Clinical trial NCT02248922
Conditions: Chronic Lung Infection With Pseudomonas Aeruginosa in Cystic Fibrosis
Keywords: Cystic Fibrosis, Pseudomonas aeruginosa, Lung Clearance Index, Multiple Breath Washout, Inhaled Tobramycin, Inhaled Antibiotics.
Sponsor: Novartis Pharmaceuticals
Start date: 2015-01-27; Completion date: 2017-04-10
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study was to evaluate lung clearance index (LCI) by a standardized procedure in a well characterized study setting and to assess feasibility of LCI as a more sensitive method than forced expiratory volume at 1 second (FEV1) to measure effectiveness of antibiotic therapy in patients with CF aged 6 years and older with mild to moderate lung disease.

Detailed description:
This study was terminated prematurely. The reason for trial termination was challenge with enrollment and patient recruitment. A significant decrease in the eligible patient population had been identified as main driver.

Arms: arm 1: 300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Interventions: intervention 1: TIS or TIP
Intervention descriptions: intervention 1: 300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)

Protocol documents:
Prot_000.pdf: 
Novartis Pharma 
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Clinical Study Protocol 
Study No. CTBM100CDE02 
Version 02, Date 03.08.2015 
TBM100/Tobramycin 
CTBM100CDE02 / NCT02248922
An 8 week open-label interventional multicenter study to 
evaluate the lung clearance index as endpoint for clinical 
trials in cystic fibrosis patients ≥ 6 years of age, chronically 
infected with Pseudomonas aeruginosa 
Author(s): 
 
Document type: 
Clinical Trial Protocol 
EUDRACTnumber : 
2014-001204-21 
Development phase: 
IV 
Version No. 
V02 (Amended protocol 2) 
Release date: 
03-08-2015
Property of Novartis Pharma 
Confidential 
PPD


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Clinical Study Protocol  
 
Study No. CTBM100CDE02 
 
 
Version 02, Date 03.08.2015 
 
 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
 


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Clinical Study Protocol  
 
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Version 02, Date 03.08.2015 
 
Signature Pages 
TBM100/Tobramycin/TOBI Podhaler®  
CTBM100CDE02 
Approved by the following 
Signatures of Novartis Personnel: 
 
 
(Clinical Trial Leader)   
 
signature  
 
date 
 
   
(Trial Statistician)   
 
signature  
 
date 
 
 
(Head Therapeutic Area) 
 
signature  
 
date 
 
PPD
PPD
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Clinical Study Protocol  
 
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Version 02, Date 03.08.2015 
 
Signature of Coordinating Investigator (LKP according to German Drug Law): 
 
 
(Coordinating Investigator [LKP]) 
signature  
 
date 
 
PPD


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Clinical Study Protocol  
 
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Version 02, Date 03.08.2015 
 
Signature Page for Investigator 
 
TBM100/Tobramycin/TOBI Podhaler®  
CTBM100CDE02 
 
I have read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with the principles outlined in the 
Declaration of Helsinki. Note: Any deviations from this protocol require a formal 
amendment to be approved by the responsible ethics committee. 
 
______________________ 
(Investigator) 
 
 
Center name / location: 
signature  
 
date 
 
institution (where applicable) 
 
city 
 
 


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Table of contents 
Table of contents ................................................................................................................. 6 
List of post-text supplements ............................................................................................... 9 
List of tables ........................................................................................................................ 9 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 10 
Amendment 2 .................................................................................................................... 12 
Amendment 1 .................................................................................................................... 13 
1 
Background ........................................................................................................................ 15 
2 
Study purpose .................................................................................................................... 16 
3 
Objectives (and related endpoints) .................................................................................... 16 
3.1 
Secondary objective(s)........................................................................................... 16 
3.2 
Exploratory objective(s) ........................................................................................ 17 
4 
Study design ...................................................................................................................... 17 
5 
Population .......................................................................................................................... 18 
5.1 
Inclusion/exclusion criteria .................................................................................... 18 
5.2 
Premature patient withdrawal ................................................................................ 20 
6 
Treatment ........................................................................................................................... 21 
6.1 
Patient numbering .................................................................................................. 21 
6.2 
Investigational and control drugs........................................................................... 21 
6.3 
Treatment arms ...................................................................................................... 22 
6.4 
Treatment assignment ............................................................................................ 22 
6.5 
Treatment blinding ................................................................................................ 22 
6.6 
Treating the patient ................................................................................................ 22 
6.6.1 
Dispensing the study drug ..................................................................... 22 
6.6.2 
Instructions for use of study drug.......................................................... 22 
6.6.3 
Study drug supply and resupply, storage, and tracking ........................ 22 
6.6.4 
Study drug compliance and accountability ........................................... 22 
6.6.5 
Disposal and destruction ....................................................................... 22 
6.6.6 
Permitted study drug dose adjustments and interruptions .................... 23 
6.6.7 
Rescue medication ................................................................................ 23 
6.6.8 
Other concomitant treatment ................................................................. 23 
6.6.8.1 
Caution for concomitant use ................................................................. 26 
6.6.9 
Study drug discontinuation ................................................................... 27 
6.6.10 
Emergency unblinding of treatment assignment ................................... 27 


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6.6.11 
Study completion and post-study treatment .......................................... 27 
7 
Visit schedule and assessments ......................................................................................... 28 
7.1 
Information to be collected on screening failures .................................................. 31 
7.2 
Patient demographics/other baseline characteristics ............................................. 31 
7.3 
Treatment exposure and compliance ..................................................................... 31 
7.4 
Efficacy .................................................................................................................. 31 
7.4.1 
Lung clearance index assessment .......................................................... 31 
7.4.2 
Spirometry assessment .......................................................................... 33 
7.4.3 
Microbiological assessment .................................................................. 34 
7.5 
Safety ..................................................................................................................... 34 
7.5.1 
Adverse events ...................................................................................... 34 
7.5.2 
Physical examination ............................................................................ 34 
7.5.3 
Vital signs.............................................................................................. 35 
7.5.4 
Laboratory evaluations .......................................................................... 35 
7.5.5 
Pregnancy test and assessments of fertility ........................................... 35 
7.6 
Tolerability/acceptability ....................................................................................... 35 
7.7 
Resource utilization ............................................................................................... 35 
7.8 
Treatment Assessment ........................................................................................... 35 
7.9 
Pharmacokinetics ................................................................................................... 35 
7.10 
Pharmacogenetics/pharmacogenomics .................................................................. 36 
7.11 
Other biomarkers ................................................................................................... 36 
8 
Safety monitoring .............................................................................................................. 36 
8.1 
Adverse events ....................................................................................................... 36 
8.1.1 
Adverse event definition and reporting ................................................. 36 
8.1.2 
Laboratory test abnormalities ................................................................ 37 
8.2 
Serious adverse events ........................................................................................... 37 
8.2.1 
Serious adverse event definition, treatment and follow-up ................... 37 
8.2.2 
Serious adverse event reporting ............................................................ 38 
8.3 
Pregnancy reporting ............................................................................................... 39 
8.4 
Reporting of adverse events and pregnancies after the last dose of study drug 
taken ....................................................................................................................... 39 
8.5 
Data Monitoring Board .......................................................................................... 39 
9 
Data review and database management ............................................................................. 39 
9.1 
Site monitoring ...................................................................................................... 39 
9.2 
Data collection ....................................................................................................... 40 
9.3 
Database management and quality control ............................................................ 40 


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10 Data analysis ...................................................................................................................... 41 
10.1 
Populations for analysis ......................................................................................... 41 
10.2 
Patient demographics/other baseline characteristics ............................................. 41 
10.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................ 41 
10.4 
Analysis of the primary objective(s)...................................................................... 41 
10.4.1 
Variable ................................................................................................. 41 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 42 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 42 
10.4.4 
Supportive analyses ............................................................................... 42 
10.5 
Analysis of secondary objectives .......................................................................... 42 
10.5.1 
Efficacy (secondary) ............................................................................. 42 
10.5.2 
Safety..................................................................................................... 42 
10.5.3 
Tolerability ............................................................................................ 43 
10.5.4 
Resource utilization ............................................................................... 43 
10.5.5 
Health-related Quality of Life ............................................................... 43 
10.5.6 
Pharmacokinetics .................................................................................. 43 
10.5.7 
Pharmacogenetics/pharmacogenomics ................................................. 43 
10.5.8 
Biomarkers ............................................................................................ 43 
10.5.9 
PK/PD ................................................................................................... 43 
10.6 
Interim analysis ...................................................................................................... 43 
10.7 
Sample size calculation.......................................................................................... 43 
10.8 
Power for analysis of critical secondary variables ................................................ 43 
11 Discussion and rationale for study design features ........................................................... 43 
12 References ......................................................................................................................... 45 
Appendix 1:  Ethical considerations and administrative procedures ................................. 48 
 
 
 


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List of post-text supplements 
None. 
List of tables 
Table 44-1 
Study design .......................................................................................... 18 
Table 6-1 
Prohibited treatment .............................................................................. 23 
Table 6-2 
Washout of prohibited treatment and study treatment/concomitant 
medication prior to study visits ............................................................. 24 
Table 7-1 
Assessment schedule ............................................................................. 29 
 
List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
b.i.d. 
bis in die/twice a day 
CF 
cystic fibrosis 
CFU 
colony-forming units 
CRF 
Case Report/Record Form 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
ECFS 
European Cystic Fibrosis Society 
FEV1 
forced expiratory volume at 1 second 
FRC 
Functional residual capacity 
HRCT 
High-Resolution Computer tomography 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System  
LCI 
lung clearance index 


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MBW 
multiple breath inert gas washout 
MIC 
minimal inhibitory concentration 
o.d. 
omnia die/once a day 
PAES 
post-authorisation Efficacy Studies 
PASS 
post-authorization safety study 
p.o. 
per os/by mouth/orally 
SAE 
serious adverse event 
Sacin 
N2 slope acinar airways 
Scond 
N2 slope conductive airways 
SOP 
standard operation procedure 
SPCS 
Study Protocol Concept Sheet 
TAQ 
treatment adherence questionnaire  
WOCBP 
Women of child-bearing potential 
Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug 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 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e., prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of each study treatment package 
which is linked to one of the treatment groups of a study 
Patient number 
A number assigned to each patient who enrolls in the study; when 
combined with the center number, a unique identifier for each 
patient in the study is created. 
Phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 


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Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug, combination of drugs 
and any control drugs including placebo 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints 
 
 
 


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Amendment 2 
 
Amendment rationale 
The protocol is being amended to allow for a more clear and detailed documentation of 
screening failures with a following re-screening of the patient. In order to limit eCRF page 
numbers per patient and to optimize the database structure and thus the usability of the data 
capturing system, a change of the individual number for patients who will be rescreend will be 
permitted. Furthermore, the change of patient no. in re-screened patients will allow for a 
unique and well matched visit numbering in the data capturing and the study management 
system. 
 
Changes to the protocol 
Section 6.1, Patient numbering: The term “and the patient no. for that individual must not be 
changed, even if the patient is re-screened” has been removed. 
 
The changes in this amended protocol are non-substantial. 
 
 


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Amendment 1 
 
Amendment rationale 
The protocol is being amended:  
1. To clarify the LCI assessment, and to align the protocol with the standard assessment 
approach for LCI of the device manufacturer. The revised section 7.4.1 reflects now 
the workflow implemented in the Exhalyzer D device by the actual “Spiroware” 
software version. Following Investigator-feedback, the upper limit for the FRC 
coefficient of variation has been increased from 10% to 25% to help reducing the 
number of MBW measurements needed in pediatric CF patients with moderate lung 
disease. In addition, this change allows for the documentation of values for LCI and 
FRC which have been automatically calculated by the device-software. A more 
detailed and step-by-step description for the LCI assessment makes it easier for the 
study team to follow the protocol.  
2. To add the change of pulmonary air trapping after 1 week, 4 weeks, and 8 weeks 
versus baseline to the protocol as an explorative objective. Air trapping will be 
assessed by the difference in FRC measured by bodyplethysmography (FRCples) and 
FRC measured by MBW (FRCMBW). In this study, spirometry is done by 
bodyplethysmography. Thus, FRCples is already documented in the source documents. 
Beneficial effects of treatment with inhaled tobramycin may include a reduction of air 
trapping by recruitment of lung units previously not contributing to ventilation. If the 
time constant in newly recruited units is slower, ventilation inhomogeneity, and 
therefore LCI, may increase despite the positive treatment effect (Robinson 2009).  
3. Following feedback of investigators, the guidance for the spirometric timeframe has 
been updated according to Borsboom 1999, to allow for a more flexible assessment 
planning.  
4. Finally, a couple of minor changes have been made to help investigators follow the 
protocol, eg. clarification regarding use of rescue medication and a table has been 
added about washout of prohibited medication.    
 
 Changes to the protocol 
Section 3.2: To explore the change in air trapping (FRCples - FRCMBW) after 1 week, 4 weeks, 
and 8 weeks versus Baseline, respectively,  has been added as exploratory objective. The third 
bullet point has been clarified.Section 4.: The term and reconfirm has been deleted 
Section 5.: Germany has been replaced by DACH region 
Section 6.4: The term and in accordance with the SmPC has been added. 
Section 6.6.4.1: An error regarding the compliance assessment has been corrected 
Section 6.6.7: Definition and the use of rescue medication has been clarified 


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Section 6.6.8: A table about washout of prohibited and concomitant medication has been 
added, inhaled steroids was changed in oral or inhaled steroids 
Section 7: Added FRCples assessment to the assessment schedule; Sputum can be collected by 
the patient at evening on the day before visit 2 if an early morning Baseline visit is not 
possible. Timeframe between MBW and spirometry assessment has been clarified. 
Section 7.4.1: Upper limits for the FRC and LCI coefficient of variation  have been increased 
to 25% and 10% respectively, the LCI assessment part has been changed to a more detailed 
step-by-step description. Washout timeframes for concomitant medication have been replaced 
by a reference to section 6.6.8. and guidance for reassessment of LCI has been clarified 
Section 7.4.2: The guidance for the spirometric timeframe has been updated: Approximately 
same timepoints at visits 2-5 for measurements in the morning and a more flexible timeframe 
for measurements after 11:00 
Section 9.3: Local laboratory data has been changed to central laboratory data 
Section 10.5.1: The term All other secondary and exploratory endpoints will be analyzed 
descriptively has been added 
Section 11: The rationale for the new explorative objective has been added. 
Section 12: The references Robinson 2009 and Borsboom 1999 have been added 
 
The changes in this amended protocol are substantial. An approval of this amended protocol 
by the Institutional Review Board (IRBs)/ Independent Ethics Committee (IECs) and Health 
Authorities prior to implementation is required. 
 


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1 
Background 
 
Cystic fibrosis (CF) patients are susceptible to respiratory infection with Pseudomonas 
aeruginosa, which is associated with decline in lung function and increased morbidity and 
mortality. Inhalation of Tobramycin, administered in repeated cycles of 28 days twice daily 
followed by 28 days off-drug, has been established as an effective and safe treatment of 
chronic P. aeruginosa infections in CF patients aged 6 years and older (Ramsey 1999, TOBI® 
2013, Bramitob® 2013, Konstan et al 2011a) and is currently antibiotic standard maintenance 
therapy in CF.  
Three different drug formulations are available in Germany: Tobramycin 300mg/5mL 
solution for nebulizers (TOBI, Novartis; Steri-neb, TEVA), Tobramycin 300mg/4mL solution 
for nebulizers (Bramitob, Chiesi) and Tobramycin powder inhaler (TOBI Podhaler, Novartis).   
 
