 and 106 (last study 
drug inhalation) at the study site is performed by the subject in the presence of the ISC.
n If a patient prematurely discontinues study drug , study drug administration in the presence of the ISC, study drug accountability, post-dose spirometry  and post-
inhalation events should be assessed at the TD visit provided the patient agrees to inhale study medication during the visit.  
o   Exit interviews should be conducted by telephone at the last follow-up visit after completion of the PRO questionnaires and preferably prior to other assessments. 
Approximately 25 patients are planned to be recruited.
p Patients with a past history of clinically significant hearing loss in the opinion of the investigator and patients with primary ciliary dyskinesia (PCD) may be eligible only if 
their hearing threshold at screening audiometry is 25dB or lower at frequencies 0.5-4 kHz.


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6.1
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next epoch
will have the study completion page for the screening epoch, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, ethnicity, and source of patient referral. Relevant medical history 
or current medical condition data include data present before signing informed consent. 
Where possible, diagnoses and not symptoms will be recorded. History of pulmonary 
exacerbations will be collected on a specific medical history CRF.
A standard 12 lead ECG will be performed at screening (Visit 1).  For eligibility in the study 
the interpretation of the tracing must be made by a qualified physician and documented.  The 
original ECGs, appropriately signed, should be collected and archived at the study site.
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection is ECG collection first, followed by 
vital signs, blood sampling, and spirometry. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. If the ECG 
findings are clinically relevant and would prevent the patient from participating in the study 
(taking into account the overall status of the patient as well as the medication profile), the 
patient should be recorded as a screen failure, should NOT be randomized and should not 
receive treatment. 
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF page as appropriate.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
Conditions associated with bronchiectasis disease and signs or symptoms including etiology 
and age at diagnostic will be captured by using a specific BE-related Medical History CRF 
page. 
Baseline data (using a specific CRF as necessary) such as spirometry, previous hospital 
admissions and exacerbations, baseline Medical Research Council (MRC) breathlessness 
score, colonization with P. aeruginosa and other organisms, and radiological changes will be 
collected for calculation of the Bronchiectasis Severity Index (BSI) for all patients. The BSI 
will serve as a disease-specific severity assessment tool (Chalmers et al 2014).


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Previous medication to be listed includes information for all antibiotics and macrolides 
administered within the last 12 months prior to Visit 1.
A sputum sample is required to be collected at Visit 1, cultured locally at the site and tested 
for the presence of P. aeruginosa, to ensure patients meet the inclusion criteria. 
6.2.1
Chest CT-scan
For each patient all reconstructed series from the most recent available digital computed 
tomography (CT) chest scan images will be sent to the Central Reader for advanced 
centralized image analysis. Before sending CT images to the Central Reader by secure file 
transfer protocol (SFTP) server, courier or eRoom, all images will be de-identified. For each 
patient CT images will be scored for the presence or absence of BE. Furthermore, all CT
images will be scored using the Bauman and Hartmann scoring systems to quantify the 
presence and extend of key lung disease features including BE, airway wall thickening, 
trapped air, parenchymal abnormalities and nodules. In addition for a subset of random 
selected CT images, advanced image analysis of the most appropriatie series for each CT scan
will be executed in random order to develop the PRAGMA-BE scoring system.
For the development of the Airway Artery (AA) method for objective measurement of airway 
dimensions CT images from a subset of approximately 30 patients will be used. The following 
structures will be manually measured: airway lumen area (Ainner), airway outer area (Aouter) 
and the area of the accompanying vessel (A) for all visible airway vessel pairs (100-300 per 
scan) (de Jong et al 2005). From these measurements the following ratios will be computed: 
Aouter/A; Ainner/A; Airway wall Area (AWA)/A. The automated airway and artery 
extraction algorithm as developed by the central reader imaging group will subsequently be 
tuned to match these manual annotations. Automated measurement will be further validated 
by determining agreement with the same measures derived from manual annotation in this 
patient cohort.  Furthermore, the manual and automated AA-method will be compared to BE 
and airway wall thickness sub-scores 
 and spirometry outcomes.
Through image analysis quantitative image analysis parameters will be allocated for each 
patient to CT images that will be included into the clinical database. The annotated images 
will be stored within the secured hospital environment on the data storage facility of the 
Central Reader.
Results from the Phase II study will be used to select the best image analysis strategy to 
phenotype BE CT images and to fine-tune the automated AA method to be used 
 
.
6.3
Treatment exposure and compliance
Assessment of compliance will be based on the electronic patient diary to capture the number 
of inhaled capsules in every morning and evening if applicable, and the number of unused 
capsules returned per patient assessed by the ISC. The ISC will then inform the investigator 
and/or study personnel who will then record the data in the CRF accordingly.  
6.4
Efficacy
The following efficacy assessments will be performed:


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
P. aeruginosa: CFU (sputum) or semi-quantitative culture data (deep-throat cough swabs 
for non-sputum producing patients)
 
 
 

Anti-pseudomonal antibiotic use (other than study drug)

Pulmonary exacerbations (total count, rate, severity and time of onset) and related signs 
and symptoms

Pulmonary function by using spirometry

Patient reported outcomes (QOL-B, 
)
6.4.1
Microbiological assessment 
Sputum 
 will be collected in sterile containers before 
study drug administration at all treatment epoch and follow-up epoch visits.  The 
 sputum 
specimen will be used to culture for the presence of P. aeruginosa (quantitative test) 
 
 
 
 Following 
alternatives can be chosen, if a patient is unable to expectorate during the visit:

Sputum will be induced at the baseline visit (Visit 2) as the 
 
specimen. 

At the other visits, a deep-throat cough swab will be collected for non-sputum 
producing patients for microbiology specimens.  Deep-throat cough swab specimens 
will be evaluated semi-quantitatively.

Patients may undergo a short physiotherapy session at any visit, if feasible, to enable 
to expectorate spontaneously.
 
 
 
 
Microbiological analyses, 
, 
will be performed centrally at a qualified microbiology laboratory. Details on the collection 
and shipment of samples, generation of data and reporting of results by the microbiology
laboratory are provided in a separate laboratory manual.


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6.4.3
Anti-pseudomonal antibiotic use
The proportion of patients having anti-pseudomonal antibiotic and duration of treatment 
(other than study drug) will be determined from the collection of concomitant medications
during the study.
A list of anti-pseudomonal antibiotics can be found in Appendix 12.
6.4.4
Pulmonary exacerbations
The rate, duration and primary precipitating factors of pulmonary exacerbations will be 
assessed during the study. Pulmonary exacerbation episodes will be collected on a specific 
CRF.
Pulmonary exacerbations are defined as: events for which it is clinically determined by the 
site investigator that antibiotic therapy is required AND 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;
A worsening of symptoms that either does not meet the above symptom definition but is 
treated by the investigator with antibiotics, or that meets the symptom definition but is not 
treated with antibiotics, is not considered a pulmonary exacerbation for the study. 


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For the above reported signs and symptoms, additional information will be collected to 
document if the reported signs and symptoms last for more than 48 hours. 
Patients should be advised to contact the site when experiencing a pulmonary exacerbation for 
advice. An unscheduled visit should occur within 2 working days of the event to confirm the 
diagnosis, unless the patient is hospitalized and thus unable to attend the site. AEs/SAEs, 
concomitant medications, and safety laboratory exams should be captured, as appropriate. 
The start date for a pulmonary exacerbation recorded in the CRF should be the first day of 
symptom worsening of at least 3 of the 6 symptoms, as defined above. The end of a 
pulmonary exacerbation episode is marked by the return to pre-exacerbation symptom status. 
An exacerbation might result in missed or rescheduled visit(s) and missing associated CRF 
data in some circumstances.
Patients who develop a pulmonary exacerbation between screening and prior to treatment will 
be screen failed but will be permitted to be re-screened once the inclusion/exclusion criteria 
have been met (see exclusion criteria).
6.4.5
Pulmonary function tests
Pulmonary function testing will be performed locally at the site using locally available 
spirometry equipment. FEV1, 
values will be recorded on the CRF as 
absolute volume measurements. The pre-dose values will be used as efficacy measurements.
Please refer to the Spirometry Guidance, in Appendix 5 for full details on scheduling and 
performing spirometry.
6.4.6
Health-related Quality of Life
The PROs QOL-B, 
 questionnaires should always be 
completed before any other assessments 
 
All patients/subjects will complete the PRO questions via a handheld electronic device or an 
electronic tablet. Patients/subjects should be given sufficient space and time to complete all 
study PROs. If patients/subjects experience any difficulties with submission after they 
complete the PROs, the study staff should assist them with submitting their PRO responses.  
Attempts should be made to collect responses to all PROs for all patients/subjects, including 
from those who prematurely discontinue prior to the study evaluation completion visit, 
however, if patients/subjects refuse to complete PROs, this should be documented in study 
source records. Patient’s refusal to complete study PROs are not protocol deviations.
Completed questionnaires will be reviewed and examined by the investigator, before the 
clinical examination, for responses that may indicate potential adverse events (AEs) or serious 
adverse events (SAEs). The investigator should review not only the responses to the questions 
in the questionnaires but also for any unsolicited comments written by the patient. If AEs or 
SAEs are confirmed, then the physician must record the events as per instructions given in 
Section 7.1 and Section 7.2 of the protocol. Investigators should not encourage the patients to 
change the responses reported in the completed questionnaires.


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Quality of Life Questionnaire-Bronchiectasis (QOL-B)
The QOL-B is a bronchiectasis specific PRO instrument that has been recently developed 
according to the principles in FDA 2009 PRO guidance (Quittner et al 2014). The QOL-B 
consists of 8 domains (Respiratory Symptoms, Physical, Emotional, Social, and Role 
Functioning, Vitality, Treatment Burden, and Health Perceptions), all have been developed 
based on patient interviews and went through preliminary validation, its validity and 
reliability has been confirmed. The respiratory domain is of particular interest. The minimal 
important difference (MID) has been found to be 8 on this domain and have shown to be 
responsive to treatment (Quittner et al 2015). The recall period is one week, and the responses 
are graded on a 4-point Likert scale.
The instrument will be administered at each of the following study visits: baseline (Visit 2)
and each of the post-baseline visits. It must be administered at the beginning of each study 
visit, before any measurements are taken (i.e., weight, lung function).
The appropriate language version(s) of the questionnaire will be used in each participating 
country. The same language version of the questionnaire should be used by a particular 
patient throughout the study.  
The study coordinator should be familiar with the instrument and the associated user guides 
and training materials provided. The patient should complete the questionnaire on his/her own 
(no family members present) in a quiet area and be allowed to ask questions; however site 
staff should take care not to influence the patient’s responses. The patient will be instructed to 
provide the truest and for them best response. 
While completing the PROs, the electronic device will prompt patients at appropriate intervals 
to ensure that they respond to all questions to minimize missing data. At later visits patients 
are not allowed to review their previous responses. The original questionnaire will be kept 
with the patient’s file as the source document. 
Exit Interviews
Novartis will conduct (by an entrusted external vendor) exit interviews with a subset of 
patients completing this trial to evaluate the content validity of the QOL-B, with particular 
emphasis on the Respiratory Symptoms subscale, as recommended in the feedback received 
from the FDA. Exit interviews will be conducted in the United Kingdom only and the planned 
recruitment is approximately 25 patients. Telephone interviews with the patients should be 
conducted at the last follow-up visit after completion of the PRO questionnaires and 
preferably prior to other assessments. The results will be independently reported.


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6.4.8
Appropriateness of efficacy assessments 
The efficacy variables selected (see Section 6.4.1 through 
) are commonly used 
for studies investigating the efficacy of antibiotics and/or the indication of BE, 
 
. Microbiological data will 
assess the direct impact of the drug on the pathogens, while spirometric data and pulmonary 
exacerbations are representative for the control of BE overall.
6.5
Safety 
The following assessments will be performed to assess study treatment safety:

Adverse events, Serious adverse events

Physical examination and vital signs

Clinical chemistry, Hematology

Urinalysis and dipstick

Post-inhalation events 

Bronchial hyperreactivity measured by change in FEV1% predicted post-inhalation 

Audiology (will be performed at selected sites and in patients who have oto-toxic AEs 
during the study)

Serum pregnancy (females of child bearing potential)

Adverse events of special interest (ototoxicity/hemoptysis/renal)

Hospitalizations for respiratory-related AE
6.5.1
Physical examination
Physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
additional exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be included in the Medical History part of the CRF. Significant findings made after first 
administration of investigational drug which meet the definition of an Adverse Event must be 
recorded on the Adverse Event section of the CRF.
6.5.2
Vital signs 
Systolic/diastolic blood pressure, radial pulse rate (over a 30 s interval), respiratory rate and 
body temperature will be recorded at Visit 1 (screening), start of treatment epoch (Visit 101), 
end of the treatment epoch (Visit 106), and end of the follow-up epoch (Visit 202). Single 
measurements will be performed before inhalation of study medication in the case of a dosing 
visit.
All blood pressure measurements should be taken after the patient has rested in the sitting 
position for at least 10 min.


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6.5.3
Height and weight 
The patient’s height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in 
indoor clothing, but without shoes) will be measured. Refer to Table 6-1 for the assessment 
schedule.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual.
Clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured.
6.5.4.2
Clinical chemistry
Urea (or BUN), creatinine, glucose, total bilirubin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, gamma glutamyl transpeptidase, sodium, 
potassium, chloride, calcium, bicarbonate, phosphate, total protein, albumin, and uric acid will 
be measured. Based on serum creatinine values, estimated glomerular filtration rate (eGFR) 
will be calculated using the MDRD (Modification of Diet in Renal Disease) criteria.
6.5.4.3
Urinalysis
Measurements for specific gravity, protein (proteinuria at all visits, urine albumin-creatinine 
ratio and urine protein-creatinine ratio at baseline and when renal alert criteria are met), 
glucose (glycosuria), and blood (hematuria) in urine will be performed. White blood cell and 
red blood cell sediments will also be measured.
6.5.5
Post-inhalation events
Events occurring within 5 minutes after inhalation of the study treatment (post-inhalation 
events) will be observed at the site by site personnel at Visits 101, 102, 103, 104, 105 and 106. 
The ISC should supervise the study treatment inhalation by the patients whether an event 
occurred or not. 
If the event is determined to be an adverse event, this should be recorded on the Adverse 
Event CRF. In addition, event details will also be captured in the Post-inhalation Adverse 
Event CRF. For post-inhalation events that are determined not to be an adverse event, event 
details will be recorded in the Post-inhalation clinical events CRF.
If a patient prematurely discontinues study drug, airway reactivity should be assessed at the 
treatment discontinuation (TD) visit provided the patient agrees to inhale study medication 
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6.5.6
Bronchial hyperreactivity
Bronchial hyperreactivity will be measured as the acute relative change from pre-dose to 
30±15 minutes post-dose in FEV1% predicted at Visits 101, 102, 103, 104, 105 and 106. A 
change of 20% or more is considered a clinically significant indication of bronchospasm/ 
bronchial hyperreactivity. 
It is at the investigators discretion to initiate treatment with a bronchodilator prior to 
inhalation of study treatment or to consider discontinuation of study treatment in the case that 
bronchial hyperreactivity is experienced.
If a patient prematurely discontinues study drug, airway reactivity should be assessed at the 
treatment discontinuation (TD) visit provided the patient agrees to inhale study medication 
during the visit.
6.5.7
Audiology
The patient should be questioned at each visit about the occurrence of any hearing 
abnormalities. If any such change is suspected by the patient, the investigator should have the 
case assessed and followed up by an audiologist, regardless of whether or not the site 
participates in the audiology sub-study. Audiological assessments will be conducted at 
selected study sites at Visits 2, 103, 104, 105, 106 (or discontinuation visit) and also at follow-
up visits 201 and 202, as relevant. For patients whose audiology is normal up to and including 
the end of the treatment epoch (Visit 106), there is no need for additional audiology at Visits 
201 and 202. If the audiology is abnormal at any visit, it should be repeated at all following 
visits including the end of study visit. 
Patients will have auditory acuity measured using a standard dual-channel audiometer at 
frequencies from 250 Hz to 8 kHz. Measurements of interoctaves are not necessary. An 
audiogram (pure-tone air conduction) and tympanogram will be performed by an audiologist. 
Bone conduction will be performed if the air conduction shows a decrease of 20 dB from the 
patient’s pre-dose measurements in either ear. Novartis and the investigator must be notified 
within 5 working days if a 20 dB drop versus as compared to the most recent pre-dose value 
(either screening or baseline) is noted in either ear. In this case, the patient will be withdrawn 
from treatment and monitored until auditory acuity values return to baseline or until the 
follow-up visit, whichever occurs first. Only at the baseline visit (Visit 2), the audiology 
assessment must be performed prior to dosing. At the following visits, audiology can be 
performed within 3 days before or after the assigned visit.
6.5.8
Pregnancy and assessments of fertility 
All female patients after the onset of menarche who are not surgically sterile will have a 
serum pregnancy test performed by the central laboratory from the blood sample taken for 
safety laboratory examination at Visits 1 and 106. Additionally, a urine pregnancy test will be 
done at Visits 2 and 202. A positive serum pregnancy test at Visit 1 leads to the exclusion of 
the patient from the study prior to the start of study treatment administration. In case of a 
positive urine pregnancy test at Visit 2, the patient must not commence inhalation of study 
medication. In these cases, a serum pregnancy test must be performed and the results awaited 
to verify the pregnancy. If a serum pregnancy test is determined to be positive, the patient 


