Long-term Inhaled Nebulized Tobramycin in Patients With Non-cystic Fibrosis Bronchiectasis. A Randomized Placebo Controlled Trial. The BATTLE Study Bronchiectasis And Tobramycin SoluTion InhaLation ThErapy.
Phase: PHASE2
Conditions: Non-CF Bronchiectasis
Sponsor: Medical Center Alkmaar

NL54939.094.16 / Long term TIS treatment in non-CF bronchiectasis 
 
 
 
 
 
 
 
PROTOCOL TITLE: 
Effects of long term ToBrAmycin InhalaTion SoluTion (TIS) once daiLy on Exacerbation rate in 
patients with non-cystic fibrosis bronchiectasis.  A double blind, randomized, placebo 
controlled trial. The BATTLE study. 
 
Protocol ID:  
54939 
Short title:  
 
Inhaled nebulized tobramycin in non-CF bronchiectasis 
EudraCT number:  
Clinical Trials:  
2016-000166-35 
NCT02657473 
Version:  
1.6 
Date:    
Accepted version 1.3: 30-06-2016 
Coordinating 
investigator/project: 
 
Dr. W.G. Boersma, pulmonologist 
Department of pulmonary diseases 
Noordwest Ziekenhuisgroep 
Location Alkmaar 
PO BOX 501 
1800AM Alkmaar 
Phone: 072-5484444 
Fax: 072-5482167 
Email: w.boersma@nwz.nl 
 

NL54939.094.16 / Long term TIS treatment in non-CF bronchiectasis 
 
 
 
Prinicipal 
investigator/project:  
 
 
 
 
 
 
 
 
 
Multicenter research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drs. L.C. Terpstra, fellow 
Department of pulmonary diseases 
Noordwest Ziekenhuisgroep 
Location Alkmaar 
PO BOX 501 
1800AM Alkmaar 
Phone: 072-5484444 
Fax: 072-5482167 
Email: l.c.terpstra@nwz.nl 
 
 
Investigator Noordwest Ziekenhuisgroep 
Drs. L.C. Terpstra 
Email: l.c.terpstra@nwz.nl 
Investigator Zuyderland MC Heerlen 
 
Dr. M. De Kruif 
Email: m.de.kruif@atriummc.nl 
Investigator Canisius ZH Nijmegen:  
Dr. Y. Berk 
Email: y.berk@cwz.nl 
Investigator Spaarne Gasthuis Hoofddorp: 
Dr. D. Snijders 
Email: DSnijders@spaarneziekenhuis.nl 
Investigator VU Medical Center: 
Dr. H. Daniels 
Email: j.daniels@vumc.nl 
Investigator UMC Utrecht 
Dr. I. Bronsveld 
Email: ibronsve@umcu.nl 
 
Sponsor:  
Noordwest Ziekenhuisgroep 
Location: Alkmaar 
PO BOX 501 
1800AM Alkmaar 
Phone: 0725484444 
Fax: 0725482167 
Email: W.G.Boersma@nwz.nl 
 
 
Grant provided by: 
TEVA Netherlands 
Subsidising party:  
 
Pulmoscience Alkmaar 
Independent expert(s): 
Drs. M. Gamala 
Noordwest Ziekenhuisgroep 

NL54939.094.16 / Long term TIS treatment in non-CF bronchiectasis 
 
 
 
Location: Alkmaar 
PO BOX 501 
1800AM Alkmaar 
Phone: 0725484444 
Fax: 0725482167 
Email: M.Gamala@nwz.nl 
 
Dr. J. Chalmers 
Department of Respiratory Medicine  
Ninewells Hospital and Medical School 
Dundee 
DD1 9SY 
Phone +(44) 01382 386339 
Email: jchalmers@dundee.ac.uk 
 
Laboratory sites:  
Dr. H. van Pelt 
Department of Clinical Chemistry, Hematology and Immunology  
Noordwest Ziekenhuisgroep 
Location MCA 
PO Box 501 
1800AM Alkmaar 
Phone +31 72-5483625 
Email: j.van.pelt@nwz.nl 
 