The only parameter of lung function that is currently recognized as a surrogate endpoint in CF 
trials is the forced expiratory volume in one second (FEV1). However, FEV1 mainly reflects 
large conducting airways (Macklem 1998) and is relatively insensitive to changes in the small 
airways, where CF lung disease starts. Bronchoscopic and HRCT data demonstrated, that 
significant structural lung damage can be present despite normal spirometry (Ellemunter et al 
2010; Gustafsson et al 2008; de Jong et al 2006). Moreover, as a consequence of improved 
patient management, many children have FEV1 within the normal range and the rate of 
decline of FEV1 has steadily decreased over the last decade (Konstan et al 2011b; Que et al 
2006). Thus, power calculations show that many hundreds of children would need to be 
treated for a long time to see any beneficial effect of a novel therapeutic approach in early 
lung disease when FEV1 is used as the primary surrogate outcome parameter (Rosenfeld 
2007; Davis et al 2007). Accordingly, there is a need for parameters that are more sensitive 
and allow detection of changes in disease severity, either naturally occurring or in response to 
interventions both long-term and short-term. 
The potential of the method of multiple-breath wash-out (MBW) has been hampered by the 
lack of a convenient method, but Horsley, and more recently, a study by Fuchs et al. 
demonstrated the sensitivity and practicability of the read out parameter Lung clearance index 
(LCI) in healthy volunteers and CF patients when measured with the newly developed MBW 
devices Exhalyzer D, EasyOne Pro MBW module, and Innocor respectively, now suitable for 
clinical practice (Fuchs et al 2008; Fuchs et al 2012; Horsley et al 2008; Kent et al 2014). 
The MBW system is based on the wash out of an inhaled inert tracer gas from the lungs 
during relaxed breathing. LCI is defined as the number of lung volume turnovers needed until 
the lungs are cleared from the tracer gas. An increased LCI (> 7.5) indicates ventilation 
inhomogeneity and thus, changes in peripheral airways.  
The technique is non-invasive, without radiation exposure, easy to perform (requires only 
tidal breathing, and no additional coordination, cooperation, or forced maneuvers) and can be 
performed at all ages, including infancy and pre-school ages. 
A previous study conducted in 142 children with CF, prospectively evaluated over an age 
range of 6 to 20 years, showed that the LCI predicts progression of pulmonary disease earlier 


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in life and with higher accuracy than FEV1 did (Kraemer et al 2005). By now, superior 
sensitivity of LCI has also been shown in adults with CF, where patients with normal 
spirometry showed increased values of LCI (Horsley et al 2008). In contrast to FEV1, LCI has 
also been shown to correlate with CT parameters and possess the greatest sensitivity for 
detecting structural CT abnormalities (a normal LCI almost ruled out the presence of CT 
abnormalities in a recent study (Gustafsson et al 2008). But so far, data about LCI used as 
parameter for measuring response to treatment is very limited and for the use as clinical 
endpoint in studies with inhaled antibiotics, LCI still needs to be evaluated. 
One disadvantage of the LCI is that obstructed and poorly ventilated lung regions do not 
contribute to the overall measurement, thus limiting the value of LCI assessment in patients 
with severe lung disease. 
In conclusion, previous studies suggest that LCI may be a more sensitive surrogate parameter 
to assess early lung disease, treatment effects in patients with milder lung disease and/or 
disease progression in CF patients. CF Patients on regular antipseudomonal standard 
inhalation therapy in an on / off regimen (e. g. Tobramycin 300mg/5mL b.i.d) are showing 
well characterized differences in FEV1 between on and off-cycles (Ramsey et al 1999; 
Konstan et al 2011a), thus allowing an evaluation of LCI on basis of these intraindividually 
observed FEV1 alterations in a comparatively simple study design.  
 
2 
Study purpose 
The purpose of the study is to evaluate LCI by a standardized procedure in a well 
characterized study setting and to assess feasibility of LCI as a more sensitive method than 
FEV1 to measure effectiveness of antibiotic therapy in patients with CF aged 6 years and older 
with mild to moderate lung disease.  
 
3 
Objectives (and related endpoints) 
The primary objective is to assess the change of LCI after 4 weeks following onset of study 
drug inhalation versus Baseline.  
3.1 
Secondary objective(s) 
 Change of FEV1 after 4 weeks following onset of study drug inhalation versus Baseline. 
 Change in CFU after 4 weeks following onset of study drug inhalation versus Baseline 
 Change of LCI after 1 week following onset of study drug inhalation versus Baseline. 
 Change of LCI, FEV1 and CFU between week 4 (end of Study drug inhalation in the 
current treatment cycle) and week 8 (prior to start of Study drug inhalation in the 
following treatment cycle). 
 Correlation between the changes of LCI, FEV1 and CFU after 1 week, 4 weeks, and 8 
weeks versus Baseline, respectively. 


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3.2 
Exploratory objective(s) 
 To explore the change in LCI between Baseline and week 4 (week 0-4), and week 4 and 
week 8 (week 4-8), respectively, in patients using Tobramycin inhalation powder 
compared to patients using Tobramycin inhalation solution. 
 To assess and compare Sacin and Scond at baseline and at Visit 4 in patients using 
Tobramycin inhalation powder vs. patients using Tobramycin inhalation solution. 
 To assess the changes in FEV1 and CFU from Baseline to Visit 3 (week 1) and to compare 
the change in FEV1 with the change in CFU and the change in LCI from baseline to Visit 
3 (week 1) with the corresponding changes in FEV1 and CFU. 
 To explore the change in air trapping (FRCples - FRCMBW) after 1 week, 4 weeks, and 8 
weeks versus Baseline, respectively. 
 To explore the association of additional markers of disease progression (need for i.v. 
antipseudomonal therapy, hospitalization due to exacerbations of lung disease) on LCI at 
Baseline. 
 To assess and compare the ratio of patients with pathological LCI and pathological FEV1 
and their mean deviation from normal LCI and FEV1 at Baseline. 
 To assess and compare the ratio of patients with pathological LCI and pathological FEV1 
and their mean deviation from normal LCI and FEV1 at week 4.  
4 
Study design 
This study uses an open-label, single arm design in patients suffering from CF, aged 6 years 
and older, with an elevated LCI of ≥ 7.5 at screening, who have a chronic pulmonary infection 
with P. aeruginosa (confirmed within the last 12 month and at screening), and who are 
receiving  inhaled Tobramycin therapy in a 28 days on / off regime in the past 3 month before 
screening.  
The study will consist of a 5 – 26 days screening period to test the presence of P. aeruginosa, 
a baseline visit, followed by the treatment phase of 28 days on-treatment period and 
subsequently 28 days off-treatment period. During the study a total of 5 visits is designated. A 
schematic overview is given in Table 4-1; for detailed visit schedule and assessments please 
refer to Table 7-1. 


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Table 4-1 
Study design 
 
5 
Population 
The study population will consist of a representative group of males and females 
aged ≥ 6 years at the time of screening with a diagnosis of CF, with an LCI of ≥ 7.5 at 
screening who have a pulmonary infection with P. aeruginosa. It is intended that 35 patients 
(children, adolescents and young adults) will be recruited in the DACH region at 
approximately 8 study sites.  
 
5.1 
Inclusion/exclusion criteria  
The investigator must ensure that all patients who meet the following inclusion and do not 
fulfill any of the exclusion criteria are offered enrollment in the study. No additional 
exclusion parameters can be applied by the investigator, in order that the study population will 
be representative of all eligible patients of the respective CF center. Patients who are not 
fulfilling all criteria, may be rescreened in the following off-treatment phase. 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Provide written informed consent and assent (as appropriate for minors) prior to the 
performance of any study-related procedure. 
2. Confirmed diagnosis of CF by one or more of the following tests for CF (current or 
historic): 
a. quantitative pilocarpine iontophoresis sweat chloride test of greater than 
60 mmol/L or 60 mEq/L 
b. genotype with 2 identifiable CF-causing mutations 
c. an abnormal nasal transepithelial potential difference characteristic of CF 
3. Male and female patients 6 - 50 years of age at screening (Visit 1). 
Visit 1 
Visit 2 
Baseline 
Visit 3 
Visit 4 
Visit 5 
End of study 
On-treatment 
phase 
(4 weeks) 
Off-treatment 
phase 
(4 weeks) 
Screening 
Period 
(3 weeks) 


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4. Patients with elevated LCI of ≥ 7.5 at screening, confirmed by a central MBW specialist. 
5. Patients with FEV1 of ≥ 50% predicted at screening 
6. P. aeruginosa must be present in two sputum or deep cough throat swab cultures or 
bronchoalveolar lavage (BAL) (only for BAL, a threshold level of 103 CFU/mL is 
required) within 12 months prior to screening or in one culture within 12 months prior to 
screening and in the sputum or deep cough throat swab culture at screening  
7. Use of inhaled Tobramycin in a 28 days on / off regimen in the past 3 months before 
screening, as prescribed by the treating physician.  
8. Clinically stable in the opinion of the investigator and likely to be able to participate in the 
study until the end of the study (Visit 5) 
 
Exclusion criteria 
Exclusion criteria: 
1. History of sputum culture or deep cough throat swab (or BAL) culture yielding 
Burkholderia cenocepacia complex within 2 years prior to screening and / or sputum 
culture yielding B. cenocepacia complex at screening (Visit 1). 
2. Hemoptysis more than 60 mL at any time within 30 days prior to screening (Visit 1). 
3. History of hearing loss or chronic tinnitus. 
4. Serum creatinine 2mg/dL or greater, BUN 40 mg/dL or greater, known local or systemic 
hypersensitivity to aminoglycosides. 
5. Patients who are regularly receiving more than 1 class of inhaled anti-pseudomonal 
antibiotic during the study or in the past 56 days (8 weeks) prior to baseline visit (Visit 2).  
6. Patients who have used oral or intravenous anti-pseudomonal antibiotics within 28 days 
prior to on-phase of study drug  (Visit 2). These patients may be rescreened after 1 month 
following stop of i.v. treatment. 
7. Change in dose, formulation or strength of the study drug in the past treatment cycle 
before screening. 
8. Patients following onset or discontinuation of therapy with macrolides, chest 
physiotherapy, nebulized hypertonic saline, dornase alpha, long acting bronchodilators, 
inhaled steroids or inhaled mannitol during the study and within 56 days (8 weeks)  prior 
to baseline visit.(V2)  
9. Use of loop diuretics within 7 days prior to first study medication administration (Visit 2). 
10. Administration of any investigational drug within 30 days or 5 half-lives, whichever is 
longer, prior to screening (Visit 1).  
11. Signs and symptoms of acute pulmonary disease, e.g. pneumonia, pneumothorax. 
12. Body mass index less than 12 kg/m2. 
13. Body weight of less than 15 kg. 


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14. History of malignancy of any organ system, treated or untreated, regardless of whether 
there is evidence of local recurrence or metastases. 
15. Patients with known or suspected neuromuscular disorders, e. g. Parkinson´s disease, 
Myasthenia gravis.  
16. Patients or caregivers who are considered potentially unreliable or considered unlikely to 
be compliant within the trial.  
17. 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 
human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL). 
18. Women who are menstruating and capable of becoming pregnant* and either not 
practicing a medically approved method of contraception (Pearl Index <1**) or not 
practicing total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient) during and up to at least 4 weeks after the end of treatment. A negative pregnancy 
test (serum) for all women and for girls entering menarche is required with sufficient lead 
time before inclusion  
*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 
months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks post-
surgical bilateral oophorectomy with or without hysterectomy 
**examples of particularly reliable methods with Pearl Index (PI) <1, according to 
guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe: 
 hormonal oral contraception (Combination of estrogen and gestagen, PI=0.1-0.9) 
 hormonal vaginal ring (combination of estrogen and gestagen, PI=0.65 uncorr.; 0.4 
corr.) 
 hormonal transdermal patch (combination of estrogen and gestagen PI= 0.72 uncorr.; 
0.9 corr.) 
 Estrogen-free ovulation inhibitors (containing desogestrel (PI=0.14) 
 Implanted hormones containing etonogestrel (PI=0-0.08) 
 Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.) 
 Intra-uterine progestine device (synthetic progestin containing IUDs,PI=0.16) 
Oral contraceptive without estrogen (e.g. "mini-pills"), nonsynthetic progesterone only 
IUDs, female condoms, cervical shield, periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.. 
19. Study personnel or first degree relatives of investigator(s) must not be included in the 
study. 
5.2 
Premature patient withdrawal 
Patients must be withdrawn from the study for any of the following reasons: 
 Withdrawal of informed consent 
 Pregnancy   


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 Discontinuation of study drug treatment for more than 3 days during the on treatment 
phase  
 Use of prohibited medication (see Table 6-1)  
Patients also should be withdrawn at any time if the investigator concludes that it would be in 
the patient’s best interest for any reason. Protocol violations should not lead to patient 
withdrawal unless they indicate a significant risk to the patient’s safety. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  
If premature withdrawal occurs for any reason, the investigator must determine the primary 
reason for a patient’s premature withdrawal from the study and record this information on the 
Study Completion CRF. 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study will not be replaced by newly 
enrolled patients.   
6 
Treatment 
6.1 
Patient numbering 
Each patient in the study is uniquely identified by a patient number which is a combination of 
his/her center number and subject number. The center number is assigned by Novartis to the 
investigative site. Upon signing the informed consent form, the patient is assigned a patient 
number by the investigator. At each site the first patient is assigned patient number 1, and 
subsequent patients are assigned consecutive numbers (e.g., the second patient is assigned 
patient number 2, the third patient is assigned patient number 3). Once assigned to a patient, a 
patient number will not be reused for any other patient. If the patient fails to enter the trial for 
any reason, the reason for not being enrolled to the trial will be entered on the Screening Log. 
 The patient list has to be kept separate from the other study documents and must not be 
transferred to the sponsor for any reason.  
 
6.2 
Investigational and control drugs 
Tobramycin, either as Tobramycin inhalation solution (TIS, 300mg/5mL or 300mg/4mL) to 
be nebulized or as Tobramycin inhalation powder (TIP, 112mg), as prescribed by the treating 
physician. Neither TIS nor TIP will be provided to the patient. 
 


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6.3 
Treatment arms 
This is a single arm study including solely patients treated routinely with inhaled Tobramycin 
(study drug) in a 28 days on / off treatment regimen.  
6.4 
Treatment assignment 
All patients will continue their standard maintenance-therapy with Tobramycin inhalation 
(study drug) in a 28 days on / off cycle, as prescribed by the treating physician and in 
accordance with the SmPC. 
6.5 
Treatment blinding 
Not applicable. This study has an open-label design. 
6.6 
Treating the patient 
6.6.1 
Dispensing the study drug 
Patients will be treated by standard of care according to investigators’ routine. Commercially 
available product will be used as prescribed by the treating physician. 
6.6.2 
Instructions for use of study drug 
Study drug will be used according to the prescription of the treating physician, in a 28 on / off 
treatment regimen and in accordance with the SmPC.  
6.6.3 
Study drug supply and resupply, storage, and tracking 
Medication will be stored by the patient following the guidance in the SmPC. Study drug will 
not be provided to the patient by Novartis.  
6.6.4 
Study drug compliance and accountability 
6.6.4.1 Study drug compliance 
In this study, patients will be treated by standard of care in investigators’ routine dosing 
frequency. Compliance will be assessed by the investigator and/or study personnel at patient 
visit 3, 4 and, if needed, 5. Information provided by the patient will be captured in the source 
data and in the CRF. To support the patient in reporting his compliance at visits 3 and 4, a 
medication diary will be provided.   
6.6.4.2 Study drug accountability 
Not applicable. Study drug will not be provided to the patient.  
6.6.5 
Disposal and destruction 
Not applicable. Study drug will not be provided to the patient.  


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6.6.6 
Permitted study drug dose adjustments and interruptions 
Study drug dose adjustments are not permitted. 
Any interruption of the inhalation of antipseudomonal antibiotics must be recorded on the 
Dosage Administration Record CRF. Discontinuation of study drug treatment for more than 3 
days during the on treatment phase leads to premature study withdrawal. 
 