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must be discontinued from the trial. In case of positive test results, the pregnancy must be 
followed up until after birth.
6.5.9
Adverse events of special interest
Certain events have been identified in the TIP AE profile for cystic fibrosis which will have a 
more detailed assessment. If an adverse event regarding ototoxicity and/or hemoptysis is 
reported, specific data which may include symptoms, medical history and relevant local 
assessment will be collected by using a specific CRF.
6.5.10
Hospitalizations for respiratory-related adverse events
Hospitalizations for respiratory-related adverse events will be recorded on a specific CRF. 
The rate and duration of hospitalization due to serious respiratory-related AEs will be 
determined, based on the information collected in the CRF.
6.5.11
Appropriateness of safety measurements 
The use of systemic aminoglycosides in humans has been related to eighth cranial nerve 
impairment (Guthrie 2008) manifested as both auditory and vestibular toxicity. The 
audiological assessment (Section 6.5.7) and questioning the patient at each visit for hearing 
abnormalities have been included in this study to closely monitor the hearing ability of 
patients exposed to TIP. Renal function is surveyed by clinical chemistry assessments as 
nephrotoxic effects have been reported from systemic aminoglycosides (Martinez-Saldago et 
al 2007). All other safety assessments selected are standard for the indication BE and this 
patient population.
6.6
Other assessments
6.6.1
Resource utilization 
At each scheduled and unscheduled visit, respiratory healthcare resource utilization for 
hospitalizations will be assessed and recorded on the appropriate CRF. Hospitalization will be 
defined as any visit to the hospital requiring an overnight stay. The total length of stay
including date of admission and discharge will be recorded for respiratory-related in-patient 
hospitalizations.
Any procedures performed during the hospitalization will be recorded in the appropriate CRF.
If AEs or SAEs are confirmed then the physician must record the events as per instructions 
given in the protocol.
6.6.2
Pharmacokinetics 
Pharmacokinetic properties of tobramycin from different doses of TIP o.d. and b.i.d. will be 
assessed at Visits 101, 102 and 104.
It is expected that few patients will be able to expectorate spontaneously multiple sputum 
samples at a given visit. As patients are required to provide pre-dose sputum samples for 
microbiology assessment (primary endpoint), for the PK sputum specimens all patients will be
requested to provide specimens of sputum post-dose per specified interval, at Visits 101 (0-1 


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h and 1-2 h post-dose measured time interval from the completion of study drug 
administration), at Visit 102 (5-6 h) and Visit 104 (3-4 h). Sputum samples for tobramycin 
concentration testing must be at least 200 mg in weight (0.2 ml in volume) and must not be 
saliva. In patients who are not able to spontaneously produce sputum, one specimen of 
induced sputum post-dose per specified interval will be collected. No induced sputum sample 
for PK will be collected at baseline in patients who had induced sputum pre-dose for 
microbiology assessments.
All patients will also provide serum specimens at Visits 101 and 102 (one specimen per 
specified interval): 0-1 hours, 1-2 hours, post-dose (measured time interval from the 
completion of study drug administration). 
To evaluate serum PK in approximately 16 patients on active treatment, at least 20-22 patients 
from each cohort (at least 60 total patients) will participate in a PK sub-study. All patients will 
be asked to participate in the sub-study until enrollment is fulfilled for each cohort. Patients in 
this PK subset (20-22 patients/ cohort) will instead provide one serum specimen per specified
interval at Visits 101 and 102: pre-dose and post-dose 0-1, 1-2, 3-4 and 5-6 h. 
If there is more than one serum or sputum sample to be collected per visit, there has to be a 
minimum of one hour difference between consecutive sampling points. Samples will be 
obtained from a peripheral site by phlebotomy or through a temporary i.v. site, but not 
through an existing central access or catheter.
If a patient discontinues early and is on study drug, the patient will be asked to provide an 
extra serum and sputum specimen at the treatment discontinuation (TD) visit.
A separate laboratory manual will be provided with instructions on tube labeling, sample 
collection, processing, storage conditions and shipping of specimens. 
The time of sputum and blood collection is to be recorded (e.g. actual time of dosing and 
actual times of sputum/blood collection have to be recorded on the PK sputum and blood 
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6.6.5
Patient diaries
All patients will be provided with an electronic Patient Diary to record dosing of study 
treatment (number of inhaled capsules every morning and evening during the treatment
epoch). 
7
Safety monitoring 
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.


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
whether it constitutes a serious adverse event (SAE – See Section 7.2 for definition of 
SAE)

action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect


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
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of bronchiectasis, not associated with any 
deterioration in patient’s condition (e.g. preplanned prophylactic i.v. antibiotic 
therapy)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day 
period after the last study visit should only be reported to Novartis if the investigator suspects 
a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs (either initial or follow-up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment, complete the SAE Report Form in 


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English, and send the completed, signed form by fax within 24 hours after awareness of the 
SAE to the local Novartis Drug Safety and Epidemiology Department. The telephone and fax 
number of the contact persons in the local department of Drug Safety and Epidemiology, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. Follow-up information should be provided using a new 
paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Liver safety monitoring
Tobramycin is not metabolized in the liver and therefore a hepatotoxicity effect is not 
expected following exposure to TIP. Standard serum chemistry, including liver enzymes, will 
be monitored during the study. 
7.4
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum renal event:

confirmed (after ≥24h) increase in serum creatinine of 25 – <50% compared to 
baseline during normal hydration status

acute kidney injury: confirmed serum creatinine increase ≥50% compared to baseline

Urine renal event

confirmed new onset (≥3+) proteinuria

confirmed new onset (≥3+) hematuria
Every renal laboratory trigger or renal event occurring after randomization as defined in Table 
14-1 in Appendix 2 should be followed up by the investigator or designated personnel at the 
trial site as summarized in Appendix 2. 


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7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) CRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Treatment error 
type
Document in Dose 
Administration (DAR) 
CRF (Yes/No)
Document in AE CRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes, 
Yes, even if not associated 
with a SAE
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
CRO representative will review the protocol and CRFs with the investigators and their staff. 
During the study, Novartis and CRO employ several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 


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check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits.  
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis or CRO monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. 
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the CRFs using 
fully validated software that conforms to US CFR 21 Part 11 requirements. Designated 
investigator site staff will not be given access to the EDC system until they have been trained. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
CRO working on behalf of Novartis. The Investigator must certify that the data entered into 
the CRFs are complete and accurate. After database lock, the investigator will receive copies 
of the patient data for archiving at the investigational site. 
8.3
Database management and quality control 
Novartis staff (or CRO working on behalf of Novartis) review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.


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Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Patients/subjects will fill in their PRO data via a handheld electronic device or an electronic 
site based tablet. The system will be supplied by a vendor(s), who will also manage the 
database. The database will be sent electronically to Novartis personnel (or designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
An independent data monitoring committee (DMC) will be set-up to review AE / SAE data 
and provide the Sponsor with guidance on safety issues.
SAEs will be reviewed on a regular basis. The DMC will also perform a pre-planned review 
of AE and additional pre-defined safety data as described in the DMC charter.
The membership of the DMC and the responsibilities of the DMC and Novartis will be 
defined in a separate ‘DMC Charter’ document. The DMC Charter will include information 
about data flow, purpose and timings of DMC meetings, communication strategy, procedures 
for ensuring confidentiality, procedures to address conflicts of interest and statistical 
monitoring guidelines. 
8.5
Adjudication Committee
Not required.


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9
Data analysis 
The study is characterized by 3 cohorts. Each of them consists of TIP, TIP/placebo cyclical, or 
placebo in a ratio of 2:2:1 for blinding purposes. For the efficacy analysis the placebo patients 
will be pooled from the three cohorts. For the safety analysis, placebo patients across the three 
cohorts will not be pooled. Data will be summarized and analyzed by treatment groups.
9.1
Analysis sets
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of study drug. Following the intent-to-treat principle, patients will be analyzed according to 
the treatment they are assigned to at randomization, which may be different from the actual 
treatment received. Patients who are mistakenly randomized or who have not taken double 
blind study drug will be excluded from the FAS.
The per-protocol set (PPS) population will include all patients in the FAS without any major 
protocol deviations.
The safety set is defined as patients who received at least one dose of study drug. In all safety 
analyses patients will be analyzed according to the actual treatment received. 
The analysis of the primary objective will be performed on the FAS. The PPS will be used for 
the supportive analysis of the primary variable. The FAS will also be used for the analysis of 
all other efficacy variables. The safety set will be used in the analysis of all safety variables.
9.2
Patient demographics and other baseline characteristics 
Descriptive statistics for patient demographics data including age, weight, height, gender, and 
other baseline characteristics will be provided to describe the study population both for 
overall population and by treatment groups. Categorical variables will be summarized with 
the number and percentage of patients in each category. Continuous variables will be 
summarized using descriptive statistics including number of patients, mean, standard 
deviation (SD), median, minimum and maximum. 
9.3
Treatments 
The prescribed dosing regimens are two o.d. (3, and 5 capsules per day) and one b.i.d. (4 
capsules twice per day) for TIP, TIP/placebo cyclical and placebo. Descriptive statistics will 
be provided by treatment group for the duration of treatment and the percent compliance to 
study drug by treatment groups. The reasons for dose changes and interruptions will be 
tabulated with number and percentage.
The number and percentage of patients taking concomitant medications will be summarized 
by treatment and by ATC classes and preferred terms. Each concomitant medication could be 
classified by more than one ATC class and will be counted for each. Summary tables will be 
created for concomitant medications started prior to study drug, started on or after start of 
study drug and for non-CF BE related medications started on or after start of study drug.
Duration of exposure (days) will defined as end date of study medication in on-treatment 
phase minus start date of study medication in on-treatment phase plus 1 day. The total 


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duration of exposure in the TIP/placebo cyclical arm will be the sum of duration from the two 
treatment cycles. The duration of exposure will be presented with standard descriptive 
statistics (n, mean, SD, minimum, median and maximum) and with number and percentage 
for pre-defined categories (≤28 days, 29-56 days, 57-84 days, 85-112 days and ≥113 days.
Discontinuations of study (yes/no) will be summarized with number and percentage of 
patients by treatment groups.
Treatment compliance with study medication over the study period will be summarized.
9.4
Analysis of the primary variable(s)
The analysis of the primary efficacy variable will be based on the FAS.
9.4.1
Variable(s)
The primary efficacy variable is the absolute change in the bacterial load in sputum as 
assessed by the change in log10 colony forming units (CFUs) of P. aeruginosa from baseline 
to Day 29 of treatment.
Baseline is defined as the last measurement prior to the first dose of blinded study medication. 
9.4.2
Statistical model, hypothesis, and method of analysis
The comparisons of TIP 3 capsules o.d, 5 capsules OD, and 4 capsules b.i.d versus placebo 
will be evaluated by testing the following null hypothesis (H0) versus the alternative 
hypothesis (Ha):
H0: TIP treatment group is equal to placebo group in bacterial load in sputum at Day 29
Ha: TIP treatment group is not equal to placebo group in bacterial load in sputum at Day 29
The primary efficacy endpoint will be analyzed using the analysis of covariance (ANCOVA) 
model. The model will contain treatment, baseline CFU, and baseline macrolide use. Pairwise 
comparisons of TIP dosing groups will be conducted versus placebo. To control the family-
wise type-I error rate (three dose levels vs. placebo) at the two-sided 5% significance level, 
the step-wise Dunnett procedure will be used.
For the primary efficacy analysis, patients from treatment arms TIP and TIP/placebo cyclical 
regimen will be pooled for each cohort. This is possible because all patients within the same 
cohort on the TIP treatment arms (cyclical or continuous) are receiving the same treatment 
during the first 28 days. Placebo patients will be pooled across the 3 cohorts, as the number of 
placebo capsules is not expected to influence the change in P. aeruginosa bacterial counts.
The estimated adjusted treatment difference (TIP – placebo) will be displayed along with the 
associated standard error, 2-sided 95% confidence interval (CI), and p-value (2-sided).
9.4.3
Handling of missing values/censoring/discontinuations
No missing value imputation will be implemented for the primary efficacy analysis. Various 
imputation methods will be explored to handle missing values due to censoring or 
discontinuations in the sensitivity analyses. 


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To account for patients who require treatment with anti-pseudomonal drugs for exacerbation, 
a sensitivity analyses will be performed using multiple imputations for the relevant efficacy 
endpoints.
Details of the sensitivity analyses will be specified in the statistical analysis plan prior to 
database lock.
9.4.4
Supportive analyses 
The non-parametric Mann-Whitney-Wilcoxon test will be carried out as a sensitivity analysis 
due to the potential non-normality of the CFU data.
The primary efficacy analysis will be repeated in the PP population as a supportive analysis. 
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
For efficacy analysis, patients assigned to placebo arms will be pooled across the 3 cohorts, as 
the number of placebo capsules is not expected to impact the efficacy assessments. Unless 
otherwise specified, the following analysis will be conducted both over the treatment epoch 
(through Day 113) and over the study period (through Day 169).
9.5.1.1
P. aeruginosa colony forming units (CFU)
Anti-microbial efficacy of TIP versus placebo over the entire study duration, as measured by 
the absolute change in P. aeruginosa colony forming units (CFU) in sputum from baseline to 
each post-baseline visit, other than Visit 103, will be assessed by biotype and sum of all 
biotypes with the same ANCOVA model as specified for the primary efficacy variable. 
9.5.1.2
Pulmonary exacerbation
The following pulmonary exacerbation-related parameters over the treatment epoch (through 
Day 113) and the study period will be summarized by treatment (pulmonary exacerbation is 
defined in Section 6.4.4). The analysis will be performed by exacerbation category wherever 
specified in the analysis plan. The following analysis will also be repeated in the subgroup of 
patients who had 3 or more pulmonary exacerbations within 12 months prior to screening, if 
data permit.    

Time to first pulmonary exacerbation by exacerbation category

The annual rate of pulmonary exacerbations overall

Duration of pulmonary exacerbations in days by exacerbation category

The percentage of patients with at least one pulmonary exacerbation 

Time to permanent study drug discontinuation due to pulmonary exacerbation

The percentage of patients who permanently discontinued study drug due to pulmonary 
exacerbation
Time-to-event variables will be analyzed using a Cox regression model stratified by baseline 
macrolide use. The model will include treatment, as fixed-effect factor, and number of 
pulmonary exacerbation in the 12 months prior to screening as covariate. The estimated 


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adjusted hazard ratio for TIP over placebo will be displayed along with the associated two-
sided 95% confidence interval and corresponding p-value.
Kaplan-Meier analysis stratified by treatment group will be also presented and displayed 
graphically.
Number of the pulmonary exacerbation will be analyzed using a generalized linear model 
assuming the negative binomial distribution including treatment, baseline macrolide use as 
fixed-effect factors, and number of pulmonary exacerbation in the 12 months prior to 
screening as covariate. The log exposure in years will be included as an offset variable in the 
model. The estimated rate ratio along with two-sided 95% interval and corresponding p-value 
will be provided.
The duration of pulmonary exacerbation is defined as the sum of the duration of days 
recorded as an exacerbation for all exacerbations recorded per patient. This will be analyzed 
using an ANCOVA model. The model will include treatment, as fixed-effect factors, and 
number of pulmonary exacerbation in the 12 months prior to screening as covariate 
9.5.1.3
Anti-pseudomonal antibiotics
Time to first use (overall, oral, and parenteral) of anti-pseudomonal antibiotics will be 
analyzed using Cox regression model stratified by baseline macrolide use. The model will 
include treatment, cohort as fixed-effect factors, and number of pulmonary exacerbation in the 
12 months prior to screening as covariate. 
Rate of usage (overall, oral, and parenteral) of anti-pseudomonal antibiotics will be analyzed 
using a generalized linear model assuming the negative binomial distribution including 
treatment, cohort, baseline macrolide use as fixed-effect factors, and number of pulmonary 
exacerbation in the 12 months prior to screening as covariate. The log exposure in years will 
be included as an offset variable in the model.
9.5.1.4
Hospitalization
Time to first hospitalization and the rate of hospitalization due to serious respiratory-related 
AEs will be analyzed using the same models as specified for the pulmonary exacerbation.


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9.5.1.6
Patient reported outcomes 
Quality of Life Questionnaire-Bronchiectasis (QoL- B)
QOL-B Respiratory Symptom domain contains 9 items, and each of the 37 items is scored 
from 1 to 4, and the overall score is standardised on a 0-100 point scale, with higher scores 
representing fewer symptoms or better functioning. 
Items in the questionnaire are expressed either “negatively” or “positively,” therefore a 
number of items must be recorded before the scores for each of the domains are calculated. 
The score is calculated by adding the score obtained for each item of a domain (scale), after 
any necessary recoding. Scoring for each domain can be computed only if at least half the 
items have been completed. If not, then the domain should not be scored and should be 
considered missing for that particular person who filled out the questionnaire.
The minimum or maximum score always corresponds to the highest QOL and the minimum 
score always corresponds to the lowest QOL.
Change from baseline in QOL-B Respiratory Symptom Score (RSS) will be analyzed using a 
linear repeated measure model. The model will contain treatment, baseline macrolide use,
visit (visits 102 to 202), and treatment-by-visit interaction as fixed effects with baseline QOL-
B RSS, baseline-by-visit interaction as covariates. The within-patient correlation will be 
modeled using the unstructured covariance matrix in the mixed model. If the model does not 
converge, then the compound symmetry covariance structure will be used Restricted 
maximum likelihood method will be used.