Pharmacy:  
Dr. P. Kloeg 
Head of hospital pharmacy Noordwest Ziekenhuisgroep 
Location MCA 
PO box 501 
1800AM Alkmaar 
Phone + 31 72-5484444 
Email: p.kloeg@nwz.nl 
 
Dr. M. Becker  
Pharmacy Haarlemse ziekenhuizen 
Stichting Apotheek Der Haarlemse Ziekenhuizen 
Boerhaavelaan 24 
2035 RC Haarlem 
Email: mbecker@sahz.nl 

NL54939.094.16 / Long term TIS treatment in non-CF bronchiectasis 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Coordinating Investigator/Project 
Leader/Principal Investigator: 
Dr. W.G. Boersma 
Noordwest Ziekenhuisgroep 
Location: Medical Center Alkmaar 
PO BOX 501 
1800AM Alkmaar 
Phone: 072-5484444 
Fax: 072-5482167 
Email: w.boersma@nwz.nl 
 
 
 
10-03-2016 
 
 

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TABLE OF CONTENTS 
 
SUMMARY .............................................................................................................................................. 8 
1. INTRODUCTION AND RATIONALE ................................................................................................... 9 
2. OBJECTIVES .................................................................................................................................... 11 
3. STUDY DESIGN ................................................................................................................................ 12 
4. STUDY POPULATION ...................................................................................................................... 14 
4.1 Population (base) ........................................................................................................................ 14 
4.2 Inclusion criteria ........................................................................................................................... 14 
4.3 Exclusion criteria ......................................................................................................................... 14 
5. TREATMENT OF SUBJECTS ........................................................................................................... 16 
5.1 Investigational product/treatment ................................................................................................ 16 
5.2 Use of co-intervention .................................................................................................................. 16 
5.3 Escape medication ...................................................................................................................... 16 
6. INVESTIGATIONAL PRODUCT........................................................................................................ 17 
6.1 Name and description of investigational product(s) .................................................................... 17 
6.2 Summary of findings from non-clinical studies ............................................................................ 17 
6.2.1 Pharmacokinetics ......................................................................................................................... 17 
6.2.2 Sputum Concentrations ................................................................................................................ 17 
6.2.3 Serum concentrations ................................................................................................................... 17 
6.2.4 Elimination .................................................................................................................................... 18 
6.3 Summary of findings from clinical studies ................................................................................... 18 
6.4 Summary of known and potential risks and benefits ................................................................... 19 
6.5 Description and justification of route of administration and dosage ............................................ 19 
6.6 Dosages, dosage modifications and method of administration ................................................... 20 
6.7 Preparation and labelling of Investigational Medicinal Product ................................................... 20 
6.8 Drug accountability ...................................................................................................................... 21 
7. METHODS ......................................................................................................................................... 21 
7.1 Study parameters/endpoints........................................................................................................ 21 
7.1.1 Main study parameter/endpoint .................................................................................................... 21 
7.1.2 Secondary study parameters/endpoints (if applicable) ................................................................ 21 
7.1.3 Other study parameters (if applicable) ......................................................................................... 21 
7.2 Randomisation, blinding and treatment allocation ...................................................................... 22 
7.3 Study procedures ........................................................................................................................ 22 
Run-in (Visit 0, week -4) ........................................................................................................................ 23 
Day 1 (Visit 1)  ....................................................................................................................................... 23 
Week 1 (Phone call) .............................................................................................................................. 24 
Week 13 (Visit 2) ................................................................................................................................... 24 
Week 26 (Visit 3) ................................................................................................................................... 24 
Week 39 (visit 4) .................................................................................................................................... 25 
Week 52 (visit 5) .................................................................................................................................... 25 
Week 56 (run out, visit 6) ....................................................................................................................... 25 
7.4 Withdrawal of the individual subjects .......................................................................................... 25 
7.5 Replacement of individual subjects after withdrawal ................................................................... 26 
7.6 Follow-up of subjects withdrawn from treatment ......................................................................... 26 
8. SAFETY REPORTING ...................................................................................................................... 27 
8.1 Section 10 WMO event ................................................................................................................ 27 
8.2 AEs, SAEs and SUSARs ............................................................................................................. 27 
8.2.1 Adverse events (AEs) ................................................................................................................... 27 
8.2.2 Serious adverse events (SAEs) ................................................................................................... 27 
8.2.3 Suspected unexpected serious adverse reactions (SUSARs) ..................................................... 28 
8.3 Annual safety report .................................................................................................................... 29 
8.4 Follow-up of adverse events........................................................................................................ 29 
8.5 Safety Committee/ Independent expert ....................................................................................... 29 
9. STATISTICAL ANALYSIS ................................................................................................................. 30 
9.1 Calculation of study numbers ...................................................................................................... 30 
9.2 Randomisation method ................................................................................................................ 30 
9.3 Analysis populations .................................................................................................................... 31 
9.3.1 Clinical Intent-To-Treat analysis (ITT) .......................................................................................... 31 