6.6.7 
Rescue medication 
Rescue medication is any on demand medication at acute clinical deterioration of the patient, 
independent of the currently used standard therapy. Short acting bronchodilators are allowed 
at any time, except 6 hours or less prior to each FEV1/Spirometry and LCI measurement.  For 
other rescue medication or concomitant treatments to relieve symptoms of the underlying 
disease, see Section 6.6.8. 
Drug and dose of used rescue medication must be recorded on the Concomitant 
medications/Significant non-drug therapies after start of study drug CRF.  
6.6.8 
Other concomitant treatment 
If a patient experiences a pulmonary exacerbation and/or worsening the disease 
condition he/she will be treated as deemed appropriate by the investigator. Following 
treatment for the Pulmonary exacerbation and/or worsening the condition, the patient will be 
expected to continue in the study if, in the opinion of the investigator, he/she can be safely 
returned to their pre-Pulmonary exacerbation concomitant medications. If the patient requires 
the prohibited treatment listed in Table 6-1, then he/she should be withdrawn from the study. 
 
Table 6-1 
Prohibited treatment  
Medication 
Action to be taken 
Any inhaled antipseudomonal antibiotics 
other than tobramycin  
Discontinue the study 
Loop Diuretics 
Discontinue the study 
 
Any iv or oral antipseudomonal antibiotic 
28 days prior baseline (V1) and 23 days 
prior end of study visit (V5) 
Discontinue the study 
Any other investigational treatments 
Discontinue the study 
Short Acting Beta Agonists (SABA) 
Held treatment at least 6 hrs prior to each 
FEV1/Spirometry and LCI measurement. 
Long Acting Beta Agonists (LABA) and 
Held treatment at least 12 hrs prior to each 


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Long 
Acting 
Muscarinic 
Antagonists 
(LAMA) 
FEV1/Spirometry and LCI measurement. 
 
Table 6-2 
Washout of prohibited treatment and study treatment/concomitant 
medication prior to study visits 
 
Treatment/medication 
Wash-out 
time 
Timepoint 
Remarks 
SABA 
6hours (h) 
Prior to 
FEV1/LCI 
Assessment 
  
LABA / LAMA 
12h 
Prior to 
FEV1/LCI 
Assessment 
  
iv/oral Antibiotics 
allowed in 
on-Phase + 
5 Days in 
following 
off 
Prior to Visit 5 
Inhalation of Tobramycin 
stopped for more than 3 days: 
Discontinue the study 
iv/oral Antibiotics 
28 days 
Prior to Visit 2 
  
Inhalation of 
Tobramycin 
1h 
Prior to 
FEV1/LCI 
Assessment 
  
Inhalation of 
Tobramycin 
10h 
Prior to sputum 
sampling 
(Sputum may be 
collected at home 
prior to visit) 
Example for V3/4: Sputum 
sampling at home followed by 
Inhalation. Visit 4 on the next 
day. 
Inhalation of Colistin or 
Aztreonam 
56 days 
Prior to visit 2 
 
Change in 
physiotherapy or 
inhalative concomitant 
medication, eg 
macrolides or steroids 
56 days 
Prior to visit 2 
Macrolides, physiotherapy, 
pulmozyme, hypertonic saline, 
bronchitol, steroids, 
bronchodilators. Stable 
treatment is allowed. 
Any other study drug 
30 days 
Prior to visit 1 
30 days or 5x T 1/2, 
whitchever is longer 
 


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The following treatments are permitted between start of the study drug administration and 
completion/termination and should be accurately documented in the CRF: 
 Anti-pseudomonal antibiotics  
 Intravenous or oral Anti-pseudomonal antibiotics are allowed for the treatment of 
Pulmonary exacerbation during the on-phase as needed by patient condition if i.v. 
treatment is completed 5 days latest after the end of the on-phase.  
 If patients are prescribed i.v. aminoglycosides for symptoms of pulmonary 
exacerbation, continuation of inhalation of Study drug is at the investigator´s 
discretion. 
- 
If inhalation of Study drug is continued during i.v. aminoglycoside therapy, 
patients will continue with the study schedule for the remainder of the 
study; however, therapeutic drug monitoring is strongly recommended with 
appropriate modification of the i.v. aminoglycoside dose as necessary; 
- 
Inhalation of antibiotics can be interrupted during i.v. aminoglycoside 
therapy (eg. due to elevated serum levels of study drug) for a maximum of 
3 days. Patients should restart inhalation of antibiotics in order to complete 
the 28 days cycle as close as possible to their initial study schedule. 
 Pre-planned anti-pseudomonal antibiotics (i.v.) in the absence of an AE 
(prophylaxis of Pulmonary exacerbation) are not permitted during the study and 28 
days prior Baseline Visit (V2)  
 Macrolides (anti-inflammatory regimen) 
Patients should have been initiated or terminated on oral chronic macrolide therapy (i.e., 
macrolides prescribed for more than 14 days) more than 56 days (8 weeks)  prior Baseline 
Visit (V2) and should remain on treatment or off treatment respectively through the 
completion/termination visit. 
 Bronchodilators 
Patients should have been kept on the same regimen more than 56 days (8 weeks) prior to 
Baseline Visit (V2) through the completion/termination visit. If patients are taking short 
acting bronchodilators, they should have been inhaled 6 hours prior to any spirometric 
assessments or MBW measurement and long-acting bronchodilators should have been 
inhaled their last dose at least 12 hours prior to any spirometric or LCI assessments. 
 Inhaled hypertonic saline 
Patients should have been initiated on therapy more than 56 days (8 weeks)  prior Baseline 
Visit (V2) and should remain on unaltered treatment through the completion/termination 
visit. In addition, patients should be instructed to take their hypertonic saline at least 1 
hour before their spirometric or LCI assessments. Patients should be consistent with the 
timing of taking their hypertonic saline at home or at the clinic prior to their spirometric or 
LCI assessments. 
 Inhaled Mannitol 


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Patients should have been initiated on therapy more than 56 days (8 weeks) prior Baseline 
Visit (V2) and should remain on unaltered treatment through the completion/termination 
visit. In addition, patients should be instructed to take their mannitol at least 1 hour before 
their spirometric or LCI assessments. Patients should be consistent with the timing of 
taking their hypertonic saline at home or at clinic prior to their spirometric or LCI 
assessments. 
 Dornase alfa 
Patients should have been initiated on therapy more than 56 days (8 weeks)  prior Baseline 
Visit (V2) and should remain on unaltered treatment through the completion/termination 
visit. 
 Oral or Inhaled corticosteroids 
Patients should have been initiated on therapy more than 56 days (8 weeks)  prior to 
Baseline and should remain on unaltered treatment through the completion/termination 
visit.  
 Use of oxygen, nutritional supplements, and enzymes is unrestricted at all times. 
 
 Use of all anti-pseudomonal antibiotics and macrolides administered within 12 months prior 
to screening will be recorded in the CRF. 
 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study. All medications and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the patient was 
enrolled in the study must be documented in the source data and listed on the Concomitant 
medications/Significant non-drug therapies in the CRF.   
6.6.8.1 
Caution for concomitant use 
 
Based on the interaction profile for tobramycin following intravenous and aerosolized 
administration, concurrent and/or sequential use of Study drug 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, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased 
nephrotoxicity);  
 platinum compounds (risk of increased nephrotoxicity and ototoxicity); 
 anticholinesterases, botulinum toxin (neuromuscular effects).  
Continuation of inhalation of Tobramycin or concomitant use of these substances is at the 
investigator’s discretion. A close monitoring is strongly recommended 
 


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6.6.9 
Study drug discontinuation 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. The following laboratory 
abnormalities require study drug discontinuation: 
 above-normal BUN (40mg/dl or greater) following an earlier result within the normal 
range 
 above-normal creatinine (2mg/dl or greater) following an earlier result within the normal 
range 
In addition, the study drug has to be discontinued on any sign of hypersensitivity against 
Tobramycin and on signs of oto- or nephrotoxicity. In case of oto-or nephrotoxicity, an 
assessment of Tobramycin serum level is recommended. If the level is fallen below 2µg/ml, a 
restart of study drug may be considered by the investigator. A therapeutic drug monitoring 
should be initiated in patients with a history of any renal dysfunction and study drug has to be 
discontinued if the Tobramycin serum level exceeds 12µg/ml. 
The last date of study drug intake should be entered into the Study Completion CRF and the 
reason for discontinuing study drug should be given on the comments page. If a patient who 
discontinued study drug therapy performed all scheduled study procedures and measurements, 
he will be counted as a study completer. 
6.6.10 
Emergency unblinding of treatment assignment 
Not applicable. This study has an open-label design. 
6.6.11 
Study completion and post-study treatment 
The study will be considered completed for an individual patient when he/she completes 
Study Visit 5. After this date, any SAEs occurring in this patient for the following 30 days 
will be reported (see Section 8.2). The investigator will follow-up any AEs ongoing or for 
which no final outcome can be reported at the termination visit. Pregnancies will be followed-
up until birth (see Section 8.3). 
The study as a whole will be completed once the clinical data base has been locked. It is 
intended that 35 patients will be recruited. Recruitment into the study is to be terminated by 
the sponsor once the targeted number of patients who start the study treatment has been met or 
is foreseen to be met with the patients already in screening. Any patient already in the 
screening phase at the time of termination of recruitment can still undergo the start of study 
processes. 
After premature withdrawal Study Visit as designated for end of study should be scheduled as 
soon as possible. 
The study can be terminated for reasons stipulated in the study contract. Should this be 
necessary, the patients should be contacted and scheduled for their end of study assessments 
as described in Section 7. Novartis will be responsible for informing IRBs and/or IECs of the 
early termination of the study.  


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7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed.  
Patients should be seen for all visits on the designated day as shown in Table 7-1.  
Patients who discontinue study drug therapy before completing the study, and those who 
prematurely withdraw from 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 (visit 5) will be 
performed.   
If they refuse to return for these assessments or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone to determine at a minimum 
the safety evaluations during the 30 days following the last dose of study drug therapy, 
including final contact at the 30-day point. Documentation of attempts to contact the patient 
should be recorded in the patient record.  
All data obtained from the assessments listed in Table 7.1 and described in detail in the 
subsections below must be supported in the patient’s source documentation.  


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Table 7-1 
Assessment schedule 
Visit 
1 
2 
3 
4 
5 ̽ 
 
days 
-26 to -
5 
Screeni
ng 
1 
Baseline 
7 
Week 1 
(+/- 2 days) 
28 
Week 4 
(- 3 days) 
56 
End of Study 
(- 3 days) 
Procedure   
Inclusion / exclusion criteria 
x 
x 
 
 
 
Demographic data 
x 
 
 
 
 
Obtain informed consent 
x 
 
 
 
 
Physical examination 
x 
x 
 
 
x 
Vital signs 
x 
x 
x 
x 
x 
Height and weight / BMI 
x 
x 
x 
x 
x 
Clinical chemistry a 
x 
 
 
 
x 
Sputum (microbiology) b 
x 
x 
x 
x 
x 
Lung function (spirometry)c 
x 
x 
x 
x 
x 
FRC (bodyplethysmography) 
 
x 
x 
x 
x 
LCI/ MBW 
x 
x 
x 
x 
x 
Serum pregnancy test 
x 
 
 
 
x 
Urine pregnancy test 
 
x 
 
 
 
Adverse events 
 
x 
x 
x 
x 
Serious Adverse events 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
̽ When a patient prematurely discontinues the study before study completion, all procedures at  
  Visit 5 should be performed. 
a. Clinical chemistry: urea, creatinine, CRP 
b. Pre-treatment sputum to be collected, preferably the first morning specimen; if the patient is unable 
to produce a sputum specimen, a deep cough throat swab or an induced sputum sample will be 
collected, at the investigator’s discretion. 
c. Spirometry should be done using a bodyplethysmograph to allow for FRCples assessment in parallel 
 
At screening (Visit 1), for patients who have consented to study participation, or on whose 
behalf informed consent has been obtained and who have assented to study participation, the 
following will be recorded: patient demographics, concomitant medication, the results from a 
physical examination including height and weight, Spirometry (FEV1), vital signs and LCI/ 
MBW. Blood, will be collected for serum pregnancy test (where applicable) and for safety 
laboratory testing. Sputum (or deep throat cough swabs, where applicable) will be collected to 
assess Burkholderia cenocepacia complex in all patients and Pseudomonas aeruginosa in 
patients for whom only one positive sputum culture in the year before screening is 
documented. 
 
Following the screening period, the eligible patients who meet all inclusion/exclusion criteria 
will be enrolled in the study. All screening safety evaluation results must be available prior to 
enrollment. Sputum sampling at Baseline (V2) will be conducted before first inhalation of 
Study drug in the current treatment cycle to collect the baseline values. Thus, it is 
recommended to schedule visit 2 early in the morning. If this is not possible, Sputum can be 
collected by the patient at home before first inhalation (either in the evening the day before 


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V2  or on the day of V2 in the morning before first inhalation). Spirometric and LCI/MBW 
measurements will be conducted before or at least 1h after inhalation of Study drug, 
measurements should start with LCI/MBW followed by spirometry after a delay of at least 15 
minutes. 
Urine sampling for pregnancy testing will be conducted where applicable. A physical 
examination will be performed, vital signs and concomitant medication will be recorded. 
Height, and weight and Body mass Index (BMI) will be recorded.  
 
Visit 3 will take place one week after baseline visit (+/- 2 days). Sputum sampling will be 
conducted before inhalation of antibiotics or at least 10h after. LCI/MBW and Spirometric 
measurements will be conducted before or at least 1h after inhalation of Study drug, 
measurements should start with LCI/MBW followed by spirometry after a delay of at least 15 
minutes. Clinical signs and symptoms, BMI, height and weight, vital signs, concomitant 
medications, adverse events and assessment of dosing frequency and compliance will be 
recorded.  
 
Visit 4 will take place 4 weeks after baseline visit at the last day of the on-cycle (- 3 days) but 
not thereafter. Sputum sampling will be conducted before inhalation of antibiotics or at least 
10h after. Spirometric and LCI/MBW measurements will be conducted before or at least 1h 
after inhalation of Study drug, measurements should start with LCI/MBW followed by 
spirometry after a delay of at least 15 minutes. Vital signs, BMI, height and weight will be 
recorded. Following Visit 4, patients will enter the off-treatment period for 28 days (no 
antibiotics inhalation, but standard care maintained).  
 
Completion/Termination: Patients return for a completion visit on the last day of the 28 days 
off-treatment period (- 3 days) but not thereafter (Visit 5). The required procedures are a 
physical examination including recording of height and weight, BMI, vital signs, spirometry 
and LCI/MBW measurement (starting with LCI/MBW followed by spirometry with a delay of 
at least 15 minutes), and recording of adverse events and concomitant medications. Blood, 
sputum (or deep throat cough swabs, where applicable), will be collected for safety laboratory 
testing and serum pregnancy test (where applicable). 
 
If the patient terminates early from the study, all examinations of Visit 5 should be performed 
as a discontinuation visit. Reasons for discontinuations should be captured in the source 
documentation and by fully completing the relevant CRF Form sections with all information 
available to the investigator. 
 


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7.1 
Information to be collected on screening failures 
Patients may discontinue from the study between Visit 1 and prior to start the first intake of 
antibiotics in context to the study at Visit 2. These patients are considered screening failures.  
Only demography data, occurred SAEs and the primary reason for discontinuation (screening 
failure log) are collected for those patients who fail to enter the treatment phase. It is not 
necessary to complete all the required evaluations at the time of discontinuation unless 
medically indicated. 
Potential severe adverse events which may have occurred from time of signing informed 
consent/written assent until screening failure time should be documented in the patient 
medical records. Reporting during this time period should be followed as described in Section 
8.2. 
7.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race and ethnicity. Furthermore, relevant medical history and current 
medical conditions present up to 6 months prior to signing of the informed consent will be 
collected. Whenever possible, diagnoses and not symptoms will be recorded.  
Conditions and signs/symptoms associated with CF disease but not limited to pancreatic 
insufficiency, sinusitis, diabetes mellitus, and clubbing will be captured by using specific CF 
related CRF page. Previous medication to be listed includes information for all anti-
pseudomonal antibiotics and macrolides administered within the last 12 months prior to 
Visit 1.  
 