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9.5.2
Safety variables 
All safety analyses will be performed using the safety population, and will be presented by 
treatment groups. Baseline for safety analyses is defined as the last measurement prior to the 
first dose of study medication in the study.
Appropriate summary statistics will be provided for laboratory test results, audiology, 
bronchial hyperreactivity and vital signs.
AEs will be deemed treatment-emergent if the onset date is on or after the date of first study 
drug and until study completion. Treatment emergent AEs will be summarized by MedDRA 
primary SOC and preferred term for each cycle and overall. The actual MedDRA version in 
effect at the time of the clinical study report will be used for coding AEs.
Audiology testing will be performed at selected centers and in patients with hearing events. 
Audiology function data will be analyzed via summary statistics by treatment and visit.
Clinical laboratory parameters will be summarized using means and mean changes from 
baseline to each post-baseline visit by treatment group. Shift-from-baseline summaries (shift 
tables) will be presented for the last available measurement (Termination Visit).
Vital sign parameters will be summarized using means and mean changes from baseline by 
treatment group and visit. 
Analysis of post-inhalation events will be conducted for the two types of events (post-
inhalation clinical events/post-inhalation adverse events). The number of patients with post-
inhalation events will be summarized by treatment. In addition, the number of these events 
and the event rate adjusted for exposure will be displayed by treatment.


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Post-inhalation events occurring at a site visit within 5 minutes (yes/no), post-inhalation 
events that are ongoing at completion of the site visit (yes/no) and for which are an action 
taken to reduce the event (yes/no), the time-point of an event  and the time of onset (≤30 
sec, >30 sec-1min, >1-2min, >2-5min, >5min) will be summarized with the number and 
percentage overall and for each cycle. Descriptive statistics including mean, standard 
deviation, minimum, median and maximum will be provided for the duration of the event in 
seconds.
Bronchial hyperreactivity will be measured as the acute relative change from pre-dose to 
30±15 minutes post-dose in FEV1% predicted at Visits 101, 102, 103, 104, 105 and 106. A 
change of 20% or more is considered a clinically significant indicative of bronchospasm/ 
bronchial hyperreactivity. This change will be summarized with the number and percentage of 
patients who experienced no change, a decrease/increase of >0-<10%, a decrease/increase of 
10-<20% or a decrease/increase ≥20%. Both analyses will also be done for the patients who 
did the post-dose spirometry test in a 60 minutes time window.
9.5.3
Resource utilization 
Data relating to resource utilization will be used for the purpose of economic evaluation 
which will be carried out and reported as a separate activity.
9.5.4
Pharmacokinetics 
The serum and sputum pharmacokinetic properties of tobramycin will be assessed by 
evaluating tobramycin concentrations in serum and sputum collected from non-CF BE 
population post administration of o.d. or b.i.d. doses of TIP. Descriptive statistics will be 
provided for tobramycin serum concentrations by scheduled visit and time of collection. 
Serum and sputum pharmacokinetics of tobramycin after TIP inhalation will be characterized 
by population non-linear mixed effects modeling techniques. 
9.5.7
PK/PD 
An exploratory analysis of the relationship of sputum concentrations (for efficacy) and/or 
systemic exposures (for safety) pooled across the arms may be conducted with endpoints 
including CFU changes from baseline, certain laboratory and clinical safety parameters, 
change in bacterial susceptibility, PROs, and exacerbations. This analysis will depend on 
performing a graphical analysis and visual inspection of the data to determine whether the 
data collected in TBM100G2202 permits a modeling approach. Longitudinal data will be 
pooled across the study cohorts, including the patients randomized to placebo. 


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PK modeling of serum and sputum concentration data will be considered to characterize the 
population PK in BE patients. If a model can be constructed then the effect of covariates (such 
as age, weight, baseline creatinine clearance, CFU/g of sputum) will also be explored in 
describing the inter-subject variability.  
Exploratory exposure-response modeling of the time course of CFU data collected during the 
treatment period in addition to the data collected post treatment may be performed if 
supported by the data. The CFU modeling will explore the relationship between exposure, 
most likely based on the sputum PK model, and CFU reduction from baseline. 
The results of these exposure-response analyses will be combined with the results from 
complementary data analyses of these same data, as well as analyses of data on other efficacy 
and safety endpoints, to support dose and regimen selection.
9.6
Interim analyses
No interim analysis for efficacy is planned. It is planned that the independent DMC will 
review semi-blinded safety data (see Section 8.4).
9.7
Sample size calculation
Sample size estimation was based on a difference of 2.0 log10 CFU/g, with standard deviations 
of 2.0 log10 CFU/g. The assumptions were based on conservative estimates from published 
results (Konstan et al 2011a, Konstan et al 2011b, Barker et al 2000, and Wilson et al 2013). 
As there are three primary comparisons between the three doses versus placebo, the 
Bonferroni multiplicity adjustment has been used (0.05/3) for sample size calculation. Using 
α=1.67% (two-sided) and 90% power, the sample size estimation yielded n = 36 subjects per 
treatment group as valid for ITT analyses. This takes into account an approximate 20%-
discontinuation rate. For the primary efficacy analysis, patients from TIP continuous and TIP 
cyclical regimen within the same cohort will be pooled as they receive exactly the same 
treatment during the first 28 days. Placebo patients will be pooled across the 3 cohorts, as the 
number of placebo capsules is not expected to influence the change in P. aeruginosa bacterial 
counts. With the current study design, the power is 94% to detect a reduction of 2.0 log10
CFU/g for each dose level versus placebo. 
For calculation of sample size, NQuery Advisor version 7.0 module MTTO-1 was used.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.


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10.2
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.


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10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request
Angrill J, Agustí C, de Celis R, et al (2002) Bacterial colonisation in patients with 
bronchiectasis: microbiological pattern and risk factors. Thorax; 57:15-19.
Barker AF, Couch L, Fiel SB, et al (2000) Tobramycin Solution for Inhalation Reduces 
Sputum Pseudomonas aeruginosa Density in Bronchiectasis. Am J Respir Crit Care Med; 
162:481-5.
Bilton D, Henig N, Morrissey B, et al (2006) Addition of inhaled tobramycin to ciprofloxacin 
for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest; 
130(5):1503-10.


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Chalmers JD, Goeminne P, Alberti S, et al (2014) The Bronchiectasis Severity Index. An 
International Derivation and Validation Study. Am J Respir Crit Care Med; 189(5):576-85.
Chalmers JD, Hill AT (2012) Mechanisms of immune dysfunction and bacterial persistence in 
non-cystic fibrosis bronchiectasis. Mol Immunol; 55(1):27-34. 
De Jong PA, Nakano Y, Hop WC, et al (2005) Changes in airways dimensions on computed 
tomography scans of children with cystic fibrosis. Am J Respir Crit Care Med; 172:218-224.
Drobnic ME, Sune P, Montoro JB, et al (2005) Inhaled tobramycin in non–cystic fibrosis 
patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. 
Ann Pharmacother; 39(1):39-44.
Geller DE, Konstan MW, Smith J, et al (2007) Novel tobramycin inhalation powder in cystic 
fibrosis subjects: pharmacokinetics and safety. Pediatr Pulmonol; 42:307-313.
Guthrie OW (2008) Aminoglycoside induced ototoxicity. Toxicology; 249(2-3):91-6.
Haworth CS, Foweraker JE, Wilkinson P, et al (2014) Inhaled colistin in patients with 
bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med; 
189(8): 975-82.
Hennig S, Standing JF, Staatz CE, et al (2013) Population pharmacokinetics of tobramycin in 
patients with and without cystic fibrosis. Clin Pharmacokinet; 52(4):289-301.
Hill AT, Haworth CS, Aliberti S, et al (2017) Pulmonary exacerbation in adults with 
bronchiectasis: a consensus definition for clinical research. Eur Respir J; 49:1700051
Ho PL, Chan KN, Ip MS, et al (1998) The effect of Pseudomonas aeruginosa infection on 
clinical parameters in steady-state bronchiectasis. Chest;114(6):1594-8.
Hurst H, Bolton J (2004) Assessing the clinical significance of change scores recorded on 
subjective outcome measures. J Manipulative Physiol Ther; 27:26-35.
International Society of Nephrology (2012) KDIGO Clinical Practice Guideline for Acute 
Kidney Injury. Kidney International Supplements; 2(1 Suppl):1-138.
Konstan MW, Geller DE, Minic P, et al (2011a) Tobramycin inhalation powder for P. 
aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol; 46(3):230-8.
Konstan MW, Flume PA, Kappler M, et al (2011b) Safety, efficacy and convenience of 
tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros; 
10(1):54-61.
Loebinger MR, Wells AU, Hansell DM, Chinyanganya N, Devaraj A, Meister M, Wilson R. 
(2009) Mortality in bronchiectasis: a long-term study assessing the factors influencing 
survival. Eur Respir J; 34(4):843-9.
Maglio D, Nightingale CH, Nicolau DP (2002) Extended interval aminoglycoside dosing: 
from concept to clinic. Int J Antimicrob Agents; 19(4):341-8.
Martinez-Saldago C, Lopez-Hernandez FJ, Lopez-Novoa JM (2007) Glomerular 
nephrotoxicity of aminoglycosides. Toxicol Appl Pharmacol; 223(1):86-98.
Murray MP, Govan JRW, Doherty CJ, et al (2011) A randomized controlled trial of nebulized 
gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med; 183(4):491-9.


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Murray MP, Pentlan JL, Turnbull K, et al (2009) Sputum colour: a useful clinical tool in non-
cystic fibrosis bronchiectasis. Eur Respir J; 34:361-364.
O’Donnell AE (2008) Bronchiectasis. Chest; 134(4):815-23.
Orriols R, Roig J, Ferrer J, et al (1999) Inhaled antibiotic therapy in non-cystic fibrosis 
patients with bronchiectasis and chronic bronchial infection by Pseudomonas aeruginosa. 
Respir Med; 93(7):476-80.
Pasteur MC, Bilton D, Hill AT (2010) British Thoracic Society guideline for non-CF 
bronchiectasis. Thorax; 65 (Suppl 1):i1-58.
Patel IS, Seemungal TA, Wilks M, et al (2002) Relationship between bacterial colonisation 
and the frequency, character, and severity of COPD exacerbations. Thorax; 57(9):759-64.
Quittner AL, Marciel KK, Salathe ML, et al (2014) A Preliminary Quality of Life 
Questionnaire-Bronchiectasis: A Patient-Reported Outcome Measure for Bronchiectasis. 
Chest; 146(2):437- 448.
Quittner AL, O’Donnell AE, Salathe ML, et al (2015) Quality of Life Questionnaire-
Bronchiectasis: final psychometric analyses and determination of minimal important 
difference scores. Thorax; 70(1):12-20.
 
Scaglione F, Paraboni L, (2006) Influence of pharmacokinetics/pharmacodynamics of 
antibacterials in their dosing regimen selection. Expert Rev Anti Infect Ther; 4(3):479-90.
Scheinberg P, Shore E (2005) A pilot study of the safety and efficacy of tobramycin solution 
for inhalation in patients with severe bronchiectasis. Chest; 127(4):1420-6.
Serisier DJ, Bilton D, De Soyza A, et al (2013) Inhaled, dual release liposomal ciprofloxacin 
in non–cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-
controlled trial. Thorax; 68(9):812-7.
Smith AL, Ramsey BW, Hedges DL, et al (1989) Safety of aerosol tobramycin administration 
for 3 months to patients with cystic fibrosis. Pediatr Pulmonol; 7(4):265-71.
Smyth A, Touw D, Tan Kelvin H-V, et al (2005) Tobramycin dosing in cystic fibrosis. Lancet; 
365(9473):1767-8.
Sweetman SC (2011). (ed) Martindale: The Complete Drug Reference [online]. London:
Pharmaceutical Press. Available from: http://www.medicinescomplete.com (Accessed 20 Oct
2011).
Ting, L, Aksenov, S, Bhansali SG (2014) Population Pharmacokinetics of Inhaled 
Tobramycin Powder in Cystic Fibrosis Patients. CPT Pharmacometrics Syst. Pharmacol.; 
3(e99)
Weycker D, Edelsberg J, Oster G, et al (2005) Prevalence and economic burden of 
bronchiectasis. Clin Pulm Med; 12(4): 205-9.


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Whitehead A, Conway SP, Etherington C, et al (2002) Once-daily tobramycin in the treatment 
of adult patients with cystic fibrosis. Eur Respir J; 19(2): 303-9.
Wilson R, Welte T, Polverino E, et al (2013) Ciprofloxacin dry powder for inhalation in non-
cystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J; 41(5):1107-15.
13
Appendix 1: Clinically notable laboratory values 
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports.  Investigators are responsible for reviewing these abnormal values 
for clinical significance, signing the laboratory reports to indicate their review, and reporting 
values considered clinically significant in the appropriate CRF. 
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.


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Appendix 2: Specific Renal Alert Criteria and Actions
Table 14-1
Specific Renal Alert Criteria and Actions
Serum Finding
Serum creatinine increase 25 –
<50% compared to baseline
Confirm 25 – <50% increase after 24-48h if possible and determine albumin-
creatinine-ratio (ACR), protein-creatinine-ratio (PCR) and eGFR.
If any of the below

serum creatinine increase is confirmed OR

eGFR ≤50mL/min/1.73m2 OR

ACR ≥30 mg/g or ≥3 mg/mmol OR

PCR ≥150 mg/g or ≥15 mg/mmol:
-
Follow up within 2-5 days to determine serum creatinine and 
eGFR. If values do not show improvement of renal function, 
consider study treatment interruption / or discontinuation based 
on clinical judgment
Acute Kidney Injury: Serum 
creatinine increase 50% 
compared to baseline
Follow up within 24-48h to confirm serum creatinine value. If serum creatinine
is increased 25 – <50% compared to baseline, 
-
Follow-up within 2-5 days to determine serum creatinine and 
eGFR. 
-
If values are not improving consider study treatment interruption 
/ or discontinuation based on clinical judgment. 
If serum creatinine increase ≥50% is confirmed
-
Discontinue study treatment 
-
Consider patient hospitalization / specialized treatment
Urine Finding
New dipstick proteinuria ≥3+
Confirm test result within 7 days, perform urine microscopy and determine 
ACR and PCR.
If proteinuria ≥3+ confirmed 
-
Discontinue study treatment.
-
Consider patient referral for specialized treatment
New dipstick hematuria* ≥3+
* not due to menstruation, 
infection, extreme
exercise, or trauma
Perform urine sediment microscopy and determine ACR and PCR on the 
same sample.
If ACR ≥30 mg/g or ≥3 mg/mmol OR
PCR ≥150 mg/g or ≥15 mg/mmol:
-
Perform serum creatinine within 5 days and follow up, as 
described above
Serum and urine findings that have been confirmed according to this appendix are considered renal serum and 
urine events.
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: serum creatinine within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: serum creatinine level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ± 50% variability over last 6 months.


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Appendix 3: Sputum/blood collection logs
Sputum sampling for pharmacokinetic assessments
At study visits 101, 102, and 104, post-dose sputum samples at specified time intervals are 
collected for pharmacokinetic analyses.
Table 15-1
Time schedule for sputum sampling for sputum pharmacokinetic 
assessments
Visit number
Study day
Scheduled time
Sample number
101
1
0-1 h post-dose
101
101
1
1-2 h post-dose
102
102
8
0-2 h post-dose
103
102
8
5-6 h post-dose
107
103
29
5-6 h post-dose
104
104
57
3-4 h post-dose
108
105
85
3-4 h post-dose
105
TD*
N/A
106
*For patients who discontinue early and are on study drug, an extra sputum sample for PK should be 
taken at the treatment discontinuation (TD) visit.
As per amendment 2, assessments have been moved from Visit 103 to Visit 102 and from visit 105 to 
visit 104.
Blood sampling for pharmacokinetic assessments
At study visits 101 and 102, post-dose serum samples at specified time intervals are collected 
for pharmacokinetic analyses.
Table 15-2
Time schedule for blood sampling for serum pharmacokinetic 
assessments
Visit number
Study day
Scheduled time
Sample number
101
1
0-1 h post-dose
201
101
1
1-2 h post-dose
202
102
8
0-1 h post-dose
206
102
8
1-2 h post-dose
207
103
29
0-1 h post-dose
203
103
29
1-2 h post-dose
204
TD*
N/A
205
*For patients who discontinue early and are on study drug, an extra blood sample for PK should be 
taken at the treatment discontinuation (TD) visit.
As per amendment 2, assessments have been moved from visit 103 to visit 102.