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9.3.2 Modified Intent-To-Treat analysis (mITT) ..................................................................................... 31 
9.3.3 Per protocol Treatment analysis (PTT) ........................................................................................ 31 
9.4 Methods of analysis ..................................................................................................................... 31 
9.4.1 General statistical considerations ................................................................................................. 31 
9.4.2 Comparison of baseline characteristics ........................................................................................ 31 
9.4.3 Primary study parameter(s) .......................................................................................................... 31 
9.4.4 Secondary study parameter(s) ..................................................................................................... 32 
9.4.5 Other study parameters ................................................................................................................ 32 
9.4.6 Interim analysis (if applicable) ...................................................................................................... 32 
10.ETHICAL CONSIDERATIONS ......................................................................................................... 32 
10.1 Regulation statement ................................................................................................................. 33 
10.2 Recruitment and consent........................................................................................................... 33 
10.3 Objection by minors or incapacitated subjects (if applicable) ................................................... 33 
10.4 Benefits and risks assessment, group relatedness ................................................................... 33 
10.5 Compensation for injury ............................................................................................................. 33 
10.6 Incentives (if applicable) ............................................................................................................ 34 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................................. 34 
11.1 Handling and storage of data and documents .......................................................................... 34 
11.2 Monitoring and Quality Assurance ............................................................................................ 34 
11.3 Amendments ............................................................................................................................. 34 
11.4 Annual progress report .............................................................................................................. 35 
11.5 End of study report .................................................................................................................... 35 
11.6 Public disclosure and publication policy .................................................................................... 35 
12. STRUCTURED RISK ANALYSIS .................................................................................................... 36 
12.1 Potential issues of concern........................................................................................................ 36 
12.2 Synthesis ................................................................................................................................... 37 
13. REFERENCES ................................................................................................................................ 38 
Appendix 1. Lower Respiratory Tract Infection Visual Analogue Scale (LRTI-VAS) -Dutch edition- .... 41 
Appendix 2. Leicester Cough Questionnaire -Dutch edition- ................................................................ 42 
Appendix 3.  Quality of Life Questionnaire Bronchiectasis (QOL-B) -Dutch edition- ............................ 44 
Appendix 4. Risico-classificatie investigator initiated onderzoek -Dutch edition- .................................. 48 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
AE 
Adverse Event   
ABPA  
Allergic Bronchopulmonary Aspergillosis 
BAT trial 
Bronchiectasis and long term Azithromycin Treatment trial 
CRF 
Case Record Form 
CF 
Cystic Fibrosis 
CFU 
 
Colony Forming Units 
DSMB 
Data Safety Monitoring Board 
EudraCT 
European drug regulatory affairs Clinical Trials  
FEV1  
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GP 
General Practitioner 
HRCT 
 High Resolution Computed Tomography 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
LTRI-VAS 
Lower Respiratory Tract Infection Visual Analogue Scale 
METC  
Medical research ethics committee (MREC); in Dutch: Medisch Ethische Toetsing 
Commissie (METC) 
MIC 
 