 
7.3 
Treatment exposure and compliance 
Assessment of compliance will be based on: 
 The number of dosing sessions per day (e.g. morning and evening) 
 The number of actual days on treatment (e.g. out of 28 in each cycle) and in the study 
Compliance will be assessed by the investigator and/or study personnel at each visit using 
information provided by the patient via a patient diary.  
7.4 
Efficacy 
7.4.1 
Lung clearance index assessment  
In general, LCI uses MBW of an inert gas (nitric oxide/oxygen) to measure ventilation 
inhomogeneity caused by airway narrowing from inflammation or partial mucus obstruction. 
Wash-out is completed by definition at the time point when the inhaled gas concentration 
declined to 1/40th of its concentration at baseline. Washout takes longer in Patients with more 


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severe disease as gas is trapped in narrowed airways (leading to a higher LCI). Alternatively, 
LCI can also be determined by the decline in concentration of exhaled nitrogen during 
inhalation of oxygen.  
In this study, LCI will be determined according to the manufacturer’s/Exhalyzer D SOP based 
on the current MBW guidelines of the European Cystic Fibrosis Society (ECFS), using the 
Exhalyzer D device and inhalation of oxygen to wash out nitrogen from the airways. A user 
guide with the MBW SOP for this study and a device specific training by the manufacturer 
will be provided to every study site. LCI will be assessed using the same equipment 
throughout all sites. This equipment will be provided by the sponsor during the study if it is 
not already available at the site.  
Children aged 6-10 may perform only two consecutive MBW measurements. Two additional 
measurements can be performed after a break of 15 minutes. From age 10-14, only 3 
consecutive measurements are allowed that may be repeated after a break of 15 minutes. 
There is no limit for older patients. 
 
 
 
 
 
 
 
 
 
 
 
 
For MBW measurements, the subjects should breathe seated, in an upright position with head 
in midline. They should wear a nose clip and maintain tight mouthpiece seal. For washout of 
concomitant medication, prior to MBW, see section 6.6.8.  
Lung function measurements should start with LCI/MBW followed by spirometry after a 
delay of at least 15 minutes following the conclusion of the MBW assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
 
  
For the measurements used to calculate the mean value, a quality control will be done by a 
central assessor (MBW specialist). For exploration and control reasons, the Scond and Sacin 
values (slope analysis) will be recorded as well. 
  
If the quality of the measurements is too low according to the judgement of the specialist:  
• 
MBW at Visit 1 may be repeated in the screening timeframe 
• 
If MBW at Visit 2 cannot be repeated at the same day, the patient has to be withdrawn 
• 
MBW’s at Visits 3 and 4 have to be repeated within 5 days after initial measurement 
or the patient has to be withdrawn. 
• 
MBW at Visit 5 cannot be repeated on the following day if the patient has already 
restarted inhalation of Tobramycin in the new treatment cycle. 
7.4.2 
Spirometry assessment 
FEV1 will be assessed as a pulmonary function by using spirometry. A bodyplethysmograph 
should be used for spirometry to allow for an assessment of FRCples in parallel.   
During each visit, pulmonary function test will be measured. For all clinic spirometry 
assessments, three acceptable maneuvers (a maximum of 8 maneuvers) should be performed 
for each time-point. The FEV1 value recorded must be the highest value measured 
irrespective of whether or not they occur on the same curve. All displaceable volumes will be 
reported in liters (L) at the following conditions: normal body temperature (37° C), ambient 
pressure, saturated with water vapor (BTPS).  
Spirometry performance of spirometric testing should be in accordance with ATS standards 
(Miller et al, 2005). Staff will be trained at the investigator’s meeting to perform spirometry 
assessments. Whenever possible the same staff member should evaluate and coach a given 
patient at each visit throughout the study. In addition the spirometer should be calibrated 
every morning before taking any spirometric measurements for this study. Calibration reports 
PPD
PPD
PPD
PPD


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should be stored as source data. Spirometric measurements shall be conducted at 
approximately the same time of day Therefore, investigators and patients should make every 
effort to conduct the spirometry at the same time of day during the study (max. +/- 1h 
difference). If the Investigator foresees difficulties in conducting the spirometry at the same 
time, eg. due to cohort separation in the CF-Center, spirometry should be scheduled always in 
the afternoon (after 11:00 AM) to minimize effects of diurnal variability in pulmonary 
function (Borsboom 1999).  
Activities that should preferably be avoided prior to lung function testing (Miller 2005) 
 Smoking within at least 1 h of testing 
 Consuming alcohol within 4 h of testing 
 Performing vigorous exercise within 30 min of testing 
 Wearing clothing that substantially restricts full chest and abdominal expansion 
 Eating a large meal within 2 h of testing 
7.4.3 
Microbiological assessment 
For microbiological assessment, sputum will be collected in sterile containers. If a patient is 
unable to expectorate, a deep-throat cough swab may be collected or sputum may be induced 
at the investigator’s discretion. Sputum will be cultured for the presence of P. aeruginosa 
(quantitative test) and B. cepacia complex,. Deep-throat cough swab specimens will be 
evaluated qualitatively only.  
Tobramycin MIC values for P. aeruginosa will be determined for specimens obtained at the 
visits listed previously to assess change in pathogen susceptibility to applied study drug 
before and after the treatment.  
Microbiological assessment will be performed in a central laboratory. 
7.5 
Safety 
7.5.1 
Adverse events 
For details on adverse event collection and reporting, refer to section 8. 
7.5.2 
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 and will not be recorded in the CRF. 
Any clinically significant conditions that are present prior to baseline visit, must be recorded 
on the Relevant Medical History/Current Medical Conditions pages of the CRF. 
Significant findings identified after enrollment to the study which meet the definition of an 
Adverse Event must be recorded on the Adverse Event part in the CRF. 


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7.5.3 
Vital signs 
Systolic/diastolic blood pressure, radial pulse rate (over a 30 s interval), respiratory rate and 
body temperature will be recorded. Single measurements will be performed before inhalation 
of study medication on the treatment period. 
All blood pressure measurements should be taken after the patient has rested in the sitting 
position for at least 10 min. 
7.5.4 
Laboratory evaluations 
Non-fasting standard laboratory tests will be conducted as indicated in Table 7-1. Subjects 
should avoid smoking within the hour preceding the blood draws.  
A central laboratory will be used for analysis of all specimens listed below, unless noted 
otherwise. Standard urine pregnancy test will be provided by the central lab and may be 
performed at site/in a local laboratory. Refer the Laboratory Manual for identification of 
laboratory reference range values and the schema for notification of site staff and Novartis for 
out of range values.  
Standard laboratory tests:  
 Clinical chemistry: Clinical chemistries will include urea, creatinine and CRP.  
7.5.5 
Pregnancy test and assessments of fertility 
All female patients after the onset of menarche, who are not surgically sterile, will have a 
serum pregnancy test carried out by the central laboratory from the blood sampled for safety 
laboratory examination at Visits 1 and 5 (or discontinuation visit). Additionally, a urine 
pregnancy test will be done at Visit 2. A positive serum pregnancy test at Visit 1 leads to the 
exclusion of the patient from the study prior to the start of study drug administration in 
context of the study. In case of a positive urine pregnancy test at Visit 2, the result should be 
verified by a  serum pregnancy test. If positive, the patient must be discontinued from the trial 
- alike for all positive test results throughout the study. In case of positive test results the 
pregnancy must be followed up until after birth. 
 
7.6 
Tolerability/acceptability 
Not applicable 
7.7 
Resource utilization  
Not applicable 
7.8 
Treatment Assessment 
Not applicable 
7.9 
Pharmacokinetics 
Not applicable 


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7.10 
Pharmacogenetics/pharmacogenomics 
Not applicable 
7.11 
Other biomarkers 
Not applicable 
8 
Safety monitoring 
8.1 
Adverse events 
8.1.1 
Adverse event definition and reporting 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after signing of informed consent, even if the event is not 
considered to be related to the diagnostic method of the study. 
Medical conditions/diseases present before first intake of study drug are only considered 
adverse events if they worsen after study start. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, require dose 
reduction or temporary or permanent study drug discontinuation or require therapy. All 
adverse events with a date of onset up to 30 days following the last dose of study drug/the last 
study examination must be reported. 
 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
and his/her parents (for minors) 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, laboratory test, or other assessments. All adverse events must be recorded on the 
Adverse Events CRF with the following information: 
1. the severity grade (mild, moderate, severe)  
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study drug or study diagnostic 
method dosage adjusted/temporarily interrupted; study drug or study diagnostic method 
permanently discontinued due to this adverse event; concomitant medication given; non-drug 
therapy given; patient hospitalized/patient’s hospitalization prolonged. The action taken to 
treat the adverse event should be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, seriousness, the suspected relationship to  study drug or 
the diagnostic method, the interventions required to treat it, and the outcome. 
 


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8.1.2 
Laboratory test abnormalities 
Laboratory abnormalities that constitute an Adverse Event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require dose reduction or temporary 
or permanent study drug discontinuation or require concomitant therapy), should be recorded 
on the Adverse Event CRF page. Whenever possible, a diagnosis, rather than a symptom 
should be provided. Laboratory abnormalities that meet the criteria for an Adverse Event 
should be followed until they have returned to normal or an adequate explanation of the 
abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events.  
A grade 3 or 4 event or laboratory abnormality (severe) as per CTCAE (if applicable) does not 
automatically indicate an SAE unless it meets the definition of serious as defined below 
and/or as per investigator´s discretion. If a lab event satisfies the regulatory definition of 
“Serious”, such an event must be reported to Novartis within 24 hours of learning of its 
occurrence. Any laboratory SAEs experienced 30 days after completion of the study period 
should only be reported to Novartis if the investigator suspects a causal relationship to the 
study treatment. 
8.2 
Serious adverse events 
8.2.1 
Serious adverse event definition, treatment and follow-up 
An SAE is defined as an event which: 
 is fatal or life-threatening  
 results in persistent or significant  disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 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, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 


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Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; SAEs in contrast to AEs need to be reported from informed 
consent on, see Section 8.2.2.  
Information about common side effects already known about study drug and diagnostic 
method can be found in Investigator Brochure (Novartis), or SmPC (other study drugs), 
respectively, or will be communicated in the form of Investigator Notifications. This 
information will be included in the patient informed consent and should be discussed with the 
patient during the study as needed. 
 
8.2.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, and until 30 days after 
the patient has stopped study participation (defined as last visit) must be reported to Novartis 
within 24 hours of learning of its occurrence.  
Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug or diagnostic method. For patients 
who discontinue study medication, SAEs still need to be reported until the end of study, 
regardless of their suspected relationship to study medication.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the German   
Novartis Clinical Safety & Epidemiology Department. The telephone and telefax number of 
the contact persons in the German department of Clinical Safety and Epidemiology, 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. 
All serious AEs occurring during the follow-up will be entered in the Adverse Events CRF 
pages. In addition, an SAE Report Form should be completed. Follow-up information is sent 
to the same person to whom the original SAE Report Form was sent, using a new SAE Report 
Form stating that this is a follow-up to the previously reported SAE and giving the date of the 
original report. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.  
If the SAE is not previously documented (new occurrence) and is thought to be related to the 
Novartis study drug, a Clinical Safety & Epidemiology Department associate may urgently 
require further information from the investigator for Health Authority reporting. Novartis may 


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need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug 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 Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
8.3 
Pregnancy reporting 
To ensure patient safety, each pregnancy in a patient on study drug 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.  
Instances of pregnancies and positive pregnancy tests should be collected for all patients who 
have conceived after receiving study drug (following Visit 2 until Visit 4). Pregnancies that 
are noted prior to administration of study medication but after signing informed consent may 
require reporting if they are considered to be associated to the conduct of the study by the 
investigator. Pregnancies that are noted following Visit 4 (off-phase) have to be reported as 
well (see 8.4). 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the German Novartis Clinical Safety & Epidemiology Department.  Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
8.4 
Reporting of adverse events and pregnancies after the last dose 
of study drug taken 
All AEs, SAEs, and pregnancies which occurred within 30 days after last intake of last dose 
of study drug  should be reported. After this 30-day period, only SAEs, and pregnancies 
should be reported until the last visit. 
 
8.5 
Data Monitoring Board 
Not applicable 
9 
Data review and database management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit, a Novartis representative will review the 
protocol and CRFs with the investigators and their staff. During the study, the field monitor 
will visit the site regularly to check the completeness of patient records, the accuracy of 


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entries on the CRFs, the adherence to the protocol and to Good Clinical Practice and the 
progress of enrollment. 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 give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.  
9.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the CRF using 
fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
investigator staff will enter the data required by the protocol into the Novartis CRFs 
Automatic validation programs check for data discrepancies in the CRFs and, by generating 
appropriate error messages, allow modification or verification of the entered data by the 
investigator staff. The investigator must certify that the data are complete and accurate by 
signing the CRF pages or a memo that will be sent to him by Novartis personnel after the last 
transfer of the data prior to analysis. After database lock, the investigator will receive a CD-
ROM or paper copies of the patient data for archiving at the investigational site.  
9.3 
Database management and quality control 
A clinical research organization (CRO) working on behalf of Novartis reviews the CRFs 
entered 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.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Spirometry data and LCI will be entered on the CRF by the site and transferred to Novartis. 
MBW plots will be transferred by Fax or secure email to the central MBW specialist. Central 
laboratory data will be transferred electronically to Novartis using an agreed Data Transfer 
Specification. 


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At the conclusion of the study,  the occurrence of any protocol violations 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 made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Trial 
Statistician and Statistical Reporting and the Clinical Trial Leader. 
10 
Data analysis 
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis 
carried out independently by the investigator(s) should be submitted to Novartis before 
publication or presentation. 
It is planned that the data from all centers that participate in this protocol will be used, so that 
an adequate number of patients will be available for analysis. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, pharmacokinetic 
measurements, and biomarker measurements. 
10.1 
Populations for analysis 
The safety set will consist of all patients that enter the study (provide Informed Consent). All 
analyses will be based on the safety set. 
10.2 
Patient demographics/other baseline characteristics 
Appropriate descriptive statistics for demographic, disease history and baseline characteristics 
will be presented to describe the study population. 
Categorical variables will be presented as the number and percentage of patients in each 
category. Continuous variables will be summarized using descriptive statistics (i.e., n, mean, 
standard deviation, median, minimum and maximum). 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Duration of exposure to Study drug during the treatment cycles and compliance will be 
summarized.  
Summary data listings will be provided for concomitant therapy both prior to and after start of 
study drug administration. The WHO Drug Reference dictionary will be used for coding of 
medications. 
10.4 
Analysis of the primary objective(s) 
10.4.1 
Variable 
The primary variable of this study is  the time course and changes in LCI from baseline to 
week 4. 


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10.4.2 
Statistical hypothesis, model, and method of analysis 
Time course and changes in LCI from baseline to week 4 will be estimated using an ANOVA 
model with factors patient and visit. Estimates will be presented as LS-Means with 95% 
confidence intervals for each visit as well as for the pairwise differences between visits, 
additionally, these results will be displayed graphically.  
10.4.3 
Handling of missing values/censoring/discontinuations 
There will be no imputation of missing data. 
10.4.4 
Supportive analyses 
Not applicable. 
10.5 
Analysis of secondary objectives 
10.5.1 
Efficacy (secondary) 
FEV1 and CFU will be analyzed analogously to LCI, the correlation between FEV1 ,CFU and 
LCI will be explored using scatterplots (for raw values as well as for changes). The 
correlation coefficients will be calculated together with their 95% confidence intervals and p-
values. All other secondary and exploratory endpoints will be analyzed descriptively. 
10.5.2 
Safety 
Safety assessments will be based mainly on the frequency of adverse events. Adverse events 
will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). All AEs will be assigned to the last 
treatment the patient received before AE start. In the data listings of adverse events, the 
severity of an AE, whether or not an AE is related to MBW or study drug, and whether or not 
it is a serious AE, will be indicated. An adverse event related to study drug is defined as one 
considered by the investigator to have a suspected relationship with the diagnostic method or 
the study drug. The adverse events will be summarized by the number and percentage of 
patients in each primary system organ class and preferred term. For summaries by severity of 
event, the most severe occurrence for a particular preferred term will be used for a given 
patient. Summary tables of adverse events by treatment and severity will be provided. 
Multiple occurrences of the same AE or SAE in the same patient in one treatment period will 
be counted only once, using the worst severity and drug relationship. Data from other tests 
(e.g. electrocardiogram or vital signs) will be listed, notable values will be flagged, and any 
other information collected will be listed as appropriate. 
Vital signs data will be listed, including change from baseline.  
All laboratory data (blood chemistry) will be listed with abnormal values flagged. The 
laboratory values will be summarized. Incidence of newly occurring or worsening notably 
abnormal laboratory values will be produced. 