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Blood sampling for pharmacokinetic sub-study assessments
At study visits 101 and 102, pre- and post-dose serum samples at specified time intervals are 
collected for pharmacokinetic analyses.
Table 15-3
Time schedule for blood sampling for serum pharmacokinetic 
assessments in PK sub-study
Visit number
Study day
Scheduled time
Sample number
101
1
Pre-dose
301
101
1
0-1 h post-dose
302
101
1
1-2 h post-dose
303
101
1
3-4 h post-dose
304
101
1
5-6 h post-dose
305
102
8
Pre-dose
312
102
8
0-1 h post-dose
313
102
8
1-2 h post-dose
314
102
8
3-4 h post-dose
315
102
8
5-6 h post-dose
316
103
29
Pre-dose
306
103
29
0-1 h post-dose
307
103
29
1-2 h post-dose
308
103
29
3-4 h post-dose
309
103
29
5-6 h post-dose
310
TD*
N/A
311
*For patients in the PK-sub-study who discontinue early, an extra blood sample for PK should be taken 
at the treatment discontinuation (TD) visit.
As per amendment 2, assessments have been moved from visit 103 to visit 102.
16
Appendix 4: Instructions for use for the T-326 Inhaler
Please read the following instructions carefully to learn how to use and care for your T-326 
Inhaler.
Clinical kit:
Each clinical kit contains five weekly packs
Inside your weekly pack:
Each weekly carton contains:

1 inhaler and its storage case

7 or 14 capsule cards (one card for each dose)

Each capsule card contains 3, 4, or 5 capsules. One capsule card corresponds to one dose


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If your capsule cards contain 3 capsules each:

You should have a total of 7 capsule cards

Take one dose (=3 capsules) once a day

You will use 1 capsule card for each day that you take the medicine
If your capsule cards contain 5 capsules each:

You should have a total of 7 capsule cards

Take one dose (=5 capsules) once a day

You will use 1 capsule card for each day that you take the medicine
If your capsule cards contain 4 capsules each:

You should have a total of 14 capsule cards

Take one dose (=4 capsules) twice a day – i.e., once in the morning, once in the evening

You will use 2 capsule cards for each day that you take the medicine


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NOTE:
If you are unsure about how many doses to take each day, ask your physician or site personnel.
Capsule card
(NOTE: Imprint on actual 
capsule card may look slightly 
different than above.)
Inhaler (T-326 Inhaler)
Storage case
How to inhale your medicine with the T-326 Inhaler

Only use the T-326 Inhaler contained in this pack.  Do not use the enclosed capsules 
with any other device, and do not use the T-326 Inhaler to take any other medicine

When you start a new weekly pack of capsules, use the new T-326 Inhaler that is supplied 
in the pack.  Each T-326 Inhaler is only used for 7 days

Do not swallow the capsules.  The powder in the capsules is for you to inhale.  Please 
inform your study coordinator or nurse immediately, if you swallow the capsule by 
mistake

Always keep the capsules in the capsule card until you need to use them.  Do not take the 
capsules out of the card in advance

Store the T-326 Inhaler in its tightly closed case when not in use


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1.
Wash and fully dry your hands.
2.
Just before use, remove the Inhaler from its case by 
holding the base and twisting off the top of the case in an 
anti-clockwise direction.  
Set the top of the case aside.
Look at the Inhaler to make sure it is not damaged or 
dirty.  
Stand the Inhaler upright in the base of the case.
3.
Hold the body of the Inhaler and unscrew the mouthpiece 
in an anti-clockwise direction.  
Set the mouthpiece aside on a clean, dry surface.
4.
Tear along the perforations on the capsule card 
lengthwise then widthwise, as indicated in pictures (a) 
and (b).
(Note: Actual imprint on the capsule card may look slightly 
different than the illustration.)


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5.
Peel back the foil from the capsule card to reveal one 
capsule only. 
Remove that capsule from the card.
(Note: Actual capsule card may look slightly different than 
the illustration.)
6.
Put the capsule into the Inhaler chamber straightaway (a).
Replace the mouthpiece.
Screw the mouthpiece on firmly until it stops.  Do not 
overtighten (b).
7.
Hold the Inhaler with the mouthpiece pointing down. 
Pierce the capsule by pressing firmly the blue button with 
your thumb as far as it will go, then release the button.
You are now ready to inhale from the capsule in 2 
separate breaths (Steps 8 and 9).
8.
Inhale the capsule – 1st breath:
Before putting the mouthpiece in your mouth, breathe out 
fully, away from the Inhaler.
Place your mouth over the mouthpiece – to make a tight 
seal.
Inhale the powder deeply with a single breath, while 
keeping your head horizontal.
Remove the Inhaler from your mouth, and hold your 
breath for about 5 seconds.
Then breathe out normally, away from the Inhaler.
9.
Inhale the capsule – 2nd breath:
Take a few normal breaths away from the Inhaler.  When 
you are ready, take your 2nd breath by repeating Step 8, 
using the same capsule.


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10. Unscrew the mouthpiece (a) and remove the capsule from 
the chamber (b).
11. Look at the used capsule.  It should appear pierced and 
empty.  If it is empty, discard the capsule.
If the capsule is pierced but still contains some powder:
Put the capsule back into the Inhaler chamber (Step 6).  
Put the pierced side of the capsule in first.
Replace the mouthpiece and repeat Steps 8, 9 and 10.
If the capsule does not look pierced:
Put the capsule back into the Inhaler chamber (Step 6)
Replace the mouthpiece and repeat Steps 7, 8 and 9.
After this if the capsule is still full and appears not to be 
pierced, replace the Inhaler with the reserve Inhaler (from 
your 5th weekly carton) and repeat Steps 2, 3, 6, 7, 8, 9 
and 10.
12. Take the other capsules (to complete a single dose) in the 
same way. If you are unsure about how many doses to take 
each day, ask your physician or site personnel.
So for each remaining capsule, repeat Steps 5, 6, 7, 8, 9, 
10 and 11.


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13. Replace the mouthpiece and screw it on firmly until it 
stops.  When the full dose has been inhaled, wipe the 
mouthpiece with a clean dry cloth.
Do not wash the inhaler with water.
14. Place the inhaler back in its storage case.
Twist the top of the case in a clockwise direction until it 
is closed tightly.
REMEMBER:

Do not swallow the enclosed capsules.  Please inform your study coordinator or nurse 
immediately, if you swallow the capsule by mistake

Only use the Inhaler contained in this pack

Always keep the capsules in the capsule card.  Only remove a capsule just before you are 
going to use it.  Do not store the capsules in the Inhaler

Always keep the capsules and the T-326 Inhaler in a dry place

Never place a capsule directly into the mouthpiece of the T-326 Inhaler

Always hold the T-326 Inhaler with the mouthpiece pointing down when piercing the 
capsule

Do not press the piercing button more than once at a time to pierce the capsule

Never blow or breathe into the mouthpiece of the T-326 Inhaler

Never wash the T-326 Inhaler with water.  Keep it dry and store it in its case


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Additional information
Occasionally, very small pieces of the capsule can get past the screen and get into your mouth.

If this happens, you may be able to feel these pieces on your tongue

It is not harmful if these pieces are swallowed or inhaled

The chances of the capsule breaking into pieces will be increased if the capsule is 
accidentally pierced more than once or if the T-326 Inhaler is not held with the 
mouthpiece pointing down during step 7
17
Appendix 5: Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print FVC tracings.  All spirometry values 
should be reported at BTPS by the method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site. 
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:


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
Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages  for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry 

Smoking within at least 1 hour of testing

Exposure to environmental smoke, dust or areas with strong odors 
Every effort should be made to assure consistent testing conditions throughout the study.  A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope.  
When possible, spirometry should be conducted by the same technician using the same 
spirometer.  To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.  
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer.  It is important that 
the height is measured accurately at the study site. Spirometry, an effort-dependent test, 
requires careful instruction and cooperation of the subject.  The technician should ensure a 
good seal around the mouthpiece, and confirm that the subject’s posture is correct. The 
subject should be instructed to perform a maximal inspiration, followed by maximum forced 
expiration until no more air can be exhaled or for at least 6 seconds. Expiration must be rapid 
with exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 
for acceptability and repeatability. Acceptability criteria should be applied before repeatability 
is determined.  
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed.  If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued. 
Acceptability
An acceptable maneuver has the following characteristics: 

No hesitation or false start;

A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures

No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, or no volume change for at least 1 second) or the subject cannot continue 
to exhale further
Repeatability
The 2 largest FVC and FEV1 values from 3 acceptable maneuvers should not vary by more 
than 0.150 L.  
Recording of data


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The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).    
Predicted normal
For subjects 3 years of age or greater, this study will utilize the spirometric predication 
equation standards from the ERS Global Lung Function Initiative 2 or Japanese Respiratory 
Society 3 for Japanese subjects 17 years of age or greater. 
References
1 Miller MR et al, Standardization of Lung Function Testing. Eur Resp J 2005; 26:153-161.
 
 
 
3 Kubota, Kobayashi, Quanjer PH, et al. Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values. Clinical Pulmonary Functions Committee of the Japanese Respiratory Society. 
Respiratory Investigations 2014, 242-250.


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Appendix 6: QOL-B


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Appendix 12: Anti-pseudomonal medications
This table is not considered all-inclusive.
Table 24-1
Anti-pseudomonal medications
Drug class
Generic name
Aminoglycosides
Amikacin
Gentamicin
Netilmicin
Streptomycin
Tobramycin
Penicillins extended spectrum
Carbenicillin
Mezlocillin
Piperacillin
Ticarcillin


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Drug class
Generic name
ticarcillin, combination potassium clavulanate
piperacillin, combination tazobactam
Azlocillin
Fluoroquinolones
Ciprofloxacin
Enoxacin
Levofloxacin
lomefloxacin  
Moxifloxacin
Norfloxacin
Oflofloxacin
Trovafloxacin
Alatrofloxacin
Gatifloxacin
Cephalosporins
Cefepime
Cefdinir
Cefoperazone
cefoperazone, combination sulbactam
Cefotaxime
Cefpirome
Ceftazidime
Ceftizoxime
Ceftriaxone
ceftriaxone, combination tazobactam
Carbapenems
Meropenem
Dorepenem
Imipenem
imipenem, combination cilastatin
Polymixins
Colistimethate
polymixin B
Miscellaneous
Aztreonam

SAP_001.pdf: 
Clinical Development
TBM100/ Tobramycin Inhalation Powder (TIPTM)
Study number: CTBM100G2202 / NCT02712983
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
Statistical Analysis Plan (SAP)
Author:
Document type:
SAP Documentation
Document status:
Final 3.0
Release date:
21May2019
Number of pages:
79
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History - Changes compared to previous version
Version
Date
Changes
Draft v1.0
27-Jan-2017
Not applicable – first final version
Draft v2.0
26-Apr-2018
Updated SAP as per protocol amendment version 02 
dated 09Feb2018
Draft v3.0
22-Nov-2018
Updated based on the TSC comments after study being 
terminated due to business (non-safety) reason
Draft v4.0
14-Dec-2018
Updated as per the Novartis comments or response
Included forest plot as per the NVS request
Draft v5.0
01Feb2019
Updated exposure categories as per DMC mock
Updated Renal safety criteria as per DMC mock
 
Updated In-text table as per the request
Final v1.0
15Feb2019
Final version
Final v2.0
19Feb2019
Updated text from “Biotype” to “Morphotype”
25Feb2019
Updated table 5-4 and table 5-5 as per PD list
27Feb2019
Removed analysis on local AEs from section 2.7.1
Final v3.0
16May2019
Updated general definition section 2.1.1: Visit 
consideration for discontinued subject
Analysis for exposure adjusted rate of hospitalization due 
to serious respiratory-related Aes in added
20 May 2019
Section 5.4 rule for exclusion is modified
21 May 2019
Table 5.1; compliance rule is updated


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Table of contents
Table of contents.....................................................................................................................3
List of tables ...........................................................................................................................5
List of figures..........................................................................................................................5
List of abbreviations ...............................................................................................................6
1
Introduction.............................................................................................................................8
1.1
Studydesign................................................................................................................8
1.2
Study objectives and endpoints .................................................................................10
1.2.1
Primaryobjectives ....................................................................................10
1.2.2
Secondaryobjectives ................................................................................10
1.2.3
Exploratory objectives..............................................................................12
2
Statistical methods................................................................................................................15
2.1
Generalinformation ..................................................................................................15
2.1.1
General definitions...................................................................................15
2.1.2
Statistical significance..............................................................................16
2.1.3
Listings.....................................................................................................16
2.2
Analysis sets..............................................................................................................16
2.2.1
Subgroups of interest................................................................................17
2.3
Patient disposition, demographics and other baseline characteristics .......................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies,compliance)
..................................................................................................................................18
2.4.1
Study treatment / compliance...................................................................18
2.4.2
Prior, concomitant and post therapies.......................................................19
2.5
Analysis of the primary objective..............................................................................20
2.5.1
Primary efficacy endpoint ........................................................................20
2.5.2
Statistical hypothesis, model, and method of analysis .............................20
2.5.3
Handling of missing values/censoring/discontinuations..........................21
2.5.4
Supportive and sensitivity analyses..........................................................21
2.6
Analysis of secondary and exploratory efficacy objective(s) ....................................21
2.6.1
Secondary endpoints ................................................................................21
23
2.6.3
Statistical hypothesis, model, and method of analysis .............................24
2.6.4
Handling of missing values/censoring/discontinuations..........................30
2.7
Safetyanalyses..........................................................................................................30
2.7.1
Adverse events (AEs)...............................................................................30
2.7.2
Deaths.......................................................................................................32
2.7.3
Laboratory data.........................................................................................32


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2.7.4
Other safety data.......................................................................................34
2.8
Pharmacokineticendpoints .......................................................................................35
2.9
PD and PK/PD analyses............................................................................................36
2.10
Patient reported outcomes.........................................................................................36
38
2.12
Interim analysis.........................................................................................................38
3
Sample size calculation.........................................................................................................39
4
Change to protocol specified analyses..................................................................................39
 
.............................................................39
5
Appendix...............................................................................................................................41
5.1
Imputation rules for complete or partial missing dates..............................................41
5.1.1
Study drug ................................................................................................41
5.1.2
Adverse event start date imputation .........................................................41
5.1.3
Adverse event end date imputation ..........................................................42
5.1.4
Relative day of AE onset and AE end imputations..................................42
5.1.5
Concomitant medication start date imputation ........................................43
5.1.6
Concomitant medication end date imputation..........................................44
5.2
Laboratoryparameters derivations............................................................................44
.46
51
52
55
.............................................56
5.5
Patient reported outcomes – questionnaires ..............................................................58
6
References.............................................................................................................................75


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List of tables
Table 1-1
Primary and secondary objectives and related endpoints......................10
Table 1-2
Exploratory objectives and related endpoints .......................................12
Table 2-1
Severity criteria for BSI ........................................................................17
Table 2-2
Summaries of safety data.......................................................................29
Table 5-1
Criteria for potentially clinically important laboratory tests..................42
Table 5-2
Coefficients for predicted values for spirometry parameters................45
Table 5-3
Spline coefficients .................................................................................45
Table 5-4
Protocol deviations that cause patients to be excluded.........................55
Table 5-5
Patient classification..............................................................................56
List of figures
Figure 1
Study design............................................................................................9


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List of abbreviations
ACR
Albumin-creatinine ratio
ADR
Adverse Drug Reaction
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
AUD
Audiology Population
b.i.d.
twice a day
BSI
Bronchiectasis Severity Index
CI
Confidence Interval
CSR
Clinical Study Report
CFUs
Colony Forming Units
DMC
Data Monitoring Committee
DSPC
1, 2-distearoyl-sn-glycero-3-phosphocholine
eGFR
estimated Glomerular Filtration Rate
ENR
Enrolled Set
FAS
Full Analysis Set
FEF25-75
Forced Expiratory Flow at 25-75%
FEV1
Forced Expiratory Volume at 1 Second
FVC
Forced Vital Capacity
eCRF
electronic Case Report Form
ISC
Independent Study Coordinators
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MIC
Minimum Inhibitory Concentration
o.d.
once a day
PCR
Protein-creatinine ratio
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PKSSAS
Pharmacokinetic Sub-Study Analysis Set
PPS
Per-Protocol Set
PRO
Patient Reported Outcomes
PSD
Premature Subject/Patient Discontinuation
PT
Preferred Term
QoL
Quality of Life
QOL-B
Quality of Life Questionnaire for Bronchiectasis
RAN
Randomized population
SAF
Safety Set
SAP
Statistical Analysis Plan
SOC
System Organ Class


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TBL
Total Bilirubin
TD
Study Treatment Discontinuation
TIP
Tobramycin inhalation powder
TFLs
Tables, Figures, Listings
ULN
Upper Limit of Normal
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) is based on the amended protocol version 02 dated 09th
February 2018, and the business decision to close the trial earlier than planned (but not due 
to safety or efficacy reasons) by the Novartis. Recruitment has been stopped on 02nd October 
2018 with 107 patients randomized as against 180 patients initially planned. With this 
premature closure and reduced sample size, the inferential analysis, regardless if it’s pre-
defined, can be considered as exploratory, the results obtained should be interpreted with the 
caution. The plan provides a technical and detailed elaboration of the statistical analyses
of the efficacy, safety and tolerability of different doses of tobramycin inhalation powder
(TIP) in patients with Non-Cystic Fibrosis Bronchiectasis and pulmonary P. aeruginosa
infection. The specifications for tables, figures, and listings (TFLs) will be included in a 
separate document.
A clinical study report (CSR) will be written based on the results of the statistical analyses
planned within this SAP. Results will also be used for the various publications.
1.1
Study design
This is a blinded, randomized, dose and regimen finding trial utilizing a 3 treatment cohort
design where active TIP, TIP/Placebo cyclical, or placebo in addition to the local standard
care within each cohort are delivered once or twice daily (Figure 1). The study will 
implement a within-cohort blinding approach. This allows assessment of the tolerability 
(defined as the rate of local AEs) of different doses and regimens of TIP, and also saves the 
treatment burden that would be imposed for blinding across all arms. Note that all of the 
patients in the study would need to inhale the maximal dose of 10 capsules every day (5
morning + 5 evening) to maintain the blind between cohorts (different dose levels) and within 
a cohort (different regimens).
Approximately 180 eligible patients will be randomized to 1 out of the 3 cohorts in a ratio of
1:1:1. The patients within each cohort will be randomized to blinded TIP or placebo with the
following randomization scheme: TIP: TIP/placebo cyclical: placebo, in a 2:2:1 ratio.
At Visit 101 (see protocol [Table 6-1 – Assessment schedule]), all eligible patients will be
randomized via Interactive Response Technology (IRT) to 1 of the treatment arms with the
randomization strata (use of macrolides as part of their standard of care therapy yes/no). To
evaluate serum pharmacokinetics (PK) in approximately 16 patients on active treatment, at
least 20-22 patients from each cohort (at least 60 total patients) will participate in a PK sub-
study. To ensure a balanced distribution across cohorts, this will be captured in IRT. The
investigator or his/her delegate will contact the IRT after confirming that the patient fulfills
all the inclusion/exclusion criteria. The IRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of investigational treatment to be dispensed to the patient. The
randomization number will not be communicated to the user.
The randomization numbers will be generated using the following procedure to ensure that
treatment assignment is unbiased and concealed from patients and investigator staff. A patient
randomization list will be produced by the IRT provider using a validated system that
automates the random assignment of patient numbers to randomization numbers. These
randomization numbers are linked to the different treatment arms, which in turn are linked to
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates
the random assignment of medication numbers to packs containing the investigational drug(s).
The treatment arms distributed among the 3 cohorts are described below. TIP is supplied in
hard capsules at 28mg dosage strength, therefore 3 cohorts correspond to 3 different dose


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levels of TIP, i.e., 84mg once a day (o.d.), 140mg o.d. and 112mg twice a day (b.i.d.).
Cohort A: 3 capsules o.d.