Minimum Inhibitory Concentration  
Non-CF 
bronchiectasis 
Non-Cystic Fibrosis bronchiectasis 
Non-PDPE  
non- protocol-defined pulmonary exacerbation 
PDPE 
protocol-defined pulmonary exacerbation 
QoL 
Quality of Life 
QoL-B  
Quality of Life Bronchiectasis 
SAE 
Serious Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatien IB1-
tekst) 
SUSAR 
Suspected unexpected serious adverse reaction 
TIS 
Tobramycin Inhalation Solution 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen) 
 
 
 
 

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SUMMARY 
 
Rationale: Patients with bronchiectasis often have exacerbations of their disease. These 
exacerbations influence the quality of life. In patients with cystic fibrosis (CF) longterm inhaled 
antibiotics lower the bacterial load in bronchial secretions and have positive effect on the number of 
exacerbations, lung function and quality of life (QoL). In patients with non-CF bronchiectasis colonized 
with Pseudomonas aeruginosa  studies with tobramycin inhalation solution (TIS) are limited, however 
with only five trials to date3,10,21,22,45. In present study the value of maintenance TIS will be investigated 
in patients with non-CF bronchiectasis colonized by different bacterial species sensitive for 
tobramycin. 
Objective: The primary outcome of the study is a 50% reduction in exacerbation rate in patients using 
maintenance TIS (OD). Secondary outcome parameters are lung function (FEV1, FVC), QoL (QOL-B), 
LTRI-VAS, Leicester cough score, bacterial load in sputum and tobramycin resistant pathogens. 
Study design: A randomised, double blind placebo controlled, multicenter study. 
Study population: Patients aged ≥ 18-year-old with confirmed bronchiectasis by (HR)CT and at least 
two exacerbations during previous 12 months. 
Intervention (if applicable): During the study each group (placebo, intervention) receives TIS or 
placebo, once daily 300mg/5ml for at least 9 months and up to 12 months.  
Main study parameters/endpoints: The primary endpoint is a reduction of exacerbations that 
patients suffer during the treatment period. Next to this parameter we expect to show a significant 
beneficial effect on lung function parameters, QoL, bacterial load of pathogens in sputum and 
tobramycin resistance. 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: After informed consent patients have 3 monthly visits. During the visits patients have to 
deliver a sputum sample, fill in the QoL questionnaires and a spirometry will be performed according 
the study schedule. Also a blood sample will be taken during the visits. All patients are instructed to 
use the nebulizer adequately. The whole procedure of TIS (preparation, inhalation and cleaning) takes 
approximately 15 minutes. Adverse effects consist of cough, wheezing and dyspnoea. In general 
practice salbutamol is used before nebulizing TIS, to relieve these symptoms. TIS has already been 
used by a number of patients with bronchiectasis and is well tolerated. Safety of TIS will be assessed 
during each contact. 
 
 
 
 
 
 
 
 

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1. INTRODUCTION AND RATIONALE 
 