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10.5.3 
Tolerability 
Not applicable 
10.5.4 
Resource utilization 
Not applicable. 
10.5.5 
Health-related Quality of Life 
Not applicable 
10.5.6 
Pharmacokinetics 
Not applicable 
10.5.7 
Pharmacogenetics/pharmacogenomics 
Not applicable 
10.5.8 
Biomarkers  
Not applicable 
10.5.9 
PK/PD  
Not applicable 
10.6 
Interim analysis 
No interim analysis will be performed. 
10.7 
Sample size calculation 
For FEV1, a change of 5% with an intraindividual SD of 9% is expected between on- and off-
treatment cycles. Under these assumptions, 28 patients will be required to detect this change 
with 80% power on a two-sided, 5% significance level. Since LCI is expected to be a more 
sensitive measure (compared to FEV1), this patient number should therefore also be sufficient 
to detect relevant changes in LCI and to explore the correlation between LCI and FEV1. To 
compensate for some protocol violations and drop-outs, a total of 35 patients should be 
recruited into this trial. 
 
10.8 
Power for analysis of critical secondary variables 
Not applicable. 
11 
Discussion and rationale for study design features  
This study was designed to evaluate LCI by a standardized procedure in a well characterized 
study setting to assess feasibility of LCI as a more sensitive method to measure effectiveness 


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of antibiotic therapy in patients with mild lung disease. In principle, a variety of available 
Devices may be used to measure LCI by multiple breath washout. However, LCI is not yet a 
fully standardized method and is not used in clinical practice. To secure reliable and 
comparable data from every single study center, the participating sites will all use the same 
device, selected from the listed devices in section 1 of the protocol. Appropriate training for 
the sites will be provided as well as a detailed user guide and MBW Standard operation 
procedure. 
The study will be conducted in patients with CF aged 6 years and older with an upper limit of 
50, representing the typical CF patient population, eligible to get inhaled antibiotics 
prescribed following onset of chronic infection with Pseudomonas aeruginosa. Additionally, 
the need for more sensitive diagnostic methods is highest in early lung disease and thus in 
children and youths, so children should not be excluded The inclusion of younger children in 
this study seems appropriate, as MBW is a non-invasive diagnostic method without any 
radiation exposure and the washout gas used in this trial (oxygen) is part of the normal 
breathing air and widely used in clinical practice. Furthermore, MBW has already been 
evaluated not even in this population, but in very young children below age of 6 as well (e. g. 
Aurora et al 2010, Hall et al 2011). Last but not least, only already prescribed in-label 
standard therapy is used for the treatment effect needed and no changes in the therapy regimen 
or any newly developed investigational drug is evaluated in this study.  
However, to limit any diagnostic burden for young children, MBW is limited by the protocol 
to two consecutive measurements at a time for these patients. 
Only patients with an abnormal LCI of more than 7.5 at screening during off-phase will be 
included in order to have most likely a treatment effect on LCI following onset of antibiotic 
inhalation after the off-phase of the standard therapy (baseline visit). As described above, LCI 
seems to be a good parameter to measure lung disease status and progression in patients with 
a milder lung disease. Patients with more severe disease will not tolerate an off-phase. Such 
patients do typically need a combination of antibiotics, e. g. Colistin / Study drug or 
Aztreonam Lysinat / Study drug (on/on respectively) as standard maintenance therapy which 
is not allowed in this study. However, to clearly define the eligible population, the FEV1 of 
the study population has been restricted to a lower limit of 50% predicted. 
Drugs that support lung clearance e. g. Pulmozyme (DNAse) or hypertonic saline or drugs 
that treat obstructive airways, e. g. long acting ß-Agonists may impact the LCI as well. In 
order to minimize the influence of these concomitant medications on the treatment effect of 
inhaled antibiotics, initiation or discontinuation of these therapies in the last 56 days (8 
weeks) prior to screening Baseline visit and during the study is not allowed. 
Beneficial effects of treatment with inhaled tobramycin may include a reduction of air 
trapping by recruitment of lung units previously not contributing to ventilation. If their time 
constants are slower, relative to the previously assessed lung units, ventilation inhomogeneity, 
and therefore LCI, will increase despite the positive treatment effect (Robinson 2009). Air 
trapping will be assessed by the difference in FRC measured by bodyplethysmography 
(FRCples) and FRC measured by MBW (FRCMBW). As spirometry is done in central European 
Cystic Fibrosis centers using bodyplethysmography, FRCples will be routinely documented in 
the source documents.Inhalation of Study drug, administered in repeated cycles of 28 days 


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twice daily followed by 28 days off-drug represents current antibiotic standard maintenance 
therapy in this patient population of CF patients aged 6 years and older CF (Ramsey 1999, 
TOBI® 2013, Bramitob® 2013, Konstan et al 2011a).  
CF Patients chronically infected with P. aeruginosa on regular antipseudomonal standard 
inhalation therapy in an on / off regimen are showing well characterized differences in FEV1 
between on and off-cycles (Ramsey et al 1999; Konstan et al 2011a). Thus, this population 
allows an evaluation of LCI based on these intraindividually observed FEV1 alterations, 
without any changes to their standard therapy.  
The microbiology parameter “colony forming units” of pseudomonas aeruginosa has been 
selected as a third efficacy marker to be compared with LCI as well, because spirometry 
(FEV1) strongly depends on daily performance and compliance to spirometry of the patient. 
LCI and FEV1, respectively, should reflect alterations in bacterial colonization.  
The study duration of 8 weeks comprises a complete on / off treatment cycle starting with 28 
days inhalation followed by 28 days without Study drug inhalation. This design allows to 
obtain baseline lung function at start of the inhalation cycle (representing minimal lung 
function at the end of the inhalation pause), the development/improvement of lung function 
after 1 and after 4 weeks of inhalation therapy (representing maximal lung function) and the 
subsequent decline in lung function after 4 weeks of cessation of inhalation therapy. The 
detected intraindividual differences between best and worst lung function then allow to 
compare LCI and FEV1 results and to assess feasibility of LCI as primary surrogate outcome 
parameter in future clinical studies. 
12 
References 
Aurora P, Stanojevic S, Wade A, Oliver C, Kozlowska W, Lum S, et al. Lung clearance index 
at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J 
Respir Crit Care Med 2011; 183: 752–8. 
Bramitob® 2013, Fachinfo BRAMITOB® 300mg/4ml Lösung für einen Vernebler. Stand: 
Oktober 2013; Chiesi GmbH, Hamburg. Zulassungsnummer: 65777.00.00 
Davis SD, Brody AS, Emond MJ, Brumback LC, Rosenfeld M. Endpoints for clinical trials in 
young children with cystic fibrosis. Proc Am Thorac Soc. 2007; 4: 418–430. 
Ellemunter H, Fuchs SI, Unsinn KM, Freund MC, Waltner-Romen M, Steinkamp G, Gappa 
M. Sensitivity of Lung Clearance Index and chest computed tomography in early CF 
lung disease. Respir Med. 2010; 104: 1834–1842. 
Fuchs SI, Sturz J, Junge S, Ballmann M, Gappa M. A novel sidestream ultrasonic flow sensor 
for multiple breath washout in children. Pediatr Pulmonol. 2008; 43: 731–738. 
Fuchs SI, Ellemunter H, Eder J, Mellies U, Grosse-Onnebrink J, Tümmler B, Staab D, Jobst 
A, Griese M, Ripper J, Rietschel E, Zeidler S, Ahrens F, Gappa M. Feasibility and 
variability of measuring the Lung Clearance Index in a multi-center setting. Pediatr 
Pulmonol. 2012 Jul;47(7):649-57 


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Borsboom GJJM, van Pelt W, van Houwelingen HC, van Vianen BG, Schouten JP, Quanjer 
PH. Diurnal Variation in Lung Function in Subgroups from Two Dutch Populations. 
Consequences for Longitudinal Analysis. Am J Respir Crit Care Med 1999; 
159:1163–1171 
Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and 
spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008; 63: 129–
134.  
Hall GL, Logie KM, Parsons F, Schulzke SM, Nolan G, et al. (2011) Air Trapping on Chest 
CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis 
Diagnosed following Newborn Screening. PLoS ONE 6(8): e23932. 
doi:10.1371/journal.pone.0023932 
Horsley AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, Davies 
JC, Cunningham S, Alton EW, Innes JA. Lung clearance index is a sensitive, 
repeatable and practical measure of airways disease in adults with cystic fibrosis. 
Thorax. 2008 Feb;63(2):135-40 
de Jong PA, Lindblad A, Rubin L, Hop WC, de Jongste JC, Brink M, Tiddens HA. 
Progression of lung disease on computed tomography and pulmonary function tests in 
children and adults with cystic fibrosis. Thorax. 2006; 61: 80–85.  
Kent L, Reix P, Innes J A, Zielen S, Le Bourgeois M, Braggion C,  Lever S, 
Arets H G M,  Brownlee K, Bradley J M, Bayfield K, O'Neill K, Savi D, Bilton D, 
Lindblad A, Davies J C, Sermet I, De Boeck K. Lung clearance index: Evidence for 
use in clinical trials in cystic fibrosis: J Cyst Fibros 2014; 13: 123-138 
Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, Zhang J, Angyalosi 
G, He E, Geller DE. Safety, efficacy and convenience of tobramycin inhalation 
powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011a 
Jan;10(1):54-61  
Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A, Morgan WJ. Clinical use 
of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis. 
Pediatr Pulmonol. 2011b; 46: 545–553.  
Kraemer R, Blum A, Schibler A, Ammann RA, Gallati S. Ventilation inhomogeneities in 
relation to standard lung function in patients with cystic fibrosis. Am J Respir Crit 
Care Med. 2005 Feb 15;171(4):371-8.  
Macklem PT. The physiology of small airways. Am J Respir Crit Care Med. 1998; 157: 
S181–S183 
Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, 
van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, 
Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force 
General considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153-61. 


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Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, 
Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force 
Standardisation of spirometry. Eur Respir J. 2005; 26(2):319-38.Que C, Cullinan P, 
Geddes D. Improving rate of decline of FEV1 in young adults with cystic fibrosis. 
Thorax. 2006; 61: 155–157. 
Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K 
M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL. Intermittent 
administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis 
Inhaled Tobramycin Study Group. N Engl J Med. 1999 Jan 7;340(1):23-30 
Robinson PD, Cooper P, Van Asperen P, Fitzgerald D, Selvadurai H. Using Index of 
Ventilation to Assess Response to Treatment for Acute Pulmonary Exacerbation in 
Children With Cystic Fibrosis. Pediatric Pulmonology 2009; 44: 733-742. 
Rosenfeld M. An overview of endpoints for cystic fibrosis clinical trials: one size does not fit 
all. Proc Am Thorac Soc. 2007; 4: 299–301.  
TOBI® 2013, Fachinfo TOBI® 300 mg/5 ml Lösung für einen Vernebler. Stand März 2013; 
Novartis Pharma GmbH, Nürnberg. Zulassungsnummer: 49612.00.00 
 


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Appendix 1:  Ethical considerations and administrative procedures 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented 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 Code of Federal Regulations Title 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.  
Responsibilities of the investigator and IRB/IEC/ 
The protocol and the proposed informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board / Independent Ethics Committee (IRB/IEC) before study start.  
Approval letters concerning protocol and informed consent will be filed by Novartis. 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 
Clinical 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. 
Informed consent procedures  
Eligible patients may only be included in the study after providing written, IRB/IEC-approved informed 
consent. 
Women of child bearing potential should be informed that taking the study drug 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. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of the 
procedures described in the protocol). The process of obtaining informed consent should 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. 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the trial to 
request approval of a protocol deviation, as no authorized deviations are permitted. If the 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 it cannot be implemented. All significant protocol deviations will be recorded and reported in 
the CSR. 
Amendments to the protocol 
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.  Only amendments that are 
required for patient safety may be implemented prior to IRB/IEC approval.  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 


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from the protocol.  In such cases, Novartis should be notified of this action and the IRB/IEC at the 
study site should be informed within 10 working days. 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical trial 
agreement. 
Publication of study design and results 
Novartis assures that 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 study will be either submitted for publication and/or posted in a publicly 
accessible database of clinical study results. 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. As part of participating in a Novartis-sponsored study, each 
site will permit authorized representatives of the sponsor(s) and regulatory agencies to examine (and 
when required by applicable law, to copy) clinical records for the purposes of quality assurance 
reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
Principal Investigator. The study case report form (CRF) is the primary data collection instrument for 
the study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported in the CRFs and all other required reports. Data reported on the CRF, that are derived 
from source documents, should be consistent with the source documents or the discrepancies should 
be explained. All data requested on the CRF must be recorded. Any missing data must be explained. 
Any change or correction to a paper CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry. For electronic CRFs an audit trail will be maintained by the 
system. The investigator should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential Documents for 
the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and/or 
guidelines. The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than fifteen 
(15) years from the completion of the Clinical Trial unless Sponsor provides written permission to 
dispose of them or, requires their retention for an additional period of time because of applicable laws, 
regulations and/or guidelines. 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names in 
any documents submitted to Novartis. Signed informed consent forms and patient enrollment log must 
be kept strictly confidential to enable patient identification at the site. 
 