TIP: 3 capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T-326
Inhaler, for 112 days (on treatment).

TIP/placebo cyclical: patients will take the same doses, i.e. 3 capsules o.d., by
alternating TIP 28-days with placebo 28-days for 2 cycles for a total of 112 days.

Placebo: The reference product consists of placebo capsules (DSPC/CaCl2). The
dose regimen for the reference product is 3 capsules blinded, inhaled o.d. via the T-
326 Inhaler, for 112 days (on treatment).
Cohort B: 5 capsules o.d.

TIP: 5 capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T-326
Inhaler, for 112 days (on treatment).

TIP/placebo cyclical: patients will take the same doses, i.e. 5 capsules o.d., by
alternating TIP 28-days with placebo 28-days for 2 cycles for a total of 112 days.

Placebo: The reference product consists of placebo capsules. The dose regimen for
the reference product is 5 capsules blinded, inhaled o.d. via the T-326 Inhaler, for
112 days (on treatment).
Cohort C: 4 capsules b.i.d.

TIP: 4 capsules of blinded TIP at 28 mg dosage strength, inhaled b.i.d. in the
morning and in the evening via the T-326 Inhaler, for 112 days of treatment.

TIP/placebo cyclical: patients will take same doses, i.e. 4 capsules b.i.d., by
alternating TIP 28-days with placebo 28-days for 2 cycles for a total of 112 days.

Placebo: The reference product consists of placebo capsules. The dose regimen for
the reference product is 4 capsules blinded, inhaled b.i.d. via the T-326 Inhaler, for
112 days (on treatment).
There will be 3 study epochs with a total of 9 visits (Figure 1):

Screening: up to 28 days with 1 clinic visit

Double-blind treatment (within cohort): 112 days with 6 clinic visits [Visit 101 (Day 1),
Visit 102 (Day 8), Visit 103 (Day 29), Visit 104 (Day 57), Visit 105 (Day 85) and Visit
106 or study treatment discontinuation (TD) (Day 113)]

Follow-up: 56 days with 2 clinic visits [Follow-up Visit 201 (Day 141) and Follow-up
Visit 202  or premature subject/patient discontinuation (PSD) (Day 169)
The total duration of the study is expected to be up to 196 days. Patients will be assessed for
safety, tolerability and efficacy (see protocol [Table 6-1 – Assessment schedule]).


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Figure 1
Study design
The primary efficacy endpoint is the absolute change from baseline to Day 29 of treatment in
the bacterial load in sputum in log10 colony forming units (CFUs) of P. aeruginosa. Baseline
is defined as the last measurement prior to the first dose of blinded study drug.
No interim analysis for efficacy is planned. There is an independent data monitoring
committee (DMC) assigned to monitor the safety during the study; further details are defined
in the DMC Charter.
1.2
Study objectives and endpoints
1.2.1
Primaryobjectives

To evaluate the effect of different doses of TIP, administered o.d. or b.i.d. , on the change
in P. aeruginosa bacterial load in sputum as assessed by the change in CFUs from
baseline to Day 29 of treatment, each compared to placebo.

To assess the safety and tolerability with different doses of TIP, administered o.d. or b.i.d.,
and different regimens (TIP and TIP/placebo cyclical) during the treatment epoch (112
days) and during the follow-up epoch (56 days), each compared to placebo.
1.2.2
Secondaryobjectives

To assess the effect of different doses of TIP administered o.d. and one b.i.d. dose and
different regimens (TIP and TIP/placebo cyclical) on the frequency, rate (by patient
months), severity and time to onset of pulmonary exacerbations at the end of the
treatment epoch and over the entire study, each compared to placebo.

To assess the efficacy profile of different doses of TIP administered o.d. and one b.i.d.
dose and different regimens (TIP and TIP/placebo cyclical), as measured by the time to
first use, proportion of patients requiring anti-pseudomonal antibiotics (overall, oral,
parenteral) and the duration of treatment, each compared to placebo.


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
To assess the time to first hospitalization, proportion of patients requiring hospitalization 
and the duration of hospitalization due to serious respiratory-related AEs (other than
those regularly scheduled hospitalization that were planned prior to study start).

To assess the pharmacokinetic concentrations of tobramycin in serum and in sputum from
different doses of TIP administered o.d. and one b.i.d. dose and different regimens (TIP
and TIP/placebo cyclical).

To assess the antimicrobial efficacy of TIP over the entire study duration, as measured by
the absolute change in P. aeruginosa -CFUs in sputum from baseline to each post-
baseline treatment visit and during the follow-up visits.

To evaluate the safety profile of TIP in terms of clinical laboratory results.

To evaluate the safety profile of TIP in terms of audiology findings throughout the
treatment epoch (subgroup of all patients that are in enrolled at sites that are adequately
equipped and trained to perform audiologic assessments).

To evaluate the safety profile of TIP in terms of acute change in forced expiratory volume
at 1 second (FEV1) % predicted values from pre-dose to 30±15 minutes after completion
of study drug administration at the clinical site at visits during the treatment epoch.

To evaluate the impact of treatment with TIP on the Respiratory Symptom Scale Quality
of Life Questionnaire for Bronchiectasis (QOL-B) by measuring change from baseline to
all post-baseline visits.
Table 1-1
Primary and secondary objectives and related endpoints
Objective
Endpoint
Statistical
Analysis
Primary
Section #
To evaluate the effect of different doses
of TIP on the change in P. aeruginosa
bacterial load in sputum at Day 29
To assess the safety and tolerability
with different doses of TIP and different
regimens, on treatment epoch and over
entire study duration
Secondary
To assess the antimicrobial efficacy of
TIP over the entire study duration
To assess the effect of different doses
of TIP and different regimens on
pulmonary exacerbation at the end of
treatment epoch (Day 113) and over the
study period
Change from baseline to Day 29 in P.
aeruginosa density in sputum (log10 CFUs)
Safety: incidence rate of AEs/Serious AEs
by MedDRA primary SOC and PT terms
Tolerability: incidence and severity of local
AEs (eg. cough, bronchospasm, dysgeusia,
dry mouth, etc. )
Change from baseline to each post-baseline
visit in P. aeruginosa density in sputum
(log10 CFUs)
Time to first pulmonary exacerbation by
exacerbation category
Duration of pulmonary exacerbations by
exacerbation category
Exposure adjusted rate of exacerbations
Proportion of patients with at least one
pulmonary exacerbation by exacerbation
category
Proportion of patients who permanently
2.5.2
2.7.1
2.6.3.1
2.6.3.2
discontinued study drug due to pulmonary


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Objective
Endpoint
Statistical
Analysis
To assess the efficacy profile of different
doses of TIP and different regimens as
measured by anti-pseudomonal
antibiotics usage during the treatment
epoch (through Day 113) and the study
period
To assess the hospitalization (other
than those regularly scheduled
hospitalization that were planned prior
to study start)
To evaluate the safety profile of TIP in
terms of clinical laboratory results
To evaluate the audiology safety profile
of TIP
To evaluate the safety profile of TIP in
terms of bronchial hyperreactivity
To evaluate the treatment effect of TIP
on the Respiratory Symptom Scale
Quality of Life Questionnaire for
Bronchiectasis (QOL-B)
Pharmacokinetic concentrations of
tobramycin in serum and in sputum
exacerbation
Time to permanent study drug
discontinuation due to pulmonary
exacerbation
Time to first use (overall, oral, and -
parenteral) of anti-pseudomonal
antibiotics usage
Proportion of patients used anti-
pseudomonal antibiotics usage
Duration of anti-pseudomonal antibiotics
usage
Time to first hospitalization due to serious
respiratory-related AEs
Number of hospitalizations due to serious
respiratory-related AEs
Proportion of patients requiring
hospitalization due to serious respiratory-
related AEs
Duration of hospitalization due to serious
respiratory-related AEs
Laboratory results (hematology, serum
chemistry, urine dipstick tests): means,
mean changes from baseline,
frequency/shift tables by visit
Audiology findings (selected centers) by
visit
Acute change in FEV1 % predicted values
from pre-dose to 30±15 minutes after
completion of study drug administration at
the clinical site at visits during the treatment
epoch
Change from baseline to all post-baseline
visits
Concentration data at scheduled visits and
timepoints
2.6.3.3
2.6.3.4
2.7.3
2.7.4.1
2.7.4.4
2.10
2.8
1.2.3
Exploratory objectives


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
To explore the characteristics of the post-inhalational events at all visits during the
treatment epoch.

To explore the impact of healthcare resource utilization of TIP treatment.
Table 1-2
Exploratory objectives and related endpoints
Objective
Endpoint
Statistical
Analysis


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Objective
Endpoint
Statistical
Analysis
To explore the characteristics of the
post-inhalational events
Separate summaries for post-inhalation
clinical events and post-inhalation adverse
events:
2.7.4.3
Proportion of patients experiencing events
at each visit
Proportion of patients experiencing events
that are ongoing at the completion of the
visit
Proportion of patients experiencing events
with an action taken to reduce the event
Time of onset of event
Duration of event
Number of post-inhalation events
Event rate adjusted for exposure
To explore the impact of healthcare
resource utilization of TIP treatment
All scheduled and unscheduled visits
2.7.4.5


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2
Statistical methods
The study is characterized by 3 cohorts (corresponding to 3 doses). Each cohort consists of
TIP, TIP/placebo cyclical, or placebo in a ratio of 2:2:1. Data will be summarized and
analyzed by cohort/dose, treatment arms (including combined treatments) and/or pooled by 
continuous, cyclic and placebo as appropriate. For the efficacy analyses, the placebo patients 
will be pooled from the 3 cohorts.
2.1
General information
. Statistical analyses will be performed using
SASVersion 9.3 (or higher).
In general, all data will be reported as observed. No imputation will be performed for the
primary efficacy analysis. Supportive and sensitivity analyses are discussed in Section 2.5.4
to evaluate the robustness of primary analysis results.
Descriptive statistics (n, mean, standard deviation [SD], median, minimum, and maximum)
will be calculated for continuous data. Minimum and maximum will be presented to the same 
number of decimal places as reported/collected, 1 additional decimal place for mean and
median, and 2 additional decimal places for SD. Derived data will be reported to 1 additional
decimal place as the reported data.
Categorical data will be summarized using n and percentages based on the number of non-
missing values. Percentages will be presented to 1 decimal place. The number of missing
values will be presented as a separate category with no percentage, but only if 1 or more
patients are missing data for the summary. Otherwise, all categories will be presented (even
if no patients are counted in the category). Counts of zero in any category will be presented
without a percentage.
2.1.1
General definitions
Study drug is defined as any single dose of TIP or placebo administered to the patient as part
of the required study procedures.
The date of first dose of study drug is defined as the date of first administration of TIP or
placebo; the date of last dose of study drug is defined as the date of the last administration of
TIP or placebo.
For dates on or after the date of first dose of study drug, study day is defined as [date of
interest – date of first dose of study drug] + 1. For dates before the date of first dose of study
drug, study day is defined as [date of first study drug – date of interest].
For each visit, the date recorded by the investigators in the eCRF (variable SVSTDTC in the
SDTM SV dataset) will be considered as the visit date in all the algorithms and the listings.
In genereal, the nominal visits will be used for the by visits summaries. However, for early 
treatment discontinued patients, data collected at end of treatment (EOT) visit will be mapped 
to next planned visits after their last scheduled visits before the discontinuation.
Baseline is defined as the last non-missing result prior to the first administration of study
drug.
End/last date of study for each patient is defined by the date of last contact as recorded in the
database.


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2.1.2
Statistical significance
The step-wise Dunnett procedure will be used for the primary efficacy analysis to control the
family-wise type-I error rate (3 dose levels versus placebo) at the 2-sided 5% significance
level (Section 2.5.2). Unless otherwise specified, other inferential analyses and confidence
intervals (CIs) will be conducted at the 2-sided 5% significance level with no multiplicity
adjustment.
2.1.3
Listings
All data collected in the eCRF and diaries will be presented in the listings.
Data will be presented in listings in the order of cohort [Cohort A: 3 capsules OD, Cohort B:
5 capsules OD and Cohort C: 4 capsules BID], treatment arm [TIP, TIP/Placebo Cyclical and
Placebo], site/patient identifier, assessment date and assessment (in order collected in the
eCRF, unless specified otherwise). AE listings will include the AE start day and AE stop day
relative to the first day of study drug. Dates will be presented in format DDMMMYYYY.
2.2
Analysis sets
Safety Set (SAF): The safety set will be used for all safety analyses, which is defined as
patients who received at least 1 dose of study drug. Patients will be analyzed according to the
actual treatment received.
For the purposes of tables and listings a further 3 populations are defined:

All enrolled patients (ENR)

Screening failure patients

Randomized population (RAN: all randomized patients)
Full Analysis Set (FAS): The full analysis set (FAS) will include all randomized patients
who received at least 1 dose of study drug. Following the intent-to-treat principle, patients
will be analyzed according to the treatment they are assigned to at randomization, which may
be different from the actual treatment received. Patients who are mistakenly randomized 
or who have not taken double blind study drug will be excluded from the FAS. This is the
primary analysis set for all efficacy analyses.
Per-Protocol Set (PPS): The per-protocol set (PPS) will include all patients in the FAS
without any major protocol deviations.
Criteria for determining protocol deviations will be defined and documented in the protocol
deviations section of the data validation specifications. Potential protocol deviators will be
identified and reviewed to determine whether they will be excluded from the PPS population.
This will take place in a blinded data review meeting prior to database lock. All protocol
deviations will be agreed and documented prior to unblinding the study. The PPS will be
used for the supportive analysis of the primary efficacy variable.
Pharmacokinetic Analysis Set (PKAS): The pharmacokinetic analysis set (PKAS) will
include all patients who are administered TIP, and for whom results of plasma concentrations
are obtained for at least one sampling point during the study.
Pharmacokinetic Sub-study Analysis Set (PKSSAS): The pharmacokinetic sub-study
analysis set (PKSSAS) will include all patients enrolled in the pharmacokinetic sub-study


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who are administered TIP, and for whom results of plasma concentrations are obtained for at
least one sampling point during the study.
Audiology Population (AUD): The audiology population is defined as all patients in the safety 
set with at least one audiology test performed.
2.2.1
Subgroups of interest
Primary endpoint analysis will be repeated in the subgroup of patients with/without macrolide
treatment at baseline, only if clinical meaningful difference was observed between the pooled 
active doses vs placebo.
2.3
Patient disposition, demographics and other baseline
characteristics
The number of patients screened and the number of screen failures will be presented (overall).
The number of patients included in each of the Randomized, SAF, FAS, PPS, AUD, 
PKAS and PKSSAS populations will be summarized for each cohort, treatment arm and 
overall.
Patients who complete the treatment phase and patients who complete the follow-up phase
will be summarized using the FAS. Patients who discontinue from the treatment phase and
patients who discontinue the follow-up phase will be summarized overall and by reason for
discontinuation using the FAS.
The FAS will be used to summarize the following by cohort and treatment arm:

Demography: age, age group (< 65 years and >=65 years), gender, race and ethnicity,
weight (kg), height (cm), body mass index (BMI).

Baseline characteristics: baseline spirometry (FEV1, 
) %predicted
values, MIC, macrolide use, bronchodilators, inhaled corticosteroids, tobramycin
MIC=>8 at baseline, BSI.

Medical history - ototoxicity

History of pulmonary exacerbations

Bronchiectasis-related medical history

Spirometry assessed at screening

Previous hospital admissions and exacerbations

Other relevant medical history
Age will be calculated as the difference between year of birth and year of informed consent.