Non-cystic fibrosis (non-CF) bronchiectasis is a chronic disorder of the major airways characterized by 
permanent dilation and destruction1. The origin of bronchiectasis varies, but the presence of microbial 
infection and a persistent inflammatory response are characteristic for the disease2;3. Colonization of 
the airway by bacteria stimulates an inflammatory response, which can become chronic if the infection 
is not eradicated4. Chronic inflammation causes host-mediated lung damage leading to a vicious cycle 
of events and decline in lung function5. This vicious cycle of infection and inflammation periodically 
develops into pulmonary exacerbations that are characterized by the following symptoms: changes in 
sputum production and purulence, increased dyspnoea, cough, wheezing, fever and fatigue. These 
exacerbations maybe associated with changes in chest sounds, radiographic abnormalities, but also 
lead to a decreased exercise tolerance and spirometer values6. Bacteria isolated from the sputum of 
patients with bronchiectasis include Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus 
influenzae, and other gram-negative bacteria including Pseudomonas aeruginosa7. P. aeruginosa may 
appear later in the disease and causes more extensive and severe symptoms than the other bacteria8. 
Non-CF bronchiectasis patients with P. aeruginosa infection have more hospitalizations, a worse 
quality of life (QoL), and a more rapid decline in lung function than patients with other lung infections9-
11. For other Gram-negative bacteria the progression of bronchiectasis as disease is less well known. 
Treatment of patients with non-CF bronchiectasis consists of postural physiotherapy, therapy with 
bronchodilators if reversible airflow obstruction is present, sometimes inhaled corticosteroids as a local 
anti-inflammatory agent, and antimicrobial therapy including immunomodulating therapy12. Treatment 
of recurrent respiratory infections is the cornerstone in patients with chronic suppurative lung disease. 
It has been reported that long-term systemic antibiotic treatment results in significant improvements in 
respiratory symptoms, pulmonary exacerbations, and health-related QoL in patients with severe 
bronchiectasis8;13-16. However, systemic antibiotics frequently fail to eradicate lung infections despite 
intensive therapy. In addition, relapse may occur when the antibiotics are stopped, and resistance 
frequently occurs with long-term use of systemic antibiotics8.  An attractive alternative is the use of an 
inhaled antibiotic that delivers drug in high concentrations directly to the site of infection, eliminating 
the need for high systemic concentrations and reducing the risk of systemic toxicity or gastrointestinal 
side effects. Tobramycin inhalation solution (TIS) has been introduced for the long-term management 
of chronic P. aeruginosa infection, with a Cochrane review suggesting some benefit from TIS in terms 
of lung function and pulmonary exacerbation rate but also concern regarding an increase in antibiotic 
resistance17. The rationale for intermittent administration of  tobramycin  was  based  on  the  
observation  that during the treatment-free period tobramycin sensitive pathogens may repopulate the 
lower airways18. A recent registry study examining data from the Cystic Fibrosis Foundation’s Patient 
Registry has suggested that TIS use is associated with reduced mortality19. TIS has also been 
demonstrated to be effective in delaying re-infection in those with early P. aeruginosa infection20. 
Because secretions in the non-CF bronchiectatic airways are similar to the purulent mucus found in 
the CF airways, and because pulmonary complications and progression of disease in non-CF 
bronchiectasis is similar to CF bronchiectasis, many centers treat patients with bronchiectasis using 
aerosolized TIS. There have been only a few small studies of aerosolized antibiotics to treat 

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pseudomonas infection in subjects with non-CF bronchiectasis3;10;21. The study of Drobnic22 showed 
that TIS has effect on the rate of hospitalization and bacterial density of sputum. However, pulmonary 
function and QoL were not influenced. In another study symptoms and QoL were improved3;10;22. 
Furthermore, the risk of adverse events such as bronchospasm may be more common in adults with 
non-CF bronchiectasis than reported in the CF population3;10. No data is available of the effect of 
maintenance use of TIS in non-CF bronchiectasis colonized by non Pseudomonas aeruginosa Gram 
negative bacteria.   
It is known that the antibiotic pharmacokinetics of CF-bronchiectasis differs from non-CF 
bronchiectasis. The twice-daily TIS dosing regimen in CF is based in large part on studies of 
tobramycin concentrations in expectorated sputum after administration of a single dose to adolescents 
and adults with CF23-25. No data are available of the sputum half-life of TIS in non-CF bronchiectasis. 
Most of these studies used the 4 weeks on-off protocol26-29 . In this study we intend to establish the 
efficacy of once daily dosing of tobramycin. This is supported by knowledge that its bactericidal activity 
is concentration-dependent with a long post-exposure antibiotic effect30-32. Studies of intravenous 
administration of tobramycin and other aminoglycosides have shown that once daily dosing is 
equivalent in terms of antimicrobial efficacy compared to more frequent dosing 33-36. Therefore a strong 
body of evidence supports once daily administration of tobramycin.  
The present study has been designed to answer the question whether maintanance treatment with TIS 
once daily may reduce the number of exacerbations in non-CF bronchiectasis compared to placebo. 
As written above, the previous studies in patients with non-CF bronchiectasis are limited, small and 
open label. Next to this argument, it is unknown if extrapolation of the data collected in patients with 
CF bronchiectasis is justified. That is the reason why the British and Dutch guideline research 
recommendation mention that randomised controlled trials are needed to investigate the efficacy of 
nebulised antibiotics in patients with bronchiectasis chronically colonised with P. aeruginosa and other 
organisms. This study is designed as a randomized controlled trial, and TIS wil be compared to 
placebo. 
 