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Audits and inspections  
Source data/documents must be available to inspections by Novartis or designee or Health Authorities 
 

SAP_001.pdf: 
Clinical Development 
TBM100/Tobramycin 
CTBM100CDE02 / NCT02248922 
An 8 week open-label interventional multicenter study to evaluate 
the lung clearance index as endpoint for clinical trials in cystic 
fibrosis patients ≥ 6 years of age, chronically infected with 
Pseudomonas aeruginosa 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
; 
Document type: 
SAP 
Document status: 
Final 
Release date: 
10-Feb-2017
Number of pages: 
28 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
PPD


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
11-Mar-2016 
Prior to 
DBL 
Creation 
of 
updated 
Draft version  
Updated 
all 
relevant 
comments received from 
reviewer(Statistician) 
Most of section 
21-Sep-2016 
Prior to 
DBL 
Creation 
of 
updated 
Draft version  
Updated 
all 
relevant 
comments received from 
reviewer 
Section 
23-Nov-2016 
Prior to 
DBL 
Creation 
of 
updated final 
version  
Updated version as per 
suggestion received from 
clinical team 
Section 2.13 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 5 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 8 
2.1 
Data analysis general information ........................................................................... 8 
2.1.1 
General definitions .................................................................................. 8 
2.2 
Analysis sets ............................................................................................................ 9 
2.2.1 
Subgroup of interest ................................................................................ 9 
2.3 
Patient disposition, demographics and other baseline characteristics ..................... 9 
2.3.1 
Patient disposition ................................................................................. 10 
2.3.2 
Protocol Deviation ................................................................................ 10 
2.3.3 
Demographic characteristics ................................................................. 10 
2.3.4 
Medical history ...................................................................................... 11 
2.3.5 
Surgical and Medical Procedures .......................................................... 11 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 11 
2.4.1 
Study drug Administration .................................................................... 11 
2.4.2 
Compliance ........................................................................................... 12 
2.4.3 
Prior, concomitant and post therapies ................................................... 12 
2.5 
Analysis of the primary objective .......................................................................... 12 
2.5.1 
Primary endpoint ................................................................................... 13 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 13 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 13 
2.5.4 
Supportive analyses ............................................................................... 13 
2.6 
Analysis of the key secondary objective ............................................................... 13 
2.6.1 
Key secondary endpoint ........................................................................ 13 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.7 
Analysis of secondary efficacy objectives ............................................................. 14 
2.7.1 
Secondary endpoints ............................................................................. 14 
2.7.2 
Handling of missing values/censoring/discontinuations ....................... 15 
2.8 
Safety analyses ....................................................................................................... 15 
2.8.1 
Adverse events (AEs) ............................................................................ 15 


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2.8.2 
Deaths .................................................................................................... 17 
2.8.3 
Other safety data ................................................................................... 18 
2.9 
Pharmacokinetic endpoints .................................................................................... 18 
2.10 
PD and PK/PD analyses......................................................................................... 18 
2.11 
Patient-reported outcomes ..................................................................................... 18 
2.12 
Biomarkers ............................................................................................................. 18 
2.13 
Other Exploratory analyses .................................................................................... 19 
2.14 
Interim analysis ...................................................................................................... 21 
3 
Sample size calculation ..................................................................................................... 21 
4 
Change to protocol specified analyses .............................................................................. 21 
5 
Appendix ........................................................................................................................... 21 
5.1 
Imputation rules ..................................................................................................... 21 
5.1.1 
Study drug ............................................................................................. 21 
5.1.2 
AE date imputation ............................................................................... 22 
Adverse event end date will not be imputed. ......................................................... 23 
5.1.3 
Concomitant medication date imputation ............................................. 23 
5.2 
AEs coding/grading ............................................................................................... 25 
5.3 
Laboratory parameters derivations ........................................................................ 25 
5.4 
Statistical models ................................................................................................... 25 
5.4.1 
Primary analysis .................................................................................... 25 
5.4.2 
Secondary analysis ................................................................................ 26 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 26 
6 
Reference ........................................................................................................................... 28 


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List of abbreviations 
AE 
Adverse event  
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT  
AST  
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT  
b.i.d.  
bis in die/twice a day  
CF  
Cystic fibrosis  
CFU  
Colony-forming units  
CRF  
Case Report/Record Form  
CPO 
Country Pharma Organization  
CRO  
Contract Research Organization  
CSR 
Clinical Study Report  
DS&E 
Drug Safety and Epidemiology  
ECG  
Electrocardiogram  
ECFS  
European Cystic Fibrosis Society  
FEV1  
Forced expiratory volume at 1 second  
FRC  
Functional residual capacity  
HRCT 
High-Resolution Computer tomography  
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee  
i.v. 
Intravenous(ly)  
IRB  
Institutional Review Board  
IVRS 
Interactive Voice Response System  
LCI  
Lung clearance index  
MBW 
Multiple breath inert gas washout 
MIC 
Minimal inhibitory concentration 
o.d. 
omnia die/once a day 
PAES 
Post-authorization Efficacy Studies 
PASS 
Post-authorization safety study 
p.o. 
per os/by mouth/orally 
TEAE 
Treatment Emergent Adverse Event 
SAE 
Serious adverse event  
Sacin 
N2 slope acinar airways  
Scond 
N2 slope conductive airways  
SOP 
Standard operation procedure  
SPCS 
Study Protocol Concept Sheet  
TAQ 
Treatment adherence questionnaire  
WOCBP 
Women of child-bearing potential  
1 
Introduction 
This document contains details of the statistical methods which will be used in the phase IV 
clinical trial of the clinical study protocol CTBM100CDE02. This statistical analysis plan 
(SAP) module is prepared based on amended protocol version 02, CRF version 3.0. Mock 
tables and listing mocks are included in TLF. The purpose of the study is to evaluate LCI by a 


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standardized procedure in a well characterized study setting and to assess feasibility of LCI as 
a more sensitive method than FEV1 to measure effectiveness of antibiotic therapy in patients 
with CF aged 6 years and older with mild to moderate lung disease. 
Data will be analyzed by statistical software SAS version 9.4 according to the data analysis 
section 10 of the study protocol which is available in Appendix 16.1.1 of the CSR.  Important 
information is given in the following sections and details are provided, as applicable, in 
Appendix 16.1.9 of the CSR. 
 
1.1 
Study design 
This study uses an open-label, single arm design in patients suffering from CF, aged 6 years 
and older, with an elevated LCI of ≥ 7.5 at screening, who have a chronic pulmonary infection 
with P. aeruginosa (confirmed within the last 12 month and at screening), and who are 
receiving inhaled Tobramycin therapy in a 28 days on / off regime in the past 3 month before 
screening. It is intended that 35 patients (children, adolescents and young adults) will be 
recruited in the DACH region at approximately 8 study sites. 
The study will consist of 5 – 26 days screening period to test the presence of P. aeruginosa, a 
baseline visit, followed by the treatment phase of 28 days on-treatment period and 
subsequently 28 days off-treatment period. During the study a total of 5 visits are designated. 
The structure of study design is as 
 


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Assessment schedule is as 
 
1.2 
Study objectives and endpoints 
The objectives of study are as 
Primary Objectives   
The primary objective is to assess the change of LCI after 4 weeks following onset of study 
drug inhalation versus Baseline.  
 
Secondary objectives  
• Change of FEV1 % predicted after 4 weeks following onset of study drug inhalation 
versus Baseline.  
• Change in CFU after 4 weeks following onset of study drug inhalation versus Baseline  
• Change of LCI after 1 week following onset of study drug inhalation versus Baseline.  
• Change of LCI, FEV1 % predicted and CFU between Week 4 (end of Study drug 
inhalation in the current treatment cycle) and Week 8 (prior to start of Study drug 
inhalation in the following treatment cycle).  
• Correlation between the changes of LCI, FEV1 % predicted and CFU after 1 week, 4 
weeks, and 8 weeks versus Baseline, respectively. 


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Exploratory objectives  
• To explore the change in LCI between Baseline and Week 4 (week 0-4), and Week 4 
and Week 8 (week 4-8), respectively, in patients using Tobramycin inhalation powder 
compared to patients using Tobramycin inhalation solution.  
• To assess and compare Sacin(N2 slope acinar airways) and Scond(N2 slope conductive 
airways) at baseline and at Visit 4 in patients using Tobramycin inhalation powder vs. 
patients using Tobramycin inhalation solution.  
• To assess the changes in FEV1 % predicted and CFU from Baseline to Visit 3 (week 
1) and to compare the change in FEV1 % predicted with the change in CFU and the 
change in LCI from baseline to Visit 3 (week 1) with the corresponding changes in 
FEV1 % predicted and CFU.  
• To explore the change in air trapping (FRCples - FRCMBW) after 1 week, 4 weeks, and 
8 weeks versus Baseline, respectively.  
• To explore the association of additional markers of disease progression (need for i.v. 
antipseudomonal therapy, hospitalization due to exacerbations of lung disease) on LCI 
at Baseline.  
• To assess and compare the ratio of patients with pathological LCI and pathological 
FEV1 and their mean deviation from normal LCI and FEV1 at Baseline.  
• To assess and compare the ratio of patients with pathological LCI and pathological 
FEV1 and their mean deviation from normal LCI and FEV1 at week 4.  
2 
Statistical methods 
2.1 
Data analysis general information 
Following standards are applied for analysis unless otherwise specified. 
The data will be analyzed by Novartis. All analyses will be performed by using SAS Version 
9.4. It is planned that the data from all centers that participate in this protocol will be used, so 
that an adequate number of patients will be available for analysis. 
All continuous variables will be summarized by simple descriptive statistics (n, mean, 
standard deviation, median, minimum, maximum). Number and percentage will be presented 
for categorical data. All statistical tests will be applied at 5% significance level. All presented 
data will be presented in the form of by-patient listings sorted with treatment dose form and 
visit (if applicable).   
2.1.1 
General definitions  
Study treatment/ Study drug: The investigational drug whose properties are being tested in the 
study. 
Date of first administration of study drug/treatment: It is defined as the date of first dose of 
study drug administration to the patient. 


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Date of last administration of study drug/treatment: It is defined as the date of last dose of 
study drug administration to the patient. 
Study day: Study day is defined as the number of days since the date of first dose of study 
drug administration. For a particular date, study day is calculated as: 
Study day = Assessment date – Date of first dose of study drug administration + 1. 
Baseline: Baseline is the last assessment obtained on or before the date of first dose of study 
drug administration. All assessments obtained after the date of first dose of study drug 
administration are considered as post-baseline unless otherwise specified. 
On-treatment period: The period where the patients are exposed to the study treatment. For 
this study the treatment phase consists of 28 days of on-treatment period. 
Lost to follow-up: The patients whose study completion status is unclear because they fail to 
appear for study visits without stating an intention to withdraw. 
2.2 
Analysis sets 
In the study protocol, the safety population was predefined as consisting of all patients that 
enter the study (provide Informed Consent). This was motivated by the fact that the primary 
focus of this study was not to describe effects of a drug intervention, but to compare the 
accuracy of two different assessment methods, namely LCI and FEV1. However, a valid 
assessment of these methods is very difficult in patients without any treatment exposure. 
Therefore, it was decided to change the definition of the Safety Set  
Safety Set: The safety set will consist of all patients that enter the study (provide Informed 
Consent) and have been exposed to at least one dose of study drug. The Safety set will be 
used for all analyses.   
 Table 1-1 Patient classification criteria 
Analysis set 
Population codes that cause 
patient to be excluded 
Non-PD criteria that cause 
patient to be excluded 
Safety set 
1 
Did not provide informed 
consent 
Did not exposed to at least one 
dose of study drug 
 Population code: 0=Include in everything, 1=Exclude from safety set. 
2.2.1 
Subgroup of interest 
All safety analysis will be performed by treatment dose form as Tobramycin inhalation 
solution (TIS, 300mg/5mL or 300mg/4mL) to be nebulized or as Tobramycin inhalation 
powder (TIP, 112mg), as prescribed by the treating physician. 
2.3 
Patient disposition, demographics and other baseline characteristics 
Appropriate descriptive statistics for patient disposition, demographic, disease history and 
baseline characteristics will be presented to describe the study population. 


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2.3.1  Patient disposition 
Total number of patients who were screened, re-screened will be presented by number and 
percentage for safety set. The summary will be presented for screening phase, end of 
treatment phase completion and study completion phase. The number and percentage will be 
presented for patients who treated and entered in the study, who completed the study, who 
discontinued the study and treatment phase along with reason of discontinuation for safety set 
by treatment dose form and overall. 
Patient identification number and whether they completed the study or discontinued from the 
study will be listed, along with date of last dose, date of discontinuation/study completion and 
primary reason of discontinuation by age group and treatment dose form. A Separate by 
patient listing of all patients along with inclusion and exclusion criteria status will also be 
provided.  
2.3.2 
Protocol Deviation 
The number and percentage of patients with protocol deviations will be tabulated by category 
and deviation for the Safety set; overall and by treatment dose form. Protocol deviations will 
be listed with date and study day of occurrence, deviation code by age group and treatment 
dose form for Safety set. 
Patient exclusion from analysis set will be listed for all patients with reasons of exclusion (i.e., 
both protocol and non-protocol deviation). 
2.3.3 Demographic characteristics 
The following demographic characteristics collected in the CRF at screening will be 
summarized using the Safety set. 
Continuous variables: 
• Age (years) 
• Height (cm) 
• Weight (Kg) 
• BMI (Kg/m2) 
Categorical variables: 
• Age categories(6 to 12 years, >12 to 17years, >17years) 
• Sex (Male, Female) 
• Race (Caucasian, Black, Asian, Other) 
• Ethnicity (Hispanic or Latino, East Asian, Southeast Asian, South Asian, West Asian, 
Russian, Mixed Ethnicity, Not Reported, Unknown, Other ) 
Descriptive statistics (n, mean, median, standard deviation, minimum and maximum) will be 
presented for continuous variables for all patients in the Safety set; overall and by treatment 
dose form. The number and percentage of patients in each category will be presented for 
categorical variables. For categorical variables, the patients in the missing category will be 
taken into account for denominator for calculating the percentage. 


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Patient demographic data will be listed with date of assessment for safety set by age group 
and treatment dose form. 
2.3.4 Medical history 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA version 18.1 and above or version used for coding). 
History/conditions will be summarized for the safety set by primary system organ class and 
preferred term; overall and by treatment dose form. Verbatim recorded history term will be 
listed together with the coded terms, date of diagnosis and whether the problem was ongoing 
by age group and treatment dose form for safety set at start of the study. Separate listing of 
cystic fibrosis will be presented with date of diagnosis by age group and treatment dose form 
for safety set. 
2.3.5 Surgical and Medical Procedures  
All surgical and medical procedures will be summarized for safety set by treatment dose form 
and overall. Patient data listing  will be provided with name of surgery, amount, reason, start 
date, and end date or ongoing at final exam, sorted with age group and treatment dose form 
and visit(if applicable). 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) 
2.4.1 
Study drug Administration 
Tobramycin, either as Tobramycin inhalation solution (TIS, 300mg/5mL or 300mg/4mL) to 
be nebulized or as Tobramycin inhalation powder (TIP, 112mg), as prescribed by the treating 
physician will be administered to each patient twice daily. Neither TIS nor TIP will be 
provided to the patient. 
The extent of exposure will be examined to determine the degree to which safety can be 
assessed for Tobramycin, either TIS or TIP. The extent of exposure to study drug will be 
characterized according to the duration of exposure and the number of patients exposed. 
Duration of exposure to the treatment will be calculated as the number of days between the 
first dose date and the last dose date exposed to that treatment over the specified period, 
expressed as: Duration of exposure = ((Date of last known dose of study drug – Date of first 
dose of study drug) + 1. If a substantial number of interruptions occur, additional tables 
accounting for interruptions may be produced. 
The duration of exposure (in days) will be summarized by treatment dose form and overall for 
the safety set as  
• a continuous variable with the standard descriptive statistics, and  
• a categorical variable classified into ≤ 14days, > 14 – 21days, > 21 – 28days, >28 
days with number and percentage of patients in each category. 


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Patient data listing will be provided along with dose administered(unit), total daily dose(unit), 
regimen, frequency, start date, study day, end date, dose permanently discontinued, and 
reason of dose discontinuation by age group and treatment dose form for safety set.  
2.4.2 
Compliance 
Compliance will be assessed by the investigator and/or study personnel at each visit using 
information provided by the patient via a patient diary. Assessment of compliance will be 
based on:  
• The number of dosing sessions per day (e.g. morning and evening)  
• The number of actual days on treatment. 
The compliance is defined as the percentage of doses taken by the patient and will be 
calculated using the following formula:  
Compliance (%) = 100 x total study dose consumed by patient/ total study dose patient     
supposed to consume.                
Compliance will be summarized by treatment form and overall for the safety set as 
• a continuous variable with the standard descriptive statistics, and  
• a categorical variable classified into < 80%,  ≥ 80% to < 100%,  ≥ 100 to < 120%, 
≥ 120%,  with number and percentage of patients in each category. 
Patient data for compliance will listed along with date of first/last dose, treatment duration, 
total dose consumed by age group and treatment dose form for safety set. 
2.4.3 
Prior, concomitant and post therapies 
Rescue medication is any on demand medication at acute clinical deterioration of the patient, 
independent of the currently used standard therapy.  
Prior medications are those concomitant medications which were taken and stopped prior to 
the first dose of study drug. 
Concomitant medications are those concomitant medications which were taken prior to and 
continued after the first dose of the study drug or those medication which were given at least 
once between the day of first dose of study treatment and the date of the last study visit.  
All prior and concomitant medication will be coded using WHO drug dictionary with updated 
version. All prior and concomitant medications will be summarized in one table.  
The number and percentage of patients taking prior medication, concomitant medications will 
be presented by ATC class and preferred term; overall and by treatment dose form.  
Subject data for prior and concomitant medication will be provided in the form of listing 
along with medication name, dose, start date/End date of medication, route, frequency, 
ongoing at final examination and reason by treatment dose form for safety set. 
2.5 
Analysis of the primary objective 
Primary effectiveness analysis will be performed on safety set.  