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The following table will be used to derive the BSI:
Table 2-1
Severity criteria for BSI
Criteria/Point
0
1
2
3
4
5
6
Age
<50
50-69
70-79
80+
BMI (kg/m2)
≥18.5
<18.5
FEV1 % predicted
>80%
50-80%
30-49%
<30%
Hospital admissions in
the past 2 years
No
Yes
Exacerbation frequency
in the last 12 months
0-2
≥3
MRC dyspoea
1-3
4
5
Colonisation status
Not
colonised
Chronic
colonisation
P.aeruginosa
colonisation
Radiological severity
<3 lobes
involved
≥3 lobes or
cystic
changes
Medical history recorded in the eCRFs will be reviewed to determine whether a patient had a
hospital admission in the past 2 years. The pulmonary exacerbation history eCRF data will be
reviewed to determine the exacerbation frequency in the 12 months prior to Screening.
If any individual severity criteria cannot be assessed for a patient due to missing or
incomplete data, the BSI total score will not be derived.
Smoking history will be listed in patient listing only.
Listings will be provided to show all demographic and baseline characteristics using the
randomized population.
Major protocol deviations will be summarized by cohort and treatment arm using the FAS.
2.4
Treatments (study treatment, rescue medication, concomitant
therapies, compliance)
2.4.1
Study treatment / compliance
Overall exposure (days) to study treatment will be summarized in terms of treatment duration,
defined as the number of days from the date of first dose of study drug taken to the date of
the last dose of study drug taken, inclusive, i.e., date of last dose of study drug – date of first
dose of study drug + 1.
Assessment of compliance will be based on the number of unused capsules returned per
patient assessed by the Independent Study Coordinators (ISC).
Compliance will be derived using the following formula:


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Compliance = (number of actual inhaled capsules / number of intended inhaled capsules
during the derived treatment period) * 100%
The number of intended inhaled capsules during the treatment period will be derived
as follows:

Cohort A: 3 * treatment duration

Cohort B: 5 * treatment duration

Cohort C: 8 * treatment duration
Compliance will also be assessed by visit period. Four specific periods will be defined, i.e.,
Visit 101 to Visit 103, Visit 103 to Visit 104, Visit 104 to Visit 105, and Visit 105 to Visit
106. This will be used to review the compliance for each on/off active treatment period for 
the cyclical TIP/placebo treatment arms.
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be presented by 
cohort and treatment arm for the FAS for overall exposure, and both compliance over the 
treatment period and compliance by visit period. Duration of exposure will be further 
categorized as 
<=22 days, 23-28 days, 29-56 days, 57-84 days, 85-112 days, >= 113 days, 
and the number and percentage of patients by cohort and treatment arm will be presented for 
each category for the FAS.
The number and percentage of patients with study drug compliance <80% and >=80% over
the treatment period and for each visit period will also be summarized by cohort and
treatment arm using the FAS.
Overall duration of study (days), defined as the number of days from the date of
randomization to the date of study completion, i.e., date of study completion – date of
randomization + 1, will be summarized descriptively (n, mean, SD, minimum, median, and
maximum) by cohort and treatment arm for the FAS.
2.4.2
Prior, concomitant and post therapies
The latest version available prior to database lock of the World Health Organization (WHO)
drug dictionary will be used to classify prior, concomitant and rescue medications by
therapeutic class.
Prior medication is defined as any medication with a stop date prior to the date of the first
dose of study drug.
Concomitant medication is defined as any medication with a start date prior to the date of the
first dose of investigational product and continuing after the first dose of investigational
product or with a start date on or after the date of the first dose of study drug.
Post-treatment medication is defined as any medication with a start date after the date of the
last dost of study drug.


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Rescue medication for pulmonary exacerbations (including systemic antibiotics) and for
bronchospasm is allowed. Use of rescue medication will be recorded on the Concomitant
medications/Significant non-drug therapies CRF.
The number and percentage of patients taking prior, concomitant and rescue medications
will be summarized by treatment and by Anatomical Therapeutic Classification (ATC) and
preferred term. Each prior, concomitant and rescue medication could be classified by more
than 1 ATC and will be counted for each. Summary tables will be provided for rescue and
concomitant medications started prior to study drug, started on or after the start of study drug
and for non-cystic fibrosis bronchiectasis related medications started on or after the start of
study drug. Multiple medication usage by a patient in the same category will be counted only
once. Summaries will be based on the SAF.
All prior, concomitant and rescue medications and therapies will also be listed.
2.5
Analysis of the primary objective
The analysis of the primary efficacy variable will be based on the FAS.
2.5.1
Primary efficacy endpoint
The primary efficacy variable is the absolute change in the bacterial load in sputum as
assessed by the change in log10 CFUs of P. aeruginosa from baseline to Day 29 of treatment.
The specimens with more than 1 bacterial morphotype, the sum of all bacterial morphotype
will be used to calculate change from baseline values.
2.5.2
Statistical hypothesis, model, and method of analysis
The comparisons of 3 doses of active treatment (TIP 3 capsules OD, 5 capsules OD, and 4
capsules BID) versus pooled placebo will be evaluated by testing the following null
hypothesis (H0) versus the alternative hypothesis (Ha):
H0: TIP treatment arm is equal to pooled placebo group in bacterial load in sputum at Day 29
Ha: TIP treatment arm is not equal to pooled placebo group in bacterial load in sputum at Day
29
The primary efficacy endpoint will be analyzed using the analysis of covariance (ANCOVA)
model. The model will contain treatment, baseline CFU (in log 10 unit), and baseline
macrolide use (yes/no). The adjusted means will be displayed together with the associated
standard error and 2-sided 95% CI. Pairwise comparisons of TIP dosing groups will be
conducted versus placebo. To control the family-wise type-I error rate (3 dose levels vs.
placebo) at the 2-sided 5% significance level, the step-wise Dunnett procedure will be used.
For the primary efficacy analysis, patients from treatment arms TIP and TIP/placebo cyclical
regimen will be pooled for each cohort. This is possible because all patients within the same
cohort on the TIP treatment arms (cyclical or continuous) are receiving the same treatment
during the first 28 days. Placebo patients will be pooled across the 3 cohorts, as the number
of placebo capsules is not expected to influence the change in P. aeruginosa bacterial counts.


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The estimated adjusted treatment difference (TIP – placebo) will be displayed along with the
associated standard error, 2-sided 95% CI, and p-value (2-sided).
The estimated treatment difference and CI will be displayed in forest plot for the treatment 
arms TIP and TIP/placebo cyclical regimen pooled for each cohort vs pooled placebo across 3 
cohorts.
For other efficacy analyses up to and including Day 29, patients from treatment arms TIP and
TIP/placebo cyclical regimen will be pooled for each cohort; placebo patients will be pooled
across the 3 cohorts.
If no P. aeruginosa isolated (NPAI) are detected, i.e, no growth detected, at a given visit
where the laboratory sample was available at that visit, the value will be imputed as 99 based
on the lower limit of detection (dilution factor is currently 1/100). Log 10(99) will be used in
the analysis.
2.5.3
Handling of missing values/censoring/discontinuations
No imputation will be performed for missing data for the primary endpoint.
2.5.4
Supportive and sensitivity analyses
1. The non-parametric Mann-Whitney-Wilcoxon test will be carried out as a sensitivity
analysis due to the potential non-normality of the CFU data.
2. The primary efficacy analysis will be repeated in the PPS as a supportive analysis.
2.6
Analysis of secondary and exploratory efficacy objective(s)
For efficacy analysis, patients assigned to placebo arms will be pooled across the 3 cohorts,
as the number of placebo capsules is not expected to impact the efficacy assessments. Unless
otherwise specified, the following analysis will be conducted both over the treatment epoch
(through Day 113) and over the entire study period (through Day 169).
2.6.1
Secondary endpoints
2.6.1.1
P. aeruginosa colony forming units (CFU)
Anti-microbial efficacy of TIP versus placebo over the entire study duration, as measured by
the absolute change in log10 CFUs of P. aeruginosa in sputum from baseline to each post-
baseline visit (Visits 102 (Day 8), 103 (Day 29), 104 (Day 57), 105 (Day 85) and 106 (Day
113)), will be assessed by morphotype and sum of all morphotypes (mucoid, dry, small
colony-variants). For patients with a negative P. aeruginosa result, i.e, NPAI, the
quantitative test result for the analysis will be imputed for each morphotype with log (99)
as this represents the detection level for a dilution of 100. Means together with the 95%
CIs will be graphically displayed over time. The summaries will be provided by treatment
groups Cohort A: TIP, Cohort A: TIP/placebo cyclical, Cohort B: TIP, Cohort B:
TIP/placebo cyclical, Cohort C: TIP, Cohort C: TIP/placebo cyclical, Pooled TIP and Pooled 
TIP/placebo cyclical and pooled placebo. Comparisons between treatment regimens across 
all cohorts versus pooled placebo will also be analyzed.
The number and percentage for patients with no P. aeruginosa in sputum and number and
percentage of patients with a positive result of P. aeruginosa in sputum will be tabulated by
cohort,
treatment
arm,
pooled arms by continuous and cyclic regimens
and
visit.
Percentages will be based on the number of patients for whom microbiology results exist 
per visit.


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The number and percentage of patients with NPAI at 2 consecutive post-baseline visits will
also be presented by cohort and treatment arm, pooled arms by continuous and cyclic 
regimens.
2.6.1.2
Pulmonary exacerbations
Patients with pulmonary exacerbations (pulmonary exacerbation is defined in [Section 6.4.4
of the protocol] will be categorized into the following:

Category 1: pulmonary exacerbations requiring oral antibiotics only

Category 2: pulmonary exacerbations requiring parenteral antibiotics and/OR
pulmonary exacerbation requiring hospitalization 
A patient could be counted in more than 1 exacerbation category.
In addition to the antibiotics listed in Appendix 12 of the protocol, concomitant medication
data will be reviewed on an ongoing basis. A list identifying all relevant antibiotics used for
the treatment of pulmonary exacerbations will be provided prior to database lock.
Pulmonary exacerbations requiring hospitalization will be identified from the adverse event –
pulmonary exacerbations eCRF data.
The following pulmonary exacerbation-related parameters over the treatment epoch (through
Day 113) and the study period (unless otherwise stated) will be summarized by cohort and
treatment arm. In addition, data will also be pooled and summarized for all three continuous TIP 
regimens together and all three cyclic TIP regimens together.

The proportion of patients with at least 1 pulmonary exacerbation overall 
and by exacerbation category

Number of pulmonary exacerbations overall and by exacerbation category

Time to first pulmonary exacerbation overall and by exacerbation category for 
overall study period

The exposure adjusted rate of pulmonary exacerbations overall

Duration of pulmonary exacerbations in days by exacerbation category

Time to permanent study drug discontinuation due to pulmonary exacerbation for 
overall study period

The proportion of patients who permanently discontinued study drug 
due to pulmonary exacerbation
In addition, the pulmonary exacerbation signs and symptoms lasting for more than 24 
hours and 48 hours, respectively, will be summarized separately (see section 2.6.3.2).


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2.6.1.3
Anti-pseudomonal antibiotics
The following anti-pseudomonal antibiotics-related parameters will be assessed by cohort
and treatment arm and also by pooled three continuous TIP regimens and pooled three cyclic 
TIP/placebo regimens.

Proportion of patients requiring anti-pseudomonal antibiotics (overall, oral,parenteral)

Time to first use of anti-pseudomonal antibiotics across the entire study period

The exposure adjusted rate of usage of anti-pseudomonal antibiotics across the entire
study period

Duration of anti-pseudomonal antibiotic use across the entire study period
Anti-pseudomonal antibiotics will be identified prior to database lock.
2.6.1.4
Hospitalization
The following hospitalization-related parameters will be assessed by cohort and treatment arm,
by pooled three continuous TIP regimens and pooled three cyclic TIP/placebo regimens:

Time to first hospitalization due to serious respiratory-related AEs across the entire
study period

Duration of hospitalization due to serious respiratory-related AEs across the entire
study period

Number of hospitalizations due to serious respiratory-related AEs across the entire
study period

Proportion of patients requiring hospitalization due to serious respiratory-related AEs
across the entire study period


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2.6.3
Statistical hypothesis, model, and method of analysis
In general, unless otherwise specified, the following 6 pairwise comparisons will be
performed for the secondary endpoints at the 5% significance level without multiplicity
adjustment, wherever an inferential analysis is specified:

TIP 3 capsules OD versus pooled placebo

TIP/placebo cyclical 3 capsules OD versus pooled placebo

TIP 5 capsules OD versus pooled placebo

TIP/placebo cyclical 5 capsules OD versus pooled placebo

TIP 4 capsules BID versus pooled placebo

TIP/placebo cyclical 4 capsules BID versus pooled placebo
Descriptive summary statistics by cohort, treatment arm, pooled treatment arm by regimen and 
pooled placebo will be provided where applicable.
In addition, data will also be summarized for selected endpoints, by pooling continuous TIP 
regimens together (i.e. TIP 3 capsules OD. from Cohort A + TIP 5 capsules OD from Cohort
B+ TIP 4 capsules BID from cohort C) and pooling cyclic TIP regimens together (i.e. 
TIP/placebo cyclical 3 capsules OD from Cohort A + TIP/placebo cyclical 5 capsules OD. from 
Cohort B+ TIP/placebo 4 capsules BID cyclical from cohort C ) vs pooled placebo. 
In addition, the following 2 pairwise comparisons will be performed for the selected 
endpoints at the 5% significance level without multiplicity adjustment: 

Pooled TIP continuous regimens versus pooled placebo

Pooled TIP/placebo cyclical regimens versus pooled placebo.
Forest plot will be plotted for below endpoints in addition to the primary endpoint for each 
treatment arm across 3 cohorts compared with pooled placebo separately and also for the 
comparison between pooled TIP continuous (pooled from 3 cohorts) with pooled placebo and for 


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the comparison between pooled TIP/placebo cyclic (pooled from 3 cohorts) with pooled placebo.

LS Mean difference in log10 CFUs of P. aeruginosa in sputum and CI

For exposure adjusted rate and CI of pulmonary exacerbations during the study

For incident rate ratio and CI for anti-pseudomonal antibiotics during the study

Incident rate ratio and CI hospitalization due to serious respiratory-related AEs across 
the entire study period

LS Mean difference in QoL-B RSS and CI
2.6.3.1
P. aeruginosa colony forming units (CFU)
The primary efficacy parameter (CFU) will be analyzed using a similar ANCOVA model as
used in primary efficacy analysis at Day 85, Day 113 and Day 169. The model will contain
treatment, baseline CFU (in log 10 unit), and baseline macrolide use (yes/no).
The analysis will not be performed by the subgroup of morphotypes. Six pairwise
comparisons will be evaluated as specified in Section 2.6.3 The estimated adjusted treatment
difference for each of the 6 comparisons (TIP–placebo) will be displayed along with the
associated standard error, 2-sided 95% CI.. In addition, CFU data will be summarized by
morphotype and sum of all morphotypes at each scheduled visit.
2.6.3.2
Pulmonary exacerbations
The proportion of patients reporting pulmonary exacerbations during the treatment period, 
follow up period and across the entire study period will be summarized by cohort and by 
treatment arm and by pooled arms by regimen for continuous and cyclic regimen
The proportion of patients in each exacerbation category (as defined in Section 2.6.1.2) will
be summarized during the treatment period, follow up period and across the study period by
cohort and treatment arm.
Overall and within each pulmonary exacerbation category, the number of events will be
summarized during the treatment period and across the study period by cohort and treatment
arm.
In addition, summaries of the number and percentage of patients experiencing individual
pulmonary exacerbation symptoms will be presented during the treatment period and across
the study period by duration of symptoms (> 24 hours and > 48 hours):

Frequency of each symptom/ finding

Any two symptoms/ findings that most often occur together and may be combined into 
one symptom

Combination of 3 symptoms/findings that occur together in the majority of Pulmonary 
Exacerbations
Symptoms will be further categorized as follows:

Sputum/viscosity/purulence > 24h [at least 1 of the 3 symptoms reported as > 24h]

Malaise/fatigue/lethargy > 24h [at least 1 of the 3 symptoms reported as >24h]

Shortness of breath at rest/exercise >24 h [at least 1 of the 2 symptoms as >24h]
The number and percentage of pulmonary exacerbations in each category will be presented 
during the treatment period and across the study period by cohort and treatment arm.
In addition, the number of pulmonary exacerbation signs and symptoms last for more than 48 


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hours will be summarized separately including below categories.

Sputum/viscosity/purulence > 48h [at least 1 of the 3 symptoms reported as > 48h]

Malaise/fatigue/lethargy > 48h [at least 1 of the 3 symptoms reported as >48h]

Shortness of breath at rest/exercise >48 h [at least 1 of the 2 symptoms as >48h]
Time to first pulmonary exacerbation
The time to first pulmonary exacerbation overall will be analyzed using a Cox regression
model stratified by baseline macrolide use. The model will include treatment as a fixed-effect
factor, and number of pulmonary exacerbations in the 12 months prior to screening as a
covariate. Six pairwise comparisons will be evaluated as specified in Section 2.6.3, in 
addition two pairwise comparisons will be evaluated between pooled continuous regimens vs 
pooled placebo and, between pooled cyclic regimens and pooled placebo. The estimated 
adjusted hazard ratio for TIP over placebo will be displayed along with the associated 2-sided 
95% CI. For analyses conducted across the treatment period, patients will be censored at the
time of last dose of study drug if they did not have a pulmonary exacerbation during the
treatment period. Similarly, for analyses conducted across the study period, patients will be
censored at the time of last contact if they did not have a pulmonary exacerbation during the 
study period.
Kaplan-Meier analysis stratified by cohort and treatment arm a n d  by pooled arms 
(continuous and alternating regimens) will be also presented and displayed graphically.
The time to first pulmonary exacerbation requiring parenteral antibiotics or hospitalization, and 
the time to first pulmonary exacerbation requiring hospitalization will also be analyzed using 
the same approach as described for the time to first pulmonary exacerbation overall.
The exposure adjusted rate of pulmonary exacerbations overall
The exposure adjusted rate of exacerbations will be determined across the treatment period
and will be derived as follows:
(Number of pulmonary exacerbations reported during the treatment period / sum of
exposure time during the treatment period for all patients during the treatment period) /
365.25
The number of pulmonary exacerbations during the treatment period will be analyzed using a
generalized linear model assuming the negative binomial distribution including treatment and
baseline macrolide use as fixed-effect factors, and number of pulmonary exacerbations in the
12 months prior to screening as a covariate. The log exposure to treatment in years will be
included as an offset variable in the model.
Six pairwise comparisons will be evaluated as specified in Section 2.6.3, in addition two 
pairwise comparisons will be evaluated between pooled continuous regimens vs pooled placebo 
and, between pooled cyclic regimens and pooled placebo. The estimated rate ratio along with
2-sided 95% interval will be provided.
The exposure adjusted rate of exacerbations across the entire study period will be derived as
follows:
(Number of patients with a pulmonary exacerbation during the study period / sum of study
period duration for all patients during the study period) / 365.25.
The number of pulmonary exacerbations during the entire study period will be analyzed in a
similar manner as the pulmonary exacerbations during the treatment period; the log time in
study in years will be included as an offset variable in the model.