 
 

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2. OBJECTIVES 
  
Primary Objective:  
The primary objective of the study is to determine whether maintenance use of TIS once daily (OD) as 
compared to placebo may reduce the number of exacerbations per year in patients with non-CF 
bronchiectasis.  
 
Secondary Objective: 
The secondary objective of this study is to evaluate the effect of TIS treatment on time to next 
exacerbation, airflow limitation (FVC% predicted, FEV1% predicted), LRTI-VAS, Quality of Life-
Bronchiectasis (QOL-B), Leicester cough score, bacterial load in sputum and tobramycin resistance, 
including MIC values, depending on the capabilities of the microbiological laboratory. 
 
 

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3. STUDY DESIGN  
 
This study will be set up as a randomized, placebo controlled, multicenter study to evaluate the 
efficacy and safety of Tobramycin Inhalation Solution (TIS) compared to placebo. The target group are 
patients with non-CF bronchiectasis with recurrent exacerbations (≥ 2 per year) and colonized by 
Gram-negative bacteria (including Haemophilus influenzae) and/or Staphylococcus aureus in sputum. 
A sufficient number of subjects across 6 sites will be enrolled to ensure 58 patients. These patients are 
randomized in a 1:1 ratio of TIS OD (29 patients) to placebo OD (29 patients). The study will compare 
the number of exacerbations for 52 weeks, as well as the other secondary endpoints.  
During the study patients visit the outpatient ward. During these visits’ actual medical history, physical 
examination and questionnaires are obtained. Next to these sputum examination, spirometry and 
safety tests (lab examination, diary card) are performed. Study medication starts after the run-in 
period. 
This study will consist of an up to 30-day screening phase, a treatment phase of 52 weeks, and a 
washout phase of 4 weeks. 
Participating patients are randomized to one of the two study arms and will be treated for at least 9 
months and up to 12 months in a double-blind fashion with placebo or TIS 300mg OD. Sputum 
samples will be collected from each subject for culture. At the Screening Visit (Visit 0) subjects will 
review and sign the informed consent form (ICF) and the screening procedures will be completed. 
Subjects meeting all study eligibility criteria will be randomized 1:1 to receive once daily inhaled 
treatment with either TIS OD or placebo. Subjects will have a screening visit and 6 additional 
scheduled visits during the study. Subjects will receive their first dose of study drug at the study site on 
day 1 during visit 1, and on day 7 they will be contacted by phone for the assessment of compliance 
and tolerance with study drug. Further visits are scheduled with 12-week intervals. Visit 7, which is the 
final visit of the study, will be conducted 4 weeks after the end of treatment period (see figure 1). 
At visit 1, subjects will be instructed on daily study drug administration by self-administering study drug 
under the supervision of study personnel at the site; subjects will self-administer study drug during the 
complete study period.  
Efficacy parameters will include assessment of pulmonary exacerbations, spirometry, LTRI-VAS, 
QOL-B and Leicester cough questionnaires. Microbiological response measurements will include 
semi-quantitative density of pathogens in sputum, including the tobramycin minimum inhibitory 
concentration (MIC) for isolated pathogens. Safety parameters will include assessment of AEs, serial 
spirometry findings, clinical laboratory test results, vital signs measurements, physical examination. 
Study drug is dispended on the regular visits. The first patients will be enrolled in the summer of 2016, 
with a treatment period of 12 months, we expect to terminate the study 31-01-2020. 
 