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2.5.1 
Primary endpoint 
The primary variable of this study is the LCI.  
The primary effectiveness variable is the time course and changes in LCI from baseline (Visit 
2) to Week 4 (Visit 4).  
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary objective of the study is to evaluate the effectiveness of antibiotic therapy 
TBM100 in patients with CF aged 6 years and older with mild to moderate lung disease. The 
effectiveness will be assessed by changes in LCI from baseline to Week 4. Baseline LCI is the 
assessment taken prior to the start of TBM100, which is typically the value at Visit 2. If 
baseline value is missing then change is taken from the data recorded at screening. The 
primary analysis will include patients with a valid observation at baseline and post-baseline 
visit.  
The summary of LCI at baseline, at each post-baseline visit and it’s change from baseline to 
each post-baseline visit will be presented using descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum). Change from baseline will be calculated as 
value at post-baseline visit minus value at baseline. 
Between visits comparison for changes in LCI from baseline will be analyzed using an 
ANOVA model with factors patient and visit. Estimates over time will be presented as LS-
Means, pairwise LS-Mean differences along with 95% confidence intervals and two sided p-
values for the pairwise differences between visits. 
Additionally, for accessing trend of change in LCI over time, mean values over time and the 
row LCI values over time for each patient will be displayed graphically for each respective 
visit. All analysis mentioned in this section will be done for safety set at 5% significance 
level. 
All efficacy data will be listed with date of assessment by age group and treatment dose form. 
2.5.3 
Handling of missing values/censoring/discontinuations 
There will be no imputation for missing data at Week 4, and the primary analysis will be 
based on only observed data. 
2.5.4 
Supportive analyses 
Not Applicable. 
2.6 
Analysis of the key secondary objective 
Not Applicable. 
2.6.1 
Key secondary endpoint 
Not Applicable. 


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2.6.2 
Statistical hypothesis, model, and method of analysis 
Not Applicable. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Not Applicable. 
2.7 
Analysis of secondary efficacy objectives 
All secondary efficacy analysis will be provided for safety set. 
2.7.1 
Secondary endpoints 
The secondary effectiveness variables are the changes in FEV1 % predicted, CFU and LCI 
and it’s comparison among themselves at respective visit will be performed for safety set. 
2.7.1.1 
Changes in FEV1 % predicted from baseline to Week 4 
The changes from baseline in FEV1 % predicted to each post-baseline visit will be analyzed in 
a similar manner as the primary variable, i.e.  
• The FEV1 % predicted and it’s mean change from baseline to each post-baseline visit will 
be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum).  
• Between visits comparison for changes in FEV1 % predicted from baseline will be 
analyzed in similar manner as primary variable. Estimates change over time will be 
presented as LS-Means, pairwise LS-Mean differences along with 95% confidence 
intervals and two sided p-values for the pairwise differences between visits. 
2.7.1.2 
Changes in CFU (/mL) from baseline to Week 4 
The changes from baseline in CFU (/mL) to each post-baseline visit will be analyzed in a 
similar manner as the primary variable, i.e.  
• The CFU and it’s mean change from baseline to each post-baseline visit will be 
summarized using descriptive statistics (n, mean, standard deviation, median, minimum 
and maximum). 
• Between visits comparison for change in CFU from baseline will be analyzed in similar 
manner as primary variable. Estimates change over time will be presented as LS-Means 
with 95% confidence intervals and two sided p-values for the pairwise differences 
between visits. 
2.7.1.3 
Change in LCI from baseline to Week 1 
This analysis is contained in the ANOVA model for LCI described above. 
2.7.1.4 
Changes in LCI, FEV1 % predicted, CFU between Week 4 and Week 8 
This analysis is contained in the ANOVA models described above. 
        


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2.7.1.5 
Correlation between change from baseline in LCI, FEV1 % predicted, CFU at 
Week 1, Week 4 and Week 8  
Correlation based on change in FEV1 % predicted, CFU and LCI will be evaluated for each 
pair using Karl Pearson correlation coefficient. Visit 2 will be considered as baseline. If 
baseline value is missing then change is taken from the data recorded at screening. Change 
from baseline will be calculated as value at post-baseline minus value at baseline. Estimates 
as Karl Pearson correlation coefficient with their 95% confidence intervals and p-values will 
be presented. Additionally, the correlation among each pairs will be explored using 
scatterplots for raw values as well as for changes at respective visit.  
       All subject efficacy data including FEV1, predicted FEV1, FRC, LCI by multiple breath 
washouts, CFU (quantitative density) will be listed by age group, treatment dose form and 
visit(as applicable) along with date of assessment for safety set.  
2.7.2 
Handling of missing values/censoring/discontinuations 
Missing data will not be imputed and the secondary analysis will be based on only observed 
data. 
2.8 
Safety analyses 
Safety analysis including TEAE, vital sign, lab parameter and it’s change from baseline will 
be evaluated based on safety set. All listings will be ordered according to age categories 6 to 
12, >12 to 17 and >17 for safety set.   
2.8.1 
Adverse events (AEs) 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1 and above, and other version used for coding.  Adverse 
events starting on or after the time of the first inhalation of study drug but not later than 7 
days (30 days in the case of a SAE) after the date of last dose of study drug taken or those AE 
present at baseline with increased severity will be classified as a treatment emergent adverse 
event and will be included in all summaries. AEs which started and ended prior to baseline 
and AEs which started prior to baseline but whose severity does not change post baseline will 
not be included in treatment emergent adverse event.  
 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Treatment emergent adverse events by primary system organ class and preferred term 
The number and percentage of patients who reported treatment emergent adverse events will 
be summarized for each primary system organ class and preferred term; overall and by 
treatment dose form. Primary system organ classes will be sorted alphabetically and, within 
each primary system organ class, the preferred terms will be sorted in descending order of 
frequency.  
If a patient reported more than one adverse event with the same preferred term, the adverse 
event will be counted only once at the preferred term level. If a patient reported more than one 


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adverse event within the same primary system organ class, the patient will be counted only 
once at the system organ class level.  
Treatment emergent adverse events by severity 
All treatment emergent adverse events will be summarized with maximum severity for each 
primary system organ class and preferred term; overall and by treatment dose form. If a 
patient reports more than one adverse event within the same primary system organ class, only 
one adverse event will be counted for that patient at the highest severity level in the total row 
for each primary system organ class. If a patient reported more than one adverse event with 
the same preferred term, the highest (maximum) severity will be presented.  
Treatment emergent adverse events suspected to be related to study drug 
An adverse event related to study drug is defined as one considered by the investigator to have 
a suspected relationship with the diagnostic method or the study drug. The treatment emergent 
adverse events suspected to be related to the diagnostic method or study drug (according to 
the investigators) will be summarized by primary system organ class and preferred term; 
overall and by treatment dose form. Relationship to study drug is considered as suspected for 
those events where "Relationship to study drug" is answered by the investigator as 
"Suspected". 
Treatment emergent adverse events leading to permanent study drug discontinuation 
Treatment emergent adverse events leading to permanent study drug discontinuation will be 
summarized by primary system organ class and preferred term using; overall and by treatment 
dose form. 
Treatment emergent adverse events requiring action taken with study treatment 
Treatment emergent adverse events requiring action to be taken with study treatment will be 
summarized by primary system organ class and preferred term; overall and by treatment dose 
form. 
Treatment emergent adverse events requiring significant additional medication or 
therapy 
Treatment emergent adverse events requiring significant additional therapy (concomitant 
medication, non- drug therapy) will be summarized by primary system organ class and 
preferred term; overall and by treatment dose form. 
Treatment emergent adverse events outcome 
Treatment emergent adverse events with outcome will be summarized by primary system 
organ class and preferred term; overall and by treatment dose form.  


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Treatment emergent serious adverse events 
Number and percentage of patients with treatment emergent serious adverse events, regardless 
of study drug relationship, will be presented by primary system organ class and preferred 
term; overall and by treatment dose form for safety set. 
The patient data listing includes, SOC/PT/Verbatim term, start date/study day, end date/study 
day, the severity of an AE, whether or not an AE is related to MBW or study drug, and 
whether or not it is a serious AE, action taken with study drug, outcome, duration. Duration 
will be calculated as end date – start date+1 and for ongoing last visit date – start date+1. 
The following patient data listings will be provided by age group and treatment dose form. 
1. Treatment emergent serious adverse event 
2. Discontinuation due to treatment emergent adverse events 
Additionally, listing of all adverse events and treatment emergent adverse event will be 
provided for safety set by age group and treatment dose form.  
TEAE of special interest 
Treatment emergent adverse events of special interest(Elevated BUN and Creatinine, Tinnitus 
and Hearing loss) will be summarized by primary system organ class and preferred term; 
overall and by treatment dose form.  
2.8.2 
Deaths 
All the deaths in the clinical database will be listed with the last dose date/visit, date of death 
and investigator-reported principal cause by age group and treatment dose form. Treatment 
emergent adverse event leading to death will be summarized with numbers and percentages; 
overall and by treatment dose form for safety set. 
Laboratory data 
Clinical laboratory parameters include creatinine, urea, C Reactive protein, Burkholderia 
complex, Pseudomonas aeruginosa, Pseudomonas aeruginosa Tobra MIC, blood urea nitrogen 
(BUN), Choriogonadotropin beta. All laboratory data (Hematology, chemistry and urinalysis) 
will be summarized for safety set by treatment dose form, overall and visit. For continuous 
data the summary statistics (number of observations, mean, standard deviation, median, 
minimum and maximum) will be provided for safety set for both actual value and change 
from baseline. Visit 2 will be considered as baseline. If baseline value is missing then change 
is taken from the data recorded at screening. Number and percentage will be provided for 
categorical data.  
Newly occurring or worsening notably abnormal laboratory values to each post-baseline time 
point will be listed for the selected parameters creatinine (>=2mg/dl, above normal), blood 
urea nitrogen (BUN) (>=40mg/dl, above normal). A case will be considered as newly 
occurring if all the components are not clinically notable at baseline but clinically notable 
thereafter. If patients have a missing baseline value for at least one component, post-baseline 
values meeting the notable criterion will be considered as newly occurring.  


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Observed value of all laboratory parameter will be listed with abnormal values flagged (if 
applicable) for safety set for all patient along with date of assessment, sorted with age group, 
treatment dose form and visit. A separate listing for pregnancy test (serum and urine) will be 
provided with date of assessment by age group and treatment dose form for safety set.  
2.8.3 
Other safety data 
2.8.3.1 
ECG and cardiac imaging data 
Not Applicable. 
2.8.3.2 
Vital signs 
Vital sign including sitting systolic/diastolic blood pressure, sitting radial pulse rate (over a 30 
second interval), respiratory rate, body temperature, height, weight, and body mass index 
(BMI) will be summarized for safety set by descriptive statistics (number of observations, 
mean, standard deviation, median, minimum and maximum) for both actual value and change 
from baseline by treatment dose form, overall and visit. If baseline value is missing then 
change is taken from the data recorded at screening. 
Vital signs data will be listed along with date of assessment, sorted with age group, treatment 
dose form and visit (if applicable), notable values will be flagged(if applicable), and any other 
information collected will be listed as appropriate. 
2.8.3.3 
Physical Examination 
Not Applicable 
2.9 
Pharmacokinetic endpoints   
Not Applicable 
2.10 PD and PK/PD analyses 
Not Applicable 
2.11 Patient-reported outcomes 
Not Applicable 
2.12 Biomarkers 
Not Applicable 


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2.13 Other Exploratory analyses 
2.13.1.1 Comparisons of change in LCI from baseline to Week 4(Week 0-4) and Week 
4 to Week 8 (Week 4-8) between the patients using Tobramycin inhalation 
powder and patients using Tobramycin inhalation solution 
Change in LCI from baseline to Week 4(week 0-4) for patients using Tobramycin inhalation 
powder and patients using Tobramycin inhalation solution will be calculated as Change=LCI 
at Week 4 – LCI at baseline. Visit 2 will be considered as baseline. If baseline value is 
missing then change is taken from the data recorded at screening.  
Addition to that, change in LCI from Week 4 to Week 8 (week 4-8) for patients using 
Tobramycin inhalation powder and patients using Tobramycin inhalation solution will be 
calculated as change=LCI at Week 8 – LCI at Week 4.  
• Summary of LCI at baseline, at Week 4 and at Week 8 will be presented standard 
descriptive statistics (n, mean, standard deviation, median, minimum and maximum) 
for both groups. 
• The mean change from baseline to Week 4 (week 0-4) and Week 4 to Week 8 (week 
4-8) will be estimated for both groups.  
Analysis will be done for safety population based on observed data. 
2.13.1.2 Comparison of Sacin(N2 slope acinar airways) and Scond(N2 slope conductive 
airways) at baseline and at Visit 4 in patients using Tobramycin inhalation 
powder vs. patients using Tobramycin inhalation solution. 
The Sacin and Scond values at baseline and at each post-baseline visit in the patients using 
Tobramycin inhalation powder and patients using Tobramycin inhalation solution will be 
summarized by descriptive statistics (n, mean, standard deviation, median, minimum and 
maximum). Comparison between the patients using Tobramycin inhalation powder and 
patients using Tobramycin inhalation solution for both parameters i.e. Sacin and Scond at 
baseline and at Visit 4 will be performed using a descriptive statistics.  
Additionally, for accessing trend of change in Sacin (N2 slope acinar airways) and Scond (N2 
slope conductive airways) over time, mean change from baseline over time will be displayed 
graphically to each respective visit. 
Analysis will be done for safety set based on observed data. 
2.13.1.3 Comparisons of changes in FEV1 % predicted, CFU and LCI from baseline to 
visit 3 (Week1)  
The change in FEV1 % predicted, CFU and LCI from baseline to Visit 3(Week1) will be 
calculated using the formula as Change= value at Week 1 – value at baseline. Visit 2 will be 
considered as baseline. If baseline value is missing then change is taken from the data 
recorded at screening. Analysis will be performed based on observed data. 
• Summary of FEV1 % predicted, CFU and LCI at baseline and at Visit 3(Week1) for 
both groups will be presented standard descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum). 


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• The mean changes in FEV1 % predicted, CFU, and LCI from baseline to visit 3 (week 
1) will be displayed for both groups.  
Comparisons of changes in FEV1 % predicted, CFU and LCI from baseline to visit 3 will be 
done based on descriptive statistics. Analysis will be done on safety set. 
2.13.1.4 Change in air trapping (FRCples - FRCMBW) from baseline to Week 1, Week 4 
and Week 8.  
Air trapping will be assessed by the difference in FRC measured by bodyplethysmography 
(FRCples) and FRC measured by MBW (FRCMBW). The air trapping (FRCples - FRCMBW) and 
its change from baseline to each post-baseline visit will be summarized by descriptive 
statistics (n, mean, standard deviation, median, minimum and maximum). The change in air 
trapping from baseline will be calculated using as Change= Value at post-baseline – value at 
baseline. Visit 2 will be considered as baseline. If baseline value is missing then change is 
taken from the data recorded at screening. Analysis will be performed based on observed data 
for safety set. 
2.13.1.5 Association of additional markers of disease progression on LCI at baseline 
Number and percentage will be presented for the patients who took i.v. antipseudomonal 
therapy, and who were hospitalized due to exacerbations of lung disease.  
Association between i.v. antipseudomonal therapy and LCI at baseline will be based on 
standard descriptive statistics (n, mean, standard deviation, median, minimum and maximum). 
Similarly, the association between hospitalization due to exacerbations of lung disease and 
LCI at baseline will be evaluated in the same way.  
       Analysis will be done for safety population based on observed data. 
2.13.1.6 Patients with pathological LCI and pathological FEV1 at Baseline and at 
Week 4 and it’s deviation from normal LCI and normal FEV1. 
Number of patients with pathological LCI (i.e. LCI above 7.5) and normal LCI will be 
summarized by frequency and proportion. The summary of normal LCI and pathological LCI 
at baseline and at Week 4 will be presented by descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum) for safety set. 
Predicted FEV1 value will be calculated using below formula (Knudson) 
Predicted FEV1 for Male subject aged <=24 yrs = 0.1168* Height (in Inches) + 0.0450*Age -4.808; 
Predicted FEV1 for Male subject aged >24 yrs = 0.1321* Height (in Inches) - 0.0270*Age -4.203; 
Predicted FEV1 for Female subject aged <=19yrs = 0.0686* Height (in Inches) + 0.0850*Age -2.703; 
Predicted FEV1 for Female subject aged >19yrs = 0.0686* Height (in Inches) - 0.0210*Age -0.794; 
Height in inches will be converted as: Height (in inches) =0.39*height (in cm).  
And percent predicted FEV1 will be calculated as: % predicted FEV1 = FEV1/Predicted FEV1*100. 
Number of patients with pathological FEV1 (i.e. FEV1 below 75% predicted) and normal 
FEV1 will be summarized by frequency and proportion. Normal FEV1 and pathological 
FEV1 at baseline and at Week 4 will be summarized by descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) for safety set. 