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Duration of pulmonary exacerbations overall
The duration of pulmonary exacerbations is defined as the sum of the duration of days
recorded as an exacerbation for all exacerbations recorded per patient. This will be derived
across the treatment period and across the study period. The duration of pulmonary
exacerbations will be analyzed using an ANCOVA model. The model will include treatment
as a fixed-effect factor, and number of pulmonary exacerbations in the 12 months prior to
screening as a covariate.
Six pairwise comparisons will be evaluated as specified in Section 2.6.3, in addition two 
pairwise comparisons will be evaluated between pooled continuous regimens vs pooled placebo 
and, between pooled cyclic regimens and pooled placebo. The estimated adjusted treatment
difference for each of the comparisons (TIP–placebo) will be displayed along with the 
associated standard error, 2-sided 95% CI.
Time to permanent study drug discontinuation due to pulmonary exacerbation
The proportion of subjects
who
permanently discontinue study drug
to pulmonary
exacerbation will be summarized by cohort and treatment arm.
The time to permanent study drug discontinuation due to pulmonary exacerbation will be
analyzed using a Cox regression model stratified by baseline macrolide use. The model will
include treatment as a fixed-effect factor, and number of pulmonary exacerbations in the 12
months prior to screening as covariate. Six pairwise comparisons will be evaluated as
specified in Section 2.6.3. in addition two pairwise comparisons will be evaluated between 
pooled continuous regimens vs pooled placebo and, between pooled cyclic regimens and pooled 
placebo. The estimated adjusted hazard ratio for TIP over placebo will be displayed along with 
the associated 2-sided 95% CI.
Patients will be censored at the time of last dose of study drug if they did not discontinue
study drug due to a pulmonary exacerbation.
Kaplan-Meier analysis stratified by treatment arm will be also presented and displayed
graphically.
2.6.3.3
Anti-pseudomonal antibiotics
Proportion of patients requiring anti-pseudomonal antibiotics
The proportion of patients requiring anti-pseudomonal antibiotics across the treatment epoch
and across the entire study period will be summarized by treatment arm and by route of
administration (overall, oral and parenteral).
Time to first use of anti-pseudomonal antibiotics across the entire study period
The time to first use of anti-pseudomonal antibiotics by route of administration (overall, oral
and parenteral) will be analyzed using a Cox regression model stratified by baseline
macrolide use. The model will include treatment as a fixed-effect factor, and number of
pulmonary exacerbations in the 12 months prior to screening as a covariate. Six pairwise
comparisons will be evaluated as specified in Section 2.6.3. in addition two pairwise 
comparisons will be evaluated between pooled continuous regimens vs pooled placebo and, 
between pooled cyclic regimens and pooled placebo. The estimated adjusted hazard ratio for
TIP over placebo will be displayed along with the associated 2-sided 95% CI.


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The exposure adjusted rate of usage of anti-pseudomonal antibiotics across
the entire study period
The number of anti-pseudomonal antibiotics across the entire study period will be analyzed by
route of administration (overall, parenteral and oral) using a generalized linear model
assuming the negative binomial distribution including treatment and baseline macrolide use as 
fixed-effect factors, and number of pulmonary exacerbations in the 12 months prior to
screening as a covariate. The log time in study in years will be included as an offset variable
in the model. Six pairwise comparisons will be evaluated as specified in Section 2.6.3, in 
addition two pairwise comparisons will be evaluated between pooled continuous regimens vs 
pooled placebo and, between pooled cyclic regimens and pooled placebo. The adjusted rate of
usage will be provided for each treatment arm. The estimated rate ratio together with the 
2-sided 95% interval will be provided.
Duration of anti-pseudomonal antibiotic use across the entire study period
The duration of anti-pseudomonal antibiotic use (days) across the entire study period will be 
summarized by cohort, treatment arm and pooled cyclic and continuous regimens and by route 
of administration (overall, parenteral and oral).
2.6.3.4
Hospitalization
Proportion of patients requiring hospitalization due to serious respiratory-
related AEs
The proportion of patients requiring hospitalization due to serious respiratory-related AEs
across the treatment period, follow up period, and across the entire study period will be
summarized by treatment arm and by pooled continuous and cyclic regimen. The number of 
events will also be summarized.
The time to first hospitalization due to serious respiratory-related AEs
The time to first hospitalization due to serious respiratory related AEs will be analyzed using
a Cox regression model stratified by baseline macrolide use. The model will include treatment 
as a fixed-effect factor, and number of pulmonary exacerbations in the 12 months prior to
screening as covariate. Six pairwise comparisons will be evaluated as specified in Section
2.6.3, in addition two pairwise comparisons will be evaluated between pooled continuous 
regimens vs pooled placebo and, between pooled cyclic regimens and pooled placebo. The
estimated adjusted hazard ratio for TIP over placebo will be displayed along with the 
associated 2-sided 95% CI.
Kaplan-Meier analysis stratified by treatment arm will be also presented and displayed
graphically.
If a small number of events occur after pooling events, only the Kaplan-Meier estimation of
time to first hospitalization due to serious respiratory-related AEs will be provided.
Duration of hospitalization due to serious respiratory-related AEs
The duration of hospitalization due to serious respiratory-related AEs (days) across the entire
study period will be summarized by treatment arm and pooled arms by continuous and cyclic 
regimens. Summaries will be event driven and not patient driven.
Number of hospitalizations due to serious respiratory-related AEs
The number and percentage of patients with 0, 1, 2, >2 hospitalizations due to serious
respiratory-related AEs across the entire study period will be summarized by treatment arm


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and pooled arms by continuous and cyclic regimens.
The exposure adjusted rate of hospitalization due to serious respiratory-related
AEs
The exposure adjusted rate of hospitalization due to serious respiratory-related AEs will be
determined across the study period.
The number of hospitalization due to serious respiratory-related AEs during the study period
will be analyzed using a generalized linear model assuming the negative binomial distribution
including treatment and baseline macrolide use as fixed-effect factors, and number of
pulmonary exacerbations in the 12 months prior to screening as a covariate. The log
exposure to treatment in years will be included as an offset variable in the model.
Six pairwise comparisons will be evaluated as specified in Section 2.6.3, in addition two 
pairwise comparisons will be evaluated between pooled continuous regimens vs pooled placebo 
and, between pooled cyclic regimens and pooled placebo. The estimated rate ratio along with
2-sided 95% interval will be provided.


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2.6.4
Handling of missing values/censoring/discontinuations
For time to event analyses, patients not experiencing that event will be censored at either the
time of last dose of study drug (if the analysis is across the treatment period) or the date of last
follow-up visit (if the analysis is across the entire study period).
2.7
Safety analyses
All safety analyses will be performed using the SAF, and will be presented by cohort and
treatment arm (TIP, TIP/placebo cyclical, placebo and pooled placebo).
Baseline for safety analyses is defined as the last measurement prior to the first dose of study
drug in the study.
Appropriate summary statistics will be provided for laboratory test results, audiology,
bronchial hyperreactivity and vital signs.
Safety data will be presented in the individual patient data listings based on the SAF. Only
descriptive analysis of safety will be performed (i.e., no statistical hypothesis testing will be
performed).
Table 2-2 shows the safety parameters (e.g., raw value, change from baseline, incidence, and
clinical abnormalities) that will be summarized for AEs/Serious AEs (SAEs), laboratory data
(serum chemistry/hematology, urinalysis), 12-lead ECG and vital signs.
For the non-AE safety evaluations, raw values, and changes from baseline will be summarized
as indicated in Table 2-2. For example, an “X” under the raw value column (second column)
means that the raw values for the safety evaluation will be summarized; an “X” under the
change column (third column) means that change will be summarized.
Throughout this section, “change” refers to absolute change from baseline.
Table 2-2
Summaries of safety data
Safety Assessment
Incidence
Raw Value
Change
Clinical
Abnormalities
AEs*
X
Not applicable
Serum Chemistry/Hematology
X
X
X
Urinalysis
X
X
X
X
12-lead ECG
Present in listing only
Vital signs
X
X
Not applicable
ECG: electrocardiogram; X: safety assessment will be summarized in tables.
*AEs, SAEs and other significant AEs or AEs of special interest, see Section 2.7.1
2.7.1
Adverse events (AEs)
An AE will be classified as a treatment emergent AE (TEAE) if it starts on or after the date of 
the first dose of study drug until study completion.
TEAEs will be summarized by System Organ Class (SOC) and Preferred Term (PT) using the
latest Medical Dictionary for Drug Regulatory Affairs (MedDRA) available at the time of
database lock.


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The number and percentage of patients experiencing TEAEs, SAEs, AEs suspected to be
related to study drug, AEs leading to study drug discontinuation and AEs leading to death will
be summarized by treatment arm and overall.
The number and percentage of patients experiencing TEAEs will be summarized by treatment
arm by SOC and PT, and by SOC, PT and maximum severity. In addition, the number and
percentage of patients experiencing AEs suspected to be related to study drug will be
summarized by treatment arm by SOC and PT.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs
which are not serious adverse events with an incidence greater than 5% and on treatment
emergent SAEs and SAEs suspected to be related to study treatment will be provided by SOC
and PT using the SAF.


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If for the same patient, several consecutive AEs (irrespective of study treatment causality,
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study
treatment / non SAE has to be checked in a block e.g., among AEs in a ≤1 day gap block, if at
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
AEs of special interest (AESIs):
The number and percentage of patients with AEs regarding ototoxicity and/or hemoptysis and
renal events will be summarized. Specific AE terms will be collected on the AESI
electronic case report forms (eCRFs). These data include symptoms, medical history and
relevant local assessment.
In addition, post-inhalational adverse events will be summarized as instructed 2.7.4.3.
2.7.2
Deaths
AEs leading to death will be listed.
2.7.3
Laboratory data
Laboratory parameters will be recorded at Visit 1 (Screening), Visit 101 (Day 1), Visit 102
(Day 8), Visit 103 (Day 29), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 or TD (Day
113), Follow-up Visit 201 (Day 141) and Follow-up Visit 202 or PSD (Day 169).
Laboratory data (hematology, serum chemistry), including changes from baseline, will be
summarized descriptively (n, mean, SD, median, minimum and maximum).
Hematology
Hematology parameters include hemoglobin, hematocrit, red blood cell (RBC) count, white
blood cell (WBC) count with differential, and platelet count.
Serum chemistry
Serum chemistry parameters include urea (or BUN), creatinine, glucose, total bilirubin (TBL),
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase
(ALP), gamma glutamyl transpeptidase, sodium, potassium, chloride, calcium, bicarbonate,
phosphate, total protein, albumin, and uric acid.


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All continuous laboratory variables will be classified according to the normal ranges (low,
normal, high) and shift tables of the categories at baseline versus the last available post-
baseline visit will be generated. In addition hematology and serum chemistry value shifts
from baseline to above upper/below lower of normal will be tabulated with number and
percentage of patients by visit and at any time post-baseline.
Urine dipstick tests
Results of the urine dipstick tests (specific gravity, protein, glucose, blood) will be presented
with number and percentage of patients with negative values and trace categories. WBC and
RBC sediments result will be summarized in the same manner as described above for
continuous laboratory parameters.
Note: a urine pregnancy test will be performed at Visit 2 (Screening 2) and Follow-up Visit
202 or PSD (Day 169). These data will be listed only.
Proportion of patients with liver events at any post-baseline visit
Elevated liver function test cases will be classified according to the following grading system:

ALT or AST > 3 × upper limit of normal (ULN)

ALT or AST > 5 × ULN

ALT or AST > 8 × ULN

ALT or AST > 10 × ULN

ALT or AST > 20 × ULN

ALP > 1.5 × ULN

ALP > 2 × ULN

ALP > 5 × ULN

TBL > ULN

TBL > 1.5 × ULN

TBL > 2 × ULN

ALT or AST > 3 × ULN and TBL > 1.5 × ULN

ALT or AST > 3 × ULN and TBL > 2 × ULN

ALT or AST > 3 × ULN and TBL > 2 × ULN without ALP > 2 × ULN
In addition, 3 x ULN < ALT / AST <= 5 x ULN will be evaluated.
For the above mentioned events patient listings will be provided (ALT, AST, TBL, ALP) , by
visit, for all visits.
Renal safety
Renal safety will be determined using the following classifications using the central
laboratory data provided:

Serum creatinine increase from baseline 25% - <50%

Serum creatinine increase from baseline >=50%

BUN increase from baseline >=1.5 x ULN, if it was normal at baseline

Estimated glomerular filtration rate (eGRF) of 50 mL/min/1.73m2 or less

Dipstick proteinuria >=3+ (not present at baseline)


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
Albumin-creatinine-ratio (ACR) >=30 mg/g or >=3 mg/mmol

Protein-creatinine-ratio (PCR )>=150 mg/g or >=15 mg/mmol

Dipstick hematuria >=3+ (not present at baseline)
For the above mentioned renal safety laboratory parameters, patient listings will be
provided (creatinine, eGFR, proteinuria, ACR, PCR) , by visit, for all visits.
2.7.4
Other safety data
2.7.4.1
Audiology testing
Audiology testing will be conducted at selected sites at Visit 2 (prior to dosing), Visit 102
(Day 8), Visit 103 (Day 29), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 or TD (Day
113), Follow-up Visit 201 (Day 141) and Follow-up Visit 202 or PSD (Day 169). Certain 
patient sub-groups are required to have audiology testing during the screening period. 
The results of audiology testing will be summarized at each visit by the number and
percentage of patients. Patients with the following decreases in consecutive frequencies will
be presented for audiology safety: any frequencies decreased, 2 consecutive frequencies
decreased, >=10 dB decrease in >=3 consecutive frequencies, >=15 dB decrease in >=2
consecutive frequencies, >=20 dB decrease in at least 1 frequency. Events can be observed in
either ear.
Results of the bone conduction test will be summarized with the number of patients who
performed the test; the number and percentage of conductive, neurosensory and mixed
hearing loss in left, right or both ears will also be given.
Summaries will be based on the AUD.
2.7.4.2
Vital signs
Systolic/diastolic blood pressure, radial pulse rate (over a 30s interval), respiratory rate and
body temperature will be recorded at Visit 1 (screening), Visit 101 (start of treatment), Visit
106 or TD (Day 113) and Follow-up Visit 202/PSD (Day 169).
Vital signs data, including changes from baseline, will be summarized for each visit using
descriptive statistics (n, mean, SD, minimum, median, and maximum).
2.7.4.3
Post-inhalation events
Events occurring within 5 minutes after inhalation of the study treatment (post-inhalation
events) will be observed at the site by site personnel at Visit 101 (start of treatment), Visit 102
(Day 8), Visit 103 (Day 29), Visit 104 (Day 57), Visit 105 (Day 85) and Visit 106 or TD
(Day 113). If the event is determined to be an adverse event, this should be recorded on the
Adverse Event eCRF. In addition, event details will also be captured in the Post-inhalation
Adverse Event eCRF. For post-inhalation events that are determined not to be an adverse
event, event details will be recorded in the Post-inhalation clinical events eCRF.