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       All by-subject exploratory efficacy data including air trapping (FRCples - FRCMBW), Sacin (N2 
slope acinar airways) and Scond (N2 slope conductive airways) will be listed by age group, 
treatment dose form and visit(as applicable) along with date of assessment for safety set.  
2.14 Interim analysis 
No interim analysis planned for this study 
3 
Sample size calculation 
The primary effectiveness outcome measure of the study will be the change from baseline to 4 
weeks in LCI in patients treated with TBM100. Therefore, sample size calculations for this 
study are based on the primary objective which produces a precise estimate of these changes 
in LCI. The precision of the estimated mean change in LCI at 4 weeks, as assessed by the 
95% confidence interval 
Since LCI is expected to be a more sensitive measure (compared to FEV1), thus the number 
of patients required to detect changes in FEV1 should also be sufficient to detect relevant 
changes in LCI and to explore the correlation between LCI and FEV1.  
For FEV1, a change of 5% with an intraindividual SD of 9% is expected between on- and off-
treatment cycles. Under these assumptions, 28 patients will be required to detect this change 
with 80% power on a two-sided, 5% significance level. To compensate for some protocol 
violations and drop-outs, a total of 35 patients should be recruited into this trial. 
4 
Change to protocol specified analyses 
The following changes from protocol have been implemented at the SAP development stage. 
Definition of safety set 
1. As per protocol: The safety set will consist of all patients that enter the study (provide 
Informed Consent). 
Changes in SAP: The safety set will consist of all patients that enter the study (provide 
Informed Consent) and have been exposed to at least one dose of study drug. 
2. As per protocol: Changes in FEV1 over time-point following onset of study drug 
inhalation versus Baseline were analyzed. 
Changes in SAP: Based on comments on Dry run output from clinical team, changes 
in FEV1 % predicted instead of changed in FEV1 (L) over time-point following onset 
of study drug inhalation versus Baseline will be analyzed. 
5 
Appendix 
All statistical output required for drafting CSR were outlined RAP module 7.  
5.1 
Imputation rules 
5.1.1 
Study drug 
Not Applicable 


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5.1.2 
AE date imputation 
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the Table 1-2 below.   
1. 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. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment.  Therefore: 
a. If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY). 
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore: 
a. If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY). 
b. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start. 
b. 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). 
c. Else if the AE month is greater than the treatment start month, the imputed AE 
start date is set to the start month point (01MONYYYY). 
Table 1-2: AE date imputation 
 
MON 
MON < CFM 
MON = CFM 
MON > CFM 
 
MISSING 
YYYY 
MISSING NULL 
NULL 
NULL 
NULL 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
( D ) = 01JULYYYY 
( C )= 15MONYYYY ( C )= 15MONYYYY ( C )= 15MONYYYY 
 
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start 
YYYY = 
CFY 
(B)= TRTSTD+1 
( C )= 15MONYYYY (A)= TRTSTD+1 
(A)= 01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY > 
CFY 
(E)= 01JANYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 


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After Treatment Start  After Treatment Start  After Treatment Start  After Treatment Start  
 
 
 
 
 
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
LEGEND: 
(A) 
         MAX(01MONYYYY,TRTSTD+1) 
 
(B) 
         TRTSTD+1 
 
 
(C) 
15MONYYYY 
 
 
(D) 
01JULYYYY 
 
 
(E) 
01JANYYYY 
 
 
Adverse event end date will not be imputed. 
5.1.3 
Concomitant medication date imputation 
Concomitant medication (CMD) date imputation uses both a comparison of the partial CMD 
start date to the treatment start date, and the value of the CMDTYP1C flag (1, 2, or 3).  Event 
date comparisons to treatment start date are made based on the year and month values only 
(any day values are ignored) in Table 1-3 below. 
1. If the CMD start date year value is missing, the date will be imputed based on the 
CMDTYP1C flag value.  If the flag value is 1 or 3, the imputed CMD start date is set to 
one day before the treatment start date.  Else, if the flag value is missing or 2, the imputed 
CMD start date is set to one day after the treatment start date.  (Note that for some legacy 
data, the CMDTYP1C variable may not exist in the data.  When this happens and the 
CMD start date year value is missing, the imputed date value will be NULL.) 
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before treatment.  Therefore: 
a. if the CMD year is less than the treatment year and the CMD month is missing, the 
imputed CMD start date is set to the mid-year point (01JulYYYY). 
b. Else if the CMD year is less than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the mid-month point 
(15MONYYYY). 
If the CMD start date year value is greater than the treatment start date year value, the CMD 
started after treatment. Therefore: 
a. If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY). 
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point 
(01MONYYYY). 
3. If the CMD start date year value is equal to the treatment start date year value: 
a. and the CMD month is missing or the CMD month is equal to the treatment start 
month, 


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i. 
If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date. 
ii. 
Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date. 
a. Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY). 
b. Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY). 
Table 1-3:  CMD date imputation 
 
MON MISSING 
MON < CFM 
MON = CFM 
MON > CFM 
YYYY 
MISSING (F) 
(F) 
(F) 
(F) 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
(D)=01JULYYYY 
(C)=15MONYY 
(C)=15MONYY 
(C)=15MONYY 
 
Before Treatment Start 
Before Treatment Start Before Treatment Start 
Before Treatment Start 
YYYY = 
CFY 
(B) 
(C)=15MONYY 
(B) 
(A)=01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY > 
CFY 
(E)= 01JANYYYY 
(A)=01MONYYYY 
(A)=01MONYYYY 
(A)=01MONYYYY 
 
After Treatment Start 
After Treatment Start After Treatment Start 
After Treatment Start 
 
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
         LEGEND: 
(A) 
MAX(01MONYYYY,TRTSTD+1) 
(B) 
 
IF CMDTYP1C IN (1,3) THEN TRTSTD-1 
     ELSE IF CMDTYP1C in(. , 2) THEN TRTSTD+1 
(C) 
15MONYYYY 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
(F) 
IF CMDTYP1C IN (1,3) THEN TRTSTD-1 
    ELSE IF CMDTYP1C in  (. , 2) THEN TRTSTD+1 
Concomitant medication end date will not be imputed. 
5.1.3.1 
Prior therapies date imputation 
Not Applicable 
5.1.3.2 
Post therapies date imputation 
Not Applicable  


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5.1.3.3 
Other imputations 
Not Applicable  
5.2 
AEs coding/grading 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1 and above or versions used for coding. 
5.3 
Laboratory parameters derivations 
Table 1-4: Criteria for clinically notable laboratory values 
Laboratory Variable 
Clinically notable 
abnormal value(range) 
Blood urea nitrogen 
> 39 mg/dL 
Creatinine 
> 1.99 mg/dL 
5.4 
Statistical models 
5.4.1 
Primary analysis 
Mixed model for LCI comparison between visit 
The SAS procedure PROC MIXED will be used for this analysis with the following code: 
Model: LCI = Visit + patients + error.  
          proc mixed data=<….>  method=reml; 
                 where visit in (2, 3, 4, 5); 
                        class visit usubjid; 
model lci= visit ; 
repeated visit/subject=usubjid type=un; 
lsmeans visit /pdiff cl; 
                       estimate “LCI at Baseline vs LCI at Visit 3”  -1 1 0 0 / cl alpha=0.05; 
                       estimate “LCI at Baseline vs LCI at Visit 4”  -1 0 1 0 / cl alpha=0.05; 
                       estimate “LCI at Baseline vs LCI at Visit 5”  -1 0 0 1 / cl alpha=0.05; 
                       estimate “LCI at Visit 3 vs LCI at Visit 4”  0 1 -1 0 / cl alpha=0.05; 
                       estimate “LCI at Visit 3 vs LCI at Visit 5”  0 1 0 -1 / cl alpha=0.05; 
                       estimate “LCI at Visit 4 vs LCI at Visit 5”  0 0 1 -1 / cl alpha=0.05; 
                ods output lsmeans=lsm diffs=diff1; 
   run; 
           where, 
            lci = LCI at each visit, 
subjid=Patient ID. 


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5.4.2 
Secondary analysis 
The SAS procedure PROC MIXED will be used for this analysis of FEV1 and CFU with the 
following code: 
Model:FEV1 = Visit + patients + error.  
 
          proc mixed data=<….> method=reml; 
                 where visit in (2, 3, 4, 5); 
                        class visit usubjid; 
model fev1= visit ; 
repeated visit/subject=usubjid type=un; 
lsmeans visit /pdiff cl; 
                       estimate “FEV1 at Baseline vs FEV1 at Visit 3”  -1 1 0 0 / cl alpha=0.05; 
                       estimate “FEV1 at Baseline vs FEV1 at Visit 4”  -1 0 1 0 /cl alpha=0.05; 
                       estimate “FEV1 at Baseline vs FEV1 at Visit 5”  -1 0 0 1 /cl alpha=0.05; 
                       estimate “FEV1 at Visit 3 vs FEV1 at Visit 4”  0 1 -1 0 /cl alpha=0.05; 
                       estimate “FEV1 at Visit 3 vs FEV1 at Visit 5”  0 1 0 -1 /cl alpha=0.05; 
                       estimate “FEV1 at Visit 4 vs FEV1 at Visit 5”  0 0 1 -1 /cl alpha=0.05; 
      ods output lsmeans=lsm diffs=diff1; 
       run; 
           where, 
fev1= FEV1 at each visit, 
subjid=Patient ID. 
Pearson correlation coefficient among the pairs based on the change from baseline in 
LCI, FEV1 and CFU after 1 week, 4 weeks, and 8 weeks  
The SAS procedure CORR will be used to compute this coefficient with the following code: 
proc corr data= <…… > pearson fisher; 
var var1; 
with var2; 
       ods output FisherPearsonCorr=cor; 
              ods output PearsonCorr=correl; 
run; 
         where, var1 and var2 are two different variables measured on the same patient.  
5.5 
Rule of exclusion criteria of analysis sets  
All protocol deviations defined at the start of the study are listed with associated population 
codes in below table. 
Deviation 
code 
Text description 
Severity 
code 
INCL01 
Patient has not provided the written informed consent. 
1 
INCL02 
Cystic fibrosis diagnosis is not confirmed by the study protocol specified tests. 0 


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INCL03 
Patient age is outside protocol specified range. Please verify Birth Year and 
Informed Consent date.   
0 
INCL04 
Elevated LCI is < 7.5 at screening, confirmed by a central MBW specialist. 
0 
INCL05 
FEV1 of < 50% predicted at screening. 
0 
INCL06 
P. aeruginosa is not present in two sputum or deep cough throat swab cultures 
or bronchoalveolar lavage (BAL) (only for BAL, a threshold level of 103 
CFU/mL is required) within 12 months prior to screening or in one culture 
within 12 months prior to screening and in the sputum or deep cough throat 
swab culture at screening 
0 
INCL07 
No use of inhaled Tobramycin in 28 days on / off regimen in the past 3 months 
before screening. 
0 
INCL08 
Patient is not clinically stable in the opinion of the investigator and unlikely to 
be able to participate in the study until the end of the study (Visit 5).  
0 
EXCL01 
History of sputum culture or deep cough throat swab (or BAL) culture yielding 
Burkholderia cenocepacia complex within 2 years prior to screening and / or 
sputum culture yielding B. cenocepacia complex at screening (Visit 1). 
0 
EXCL02 
Hemoptysis more than 60 mL at any time within 30 days prior to screening 
(Visit 1). 
0 
EXCL03 
Patient has history of hearing loss or chronic tinnitus. 
0 
EXCL04 
Serum creatinine 2mg/dL or greater, BUN 40 mg/dL or greater, known local or 
systemic hypersensitivity to aminoglycosides.  
0 
EXCL05 
Patients who are regularly receiving more than 1 class of inhaled anti-
pseudomonal antibiotic during the study or in the past 56 days (8 weeks) prior 
to baseline visit (Visit 2). 
0 
EXCL06 
Patients who have used oral or intravenous anti-pseudomonal antibiotics 
within 28 days prior to on-phase of study drug (Visit 2). These patients may be 
rescreened after 1 month following stop of i.v. treatment. 
0 
EXCL07 
Change in dose, formulation or strength of the study drug in the past treatment 
cycle before screening. 
0 
EXCL08 
Patients following onset or discontinuation of therapy with macrolides, chest 
physiotherapy, nebulized hypertonic saline, dornase alpha, long acting 
bronchodilators, inhaled steroids or inhaled mannitol during the study and 
within 56 days (8 weeks)  prior to baseline visit (V2).  
0 
EXCL09 
Use of loop diuretics within 7 days prior to first study medication 
administration (Visit 2).  
0 
EXCL10 
Administration of any investigational drug within 30 days or 5 half-lives, 
whichever is longer, prior to screening (Visit 1). 
0 
EXCL11 
Signs and symptoms of acute pulmonary disease, e.g. pneumonia, 
pneumothorax. 
0 
EXCL12 
Body mass index less than 12 kg/m2 
0 
EXCL14 
History of malignancy of any organ system, treated or untreated, regardless of 
whether there is evidence of local recurrence or metastases. 
0 
EXCL15 
Patients with known or suspected neuromuscular disorders, e. g. Parkinson´s 
0 


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disease, Myasthenia gravis. 
EXCL16 
Patients or caregivers who are considered potentially unreliable or considered 
unlikely to be compliant within the trial. 
0 
EXCL17 
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 human chorionic gonadotropin (hCG) laboratory test (> 5 
mIU/mL).  
0 
EXCL19 
Study personnel or first degree relatives of investigator(s) must not be included 
in the study.  
0 
EXCL 13 
Body Weight of less than 15kg. 
0 
COMD01 
Use of loop diuretics during administration of study drug. 
0 
COMD02 
Use of iv or oral antipseudomonal antibiotic in the 23 days prior and of study 
visit (V5). 
0 
COMD03 
Use of short acting ß-agonists (SABA) in the 6 hours prior to each 
FEV1/Spirometry or LCI assessment.  
0 
COMD04 
Use of long acting ß-agonists (LABA) in the 12 hours prior to each 
FEV1/Spirometry or LCI assessment. 
0 
COMD05 
Use of long acting muscarinic antagonists (LAMA) in the 12 hours prior to 
each FEV1/Spirometry or LCI assessment. 
0 
COMD06 
Inhalation of study drug is interrupted for more than 3 days during the "on-
phase". 
0 
COMD07 
Any use of iv antipseudomonal antibiotic in the absence of an AE during the 
study. 
0 
COMD08 
Any inhaled antipseudomonal antibiotics other than tobramycin during the 
study. 
0 
EXCL 18 
Women who are menstruating and capable of becoming pregnant and either 
not practicing a medically approved method of contraception or not practicing 
total abstinence during and up to at least 4 weeks after the end of treatment. 
0 
OTH10 
Spirometry was not conducted according to ATS criteria. 
0 
Med 
Patient did not receive at least one dose of study drug 
1 
6 
Reference 
Not Applicable.