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The number and percentage of patients experiencing post-inhalation events occurring at a site
visit within 5 minutes (yes/no), experiencing post-inhalation events that are ongoing at the
completion of a site visit (yes/no), experiencing post-inhalation events which have an action
taken to reduce the event (yes/no) will be presented for each visit. The number and percentage
of patients for each time of onset category (≤30 sec, >30 sec-1min, >1-2min, >2-5min, >5min)
will be presented for each visit.
Descriptive statistics including mean, SD minimum, median and maximum will be provided
for the duration of the events in minutes for each visit.
Summaries of post-inhalation events will be conducted for the 2 types of events, i.e., post-
inhalation clinical events and post-inhalation adverse events. The number of patients with
post-inhalation events will be summarized by treatment. In addition, the number of these
events and the event rate adjusted for exposure will be displayed by treatment.
An AE occurring after 5 minutes post-inhalation will be reported as an AE.
2.7.4.4
Bronchial hyperreactivity
Bronchial hyperreactivity will be measured as the acute relative change from pre-dose to
30±15 minutes post-dose in FEV1% predicted at Visit 101 (start of treatment), Visit 102 (Day
8), Visit 103 (Day 29), Visit 104 (Day 57), Visit 105 (Day 85) and Visit 106 or TD (Day 113).
A
change
of
20%
or
more
is
considered
a
clinically
significant
indicative
of
bronchospasm/bronchial hyperreactivity. This change will be summarized with the number
and percentage of patients who experienced no change, a decrease/increase of >0-<10%, a
decrease/increase of 10-<20% or a decrease/increase >=20%. Both summaries will also be
performed for the patients who did the post-dose spirometry test in a 60 minute time window.
2.7.4.5
Resource utilization
Data as reported on the resource utilization eCRF will be listed for all patients with data.
2.8
Pharmacokineticendpoints
The serum and sputum pharmacokinetic properties of tobramycin will be assessed by
evaluating tobramycin concentrations in serum and sputum collected from non-CF BE
population post administration of o.d. or b.i.d. doses of TIP.
Serum specimens for PK tobramycin concentration will be assessed at Visit 101 (start of
treatment) 0-1 and 1-2 h post-dose and Visit 103 (Day 29) 0-1 and 1-2 h post-dose.
Sputum specimens for PK tobramycin concentration will be assessed at Visit 101 (start of
treatment) 0-1 and 1-2 h post-dose, Visit 102 (Day 8) 0-2 h post-dose, Visit 103 (Day 29) 5-6
h post-dose and Visit 105 (Day 85) 3-4 h post-dose
Tobramycin concentrations in serum and sputum specimens will be summarized descriptively
(n, mean, SD, minimum, median and maximum) by scheduled visit and timepoint for the PAS.


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A separate PK sub-study is included in this study which collects additional PK samples.
Patients included in this sub-study will provide 1 serum specimen per specified interval at
Visit 101 (start of treatment) and Visit 103 (Day 29): pre-dose, 0-1, 1-2, 3-4 and 5-6 h.
Descriptive statistics (n, mean, SD, minimum, median and maximum) will be provided for the 
PSSAS by scheduled visit and time point.
All PK data will be presented in individual patient data listings.
2.9
PD and PK/PD analyses
The independent bio-analytical report (including PK model and if possible PK/PD model) will
be done by Ventiv or Novartis and is not covered in this SAP.
2.10
Patient reported outcomes
Quality of Life Questionnaire-Bronchiectasis (QoL- B)
QoL-B is assessed at Visit 2 (Baseline), Visit 102 (Day 8), Visit 103 (Day 29), Visit 104 (Day
57), Visit 105 (Day 85), Visit 106 or TD (Day 113), Follow-up Visit 201 (Day 141) and
Follow-up Visit 202 or PSD (Day 169).
The QoL-B consists of 37 items across 8 domains: Physical, Role Functioning, Vitality,
Emotional
Function,
Social
Functioning,
Treatment
Burden,
Health
Perception
and
Respiratory Symptoms. Each of the 37 items is scored from 1 to 4.
Items in the questionnaire are expressed either ‘negatively’ or ‘positively’, therefore a number
of items must be recorded before the scores for each of the domains are calculated. The score
is calculated by adding the score obtained for each item of a domain (scale), after any
necessary recoding. Scoring for each domain can be computed only if at least half the items
have been completed. If not, then the domain should not be scored and should be considered
missing for that particular person who filled out the questionnaire.
Descriptive statistics will be provided for each domain score for all applicable visits for the
FAS by treatment arm and pooled arms by continuous and cyclic regimens. Changes from
baseline to each post-baseline visit will also be summarized. For the QoL-B Respiratory
Symptom Score (RSS), further summaries will be provided for:

Patients with/without pulmonary exacerbations during the treatment period

Patients with overall study drug compliance >=80%
The change from baseline in QoL-B RSS will be analyzed using a linear repeated measure
model. The model will contain treatment, baseline macrolide use, visit (visits 102 to 202), and 
treatment-by-visit interaction as fixed effects with baseline QoL-B RSS, baseline-by-visit
interaction as covariates. The within-patient correlation will be modeled using the
unstructured covariance matrix in the mixed model. If the model does not converge, then the
compound symmetry covariance structure will be used. The restricted maximum likelihood
method will be used.
QoL-B correlation with other patient reported outcome measures will be performed by
RTI health solutions; consequently these are not detailed within this SAP.


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Details on deriving the domain scores can be found in Section 5.5.


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2.12
Interim analysis
No interim analysis of efficacy is planned for this study.
The final analysis will be performed after the database is locked, the treatment assignments
are unblinded using the actual randomization, and the database released.
An independent DMC is set-up to review safety data and provide the Sponsor with guidance
on safety issues. SAE listings generated from the Novartis safety database, ARGUS, will be
reviewed monthly by the DMC. The DMC will also perform a pre-planned review of AE and
additional pre-defined safety data when approximately 50% of patients have completed the 28
days of treatment.


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The membership of the DMC and the responsibilities of the DMC,
will be
defined in a separate ‘DMC Charter’ document. The DMC Charter will include information
about data flow, purpose and timings of DMC meetings, communication strategy, procedures
for ensuring confidentiality, procedures to address conflicts of interest and statistical
monitoring guidelines.
3
Sample size calculation
Sample size estimation was based on a difference of 2.0 log10 CFU/g, with standard
deviations of 2.0 log10 CFU/g. The assumptions were based on conservative estimates from
published results (Konstan et al 2011a, Konstan et al 2011b, Barker et al 2000, and Wilson et
al 2013).
As there are 3 primary comparisons between the 3 doses versus placebo, the Bonferroni
multiplicity adjustment has been used (0.05/3) for sample size calculation. Using α=1.67% (2-
sided) and 90% power, the sample size estimation yielded n = 36 patients per treatment arm as
valid for intent-to-treat (ITT) analyses. This takes into account an approximate 20%-
discontinuation rate. For the primary efficacy analysis, patients from TIP continuous and TIP
cyclical regimen within the same cohort will be pooled as they receive exactly the same
treatment during the first 28 days. Placebo patients will be pooled across the 3 cohorts, as the
number of placebo capsules is not expected to influence the change in P. aeruginosa bacterial
counts. With the current study design, the power is 94% to detect a reduction of 2.0 log10
CFU/g for each dose level versus placebo.
For calculation of sample size, NQuery Advisor version 7.0 module MTTO-1 was used.
4
Change to protocol specified analyses
The annual rate of pulmonary exacerbations will be summarized overall. Analyses on the
number of pulmonary exacerbations will only be performed overall and not by exacerbation
category.


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5
Appendix
5.1
Imputation rules for complete or partial missing dates
5.1.1
Study drug
When the date of the last dose of study drug is missing for a patient in the SAF, all efforts
should be made to obtain the date from the investigator. If it is still missing after all efforts,
then the last visit date when study drug was returned will be used in the calculation of
treatment duration.
5.1.2
Adverse event start date imputation
The following table explains the notation used in the logic matrix. Please note that missing
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( D )
No convention
( D )
No convention
( D )
No convention
( D )
No convention
YYYY < TRTY
( D )
Before Treatment Start
( D )
Before Treatment Start
( D )
Before Treatment Start
( D )
Before Treatment Start
YYYY = TRTY
( o )
Uncertain
( o )
Before Treatment Start
( o )
Uncertain
( o )
After Treatment Start
YYYY > TRTY
( D )
After Treatment Start
( D )
After Treatment Start
( D )
After Treatment Start
( D )
After Treatment Start
Before imputing AE start date, find the AE start reference date.

If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min (informed consent date, earliest visit date).

Else AE start reference date = treatment start date 
Impute AE start date -

If the AE start date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set
to NULL.


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
If the AE start date year value is less than the treatment start date year value, the AE
started before treatment. Therefore:

If AE month is missing, the imputed AE start date is set to the mid-year point
(01JulYYYY).

Else if AE month is not missing, the imputed AE start date is set to the mid-month point
(15MONYYYY).

If the AE start date year value is greater than the treatment start date year value, the AE
started after treatment. Therefore:

If the AE month is missing, the imputed AE start date is set to the year start point
(01JanYYYY).

Else if the AE month is not missing, the imputed AE start date is set to the later of (month
start point (01MONYYYY), AE start reference date + 1 day).

If the AE start date year value is equal to the treatment start date year value:
o And the AE month is missing the imputed AE start date is set to the AE reference start
date + 1 day.
o Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
o Else if the AE month is equal to the treatment start date month or greater than the
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end
date.
5.1.3
Adverse event end date imputation

If the AE end date month is missing, the imputed end date should be set to the earliest of
the (treatment follow up period date, 31DECYYYY, date of death).

If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death).

If AE year is missing or AE is ongoing, the end date will not be imputed.
5.1.4
Relative day of AE onset and AE end imputations
The relative day of AE onset will be calculated as follows:

AE start date - date of first dose of study drug (if AE start date is completely known)

missing (if AE onset date is incomplete or unknown) 
The relative day of AE end will be calculated as follows:

AE end date – date of first dose of study drug (if AE end date is completely known)

missing (if AE end date is incomplete or unknown) 
The duration of an AE will be calculated as follows:

AE end date – AE start date + 1 (when both dates are completely known)


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
Date of end of study completion/discontinuation – AE start date + 1 (when the AE
onset date is fully known but the AE is not resolved at the end of the trial): in this case 
the duration will be presented as “>x days” in the listing rather than “x days”

missing (when the AE start date is incomplete or unknown, or when the AE has
resolved but with an incomplete or unknown end date, or when the AE onset date is > 
date of end of completion/discontinuation and the AE is not resolved)
5.1.5
Concomitant medication start date imputation
The following table explains the notation used in the logic matrix. Please note that missing
start dates will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( D )
Uncertain
( D )
Uncertain
( D )
Uncertain
( D )
Uncertain
YYYY < TRTY
( o )
Before Treatment Start
( o )
Before Treatment Start
( o )
Before Treatment Start
( o )
Before Treatment Start
YYYY = TRTY
( o )
Uncertain
( o )
Before Treatment Start
( o )
Uncertain
( o )
After Treatment Start
YYYY > TRTY
( o )
After Treatment Start
( o )
After Treatment Start
( o )
After Treatment Start
( o )
After Treatment Start

If the CM start date year value is missing, the imputed CM start date is set to 1 day prior
to treatment start date.

If the CM start date year value is less than the treatment start date year value, the CM
started before treatment. Therefore:
o If the CM month is missing, the imputed CM start date is set to the mid-year point
(01JulYYYY).
o Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).

If the CM start date year value is greater than the treatment start date year value, the CM
started after treatment. Therefore:
o If the CM month is missing, the imputed CM start date is set to the year start point
(01JanYYYY).


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o Else if the CM month is not missing, the imputed CM start date is set to the month
start point (01MONYYYY).

If the CM start date year value is equal to the treatment start date year value:
o And the CM month is missing or the CM month is equal to the treatment start date
month, then the imputed CM start date is set to 1 day prior treatment start date.
o Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY).
o Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM
end date.
5.1.6
Concomitant medication end date imputation

If CM end day is missing and CM month/year are non-missing then impute CM day as the
minimum of treatment end date and the last day of the month.

If CM end day/month are missing and CM year is non-missing then impute CM day as the
minimum of treatment end date and the end of the year (31DECYYYY).

Only include if ongoing records will have an imputed CM end date. If CM day/month/year
is missing then use the treatment end date + 1 day as the imputed CM end date.
If imputed CM end date is less than the CM start date, use the CM start date as the imputed
CM end date.
5.1.6.1
Prior therapies date imputation
Not applicable
5.1.6.2
Post therapies date imputation
Not applicable
5.1.6.3
Other imputations
Not applicable
5.2
Laboratory parameters derivations
Table 5-1
Criteria for potentially clinically important laboratory tests
Parameter
SI Unit
Lower Limit
< or =
Higher Limit
> or =
Hematology
WBC
x10^9/L
2.50
30.00


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HGB
g/dL
8.0
18.0
Platelets
x10^9/L
50
1,000
Platelets, Na Citrate
x10^9/L
39
914
Chemistry
Calcium
mmol/L
1.50
3.50
Potassium
mmol/L
2.5
6.5
Fasting Glucose, Serum
mmol/L
2.20 (Female)
2.80 (Male)
22.20
Random Glucose, Serum
mmol/L
2.20 (Female)
2.80 (Male)
22.20
Urea (BUN)
mmol/L
> 1.5 x ULN
Creatinine Enzymatic
umol/L
> 1.25 x ULN
Creatinine Kinase
U/L
850 (Female)
975 (Male)
Total Bilirubin
umol/L
57.0
eGFR by MDRD
mL/min/S
SA
50
Endocrinology
HCG (Quantitative)
IU/L
5.01 (Female)
Urinalysis
Protein, Urine
mg/dL
30
Glucose, Urine
mg/dL
250
Blood, Urine
Small
Albumin-Creatinine
Ratio
mg/g
30
Protein-Creatinine Ratio
Ratio
0.15
LLN: Lower limit of normal value provided by the laboratory
ULN: Upper limit of normal value provided by the laboratory


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5.5
Patient reported outcomes – questionnaires
QoL-B
Step 1: Item-by-item responses
The values assigned to participants’ responses for each question are listed below.
For questions 1 – 4: A lot of difficulty = 1, Moderate difficulty = 2, A little difficulty = 3, No
difficulty=4
For questions 5 – 11: Always = 1, Often = 2, Sometimes = 3, Never = 4
For questions 12 – 15: Use the assigned number designated for each specific response
For questions 16 – 26: Completely true = 1, Mostly true = 2, A little true = 3, Not at all true
= 4
For question 27: Use the assigned number designated for each specific response
Forquestion28:Always=1,Often=2,Sometimes=3,Never=4
For questions 29 – 31: A lot = 1, A moderate amount = 2, A little = 3, Not at all = 4
For question 32: Clear = 1, Clear to yellow = 2, Yellowish-green = 3, Brownish-dark = 4,
Green with traces of blood = 4, Don’t know = 6
    Forquestions33 – 37: Always= 1,Often= 2,Sometimes = 3,Never= 4


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Step 2:Scoringmultipleresponsesorskippedquestions
If two responses are marked and there is no opportunity to ask the respondent which one is
correct, the worst response should be selected for data entry and scoring. This provides a
conservative estimate of their response to this item. For example, item #29 asks: “Have you
felt congestion in your chest?” The response choices range from “A lot” to “Not at all.” If the
respondent marks “a lot” and “a moderate amount” you should enter “a lot” for this question.
Please note that some items are reverse-keyed and therefore, the worst response is not
necessarily the lower number.
If participants skip a question, do not assign a response value (i.e. leave it blank). 
Step 3: Scaling item 32 and reverse coding
Item 32 (resp32) has 5 possible answers that are scored and all other items on the QOL-B
questionnaire have only 4 possible answers. Possible scores for resp32 are 1, 2, 3, 4, 5 and 6,
whereas for other questions the possible scores are 1, 2, 3, and 4. Resp32 and eight other
items are also reverse coded; because of the wording for these particular items, reverse coding 
is necessary to make higher scores correspond to better health outcomes. Reverse coding is
conducted for resp32, and for health5, vital8, treat12, treat14, health15, role20, health24, and
role27.
For item 32: Original value = Reverse-coded value
1 = 4
2 = 3
3 = 2
4 = 1
6 = Not scored
For item 19: “doesn’t apply” = Not scored
For items 5, 8, 12, 14, 15, 20, 24, 27: Original value = Reverse-coded value
1 = 4
2 = 3
3 = 2
4 = 1
Step 4: Preparing to calculate scaled scores and missing values
If the responses are missing for more than half the items in a scale, the score for that scale
should not be calculated. Missing values are not imputed. Note that missing responses within
a scale will change the number of points corresponding to a change of one answer category
for one item for that respondent.
Step 5: Calculate the scaled scores
Calculate scores for the eight QOL-B domains
Physical Functioning Domain (5 items)


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1.
2.
3.
4.
16.
If 3 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses)-1)/3] x 100
Role Functioning Domain (5 items)
17. 
20. 
25. 
27. 
28. 
If 3 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses )-1)/3] x 100
Vitality Domain (3 items)
6. 
8. 
9. 
If 2 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses )-1)/3] x 100
Emotional Functioning Domain (4 items)
7. 
10. 
11. 
23. 
If 3 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses)-1)/3] x 100
Social Functioning Domain (4 items)
18. 
19.
(* “doesn’t apply” = Not scored)
22. 
26. 
If 3 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses)-1)/3] x 100
Treatment Burden Domain (3 items)
12. 
13. 


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14.
If 2 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses)-1)/3] x 100
Health Perceptions Domain (4 items)
5. 
15. 
21. 
24. 
If 3 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses)-1)/3] x 100
Respiratory Symptoms Domain (9 items)
29. 
30. 
31. 
32. 
33. 
34. 
35. 
36. 
37. 
If 5 or more responses are missing, do not score this domain. Scaled score = [((mean of
responses)-1)/3] x 100


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6
References
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Sputum Pseudomonas aeruginosa Density in Bronchiectasis. Am J Respir Crit Care Med;
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[Konstan MW, Geller DE, Minic P, et al (2011a) ] Tobramycin inhalation powder forP.
aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol; 46(3):230-8.
[Konstan MW, Flume PA, Kappler M, et al (2011b) ] Safety, efficacy and convenience of
tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros;
10(1):54-61.
[Wilson R, Welte T, Polverino E, et al (2013) ] Ciprofloxacin dry powder for inhalation in
noncystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J; 41(5):1107-15.
[The European Bronchiectasis Registry] Calculation of the bronchiectasis severity index (BSI).