In subjects who experience a pulmonary exacerbation, every effort should be made to continue their 
allocated inhaled study drug, unless the study drug is not tolerated, or the pulmonary exacerbation is 
believed to be related to study drug. All subjects who receive any study drug need to complete the visit 
7 assessments. Subjects who are prematurely withdrawn from study drug will be encouraged to 

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remain in the study and attend subsequent study visits; at a minimum, they should complete the visit 7 
assessments as an early termination visit. 
 
An independent expert will be established to conduct periodic reviews of subject safety for this 
protocol. The independent expert will also perform a blinded analysis of the pulmonary exacerbation 
data to check whether the assumptions for sample size estimation are valid, and if they are not, the 
sample size may be increased. 
 
This study will be conducted in the Noordwest Ziekenhuisgroep, Canisius ZH Nijmegen, Spaarne 
Gasthuis Hoofddorp, Zuyderland MC Heerlen, VU Medical Center Amsterdam and UMC Utrecht. 
 

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4. STUDY POPULATION 
 
4.1 Population (base)  
Non-cystic fibrosis bronchiectasis remains an important cause of chronic respiratory morbidity with a 
considerable healthcare. The prevalence and incidence of bronchiectasis are not known accurately, 
however in the last years, there is an increase in prevalence. In this study a total of 58 patients with 
clinically significant and radiological proven bronchiectasis are recruited from the outpatient clinic. 
Patients have at least two pulmonary exacerbations in the past year, for further inclusion and 
exclusion criteria see 4.2 and 4.3. The patients will be enrolled in the study and will be divided into two 
equally groups of 29 patients. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria:  
1. Age ≥ 18 years  
2. The presence of chronic respiratory symptoms such as cough, dyspnoea, expectoration of sputum 
3. Confirmed non-CF bronchiectasis by (HR)CT 
4. Documented history of at least 2 pulmonary exacerbations treated with courses of antibiotics within 
12 months before inclusion.  
5. No course of antibiotics or maintenance antibiotics (except for macrolides) 1 month prior to the start 
of the study. 
6. Minimal one documented sputum or BAL-fluid culture with gram-negative bacteria or S. aureus 
within 12 months.  
7. Growth of protocol defined pathogens in sputum  
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: 
1. Any exacerbation within the month prior to the start of the study 
2. Diagnosis of cystic fibrosis 
3. Active allergic bronchopulmonary aspergillosis (ABPA) 
4. Any oral, IV or inhaled antibiotics (except for macrolides) within 1 month prior to the start of the 
study 
5. Any IV or IM corticosteroids or change in oral corticosteroids (> 10 mg) within 1 month prior to the 
start of the study 
6. Any change/start treatment regimens macrolides, hypertonic saline, inhaled mannitol or other 
mucolytics, corticosteroids within 1 month prior to the start of the study 
7. Severe immunosuppression or active malignancy 
8. Active tuberculosis 
9. Chronic renal insufficiency (eGFR < 30 ml/min) 
10. Use of loopdiuretics, urea or mannitol 
11. Earlier diagnosed hearing impairment, balance disorders or neuromuscular disorders  

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12. Serious active haemoptysis 
13. Have received an investigational drug or device within 1 month prior to the start of the study 
14. Serious or active medical or psychiatric illness 
15. Pregnancy and child bearing 
16. History of poor cooperation or non-compliance 
17. Unable to use nebulizers 
18. Allergic for tobramycin or NaCl 0.9% 
 
4.4 Sample size calculation 
The hypothesis is that prolonged treatment with tobramycin reduces the number of exacerbations per 
patient by 50%. This reduction seems clinically relevant and is based on the assumption that 
maintenance treatment with TIS OD as well as intermittent TIS BID is comparable to that of 
azithromycin treatment. This assumption is derived from the data of the BAT trial (placebo: mean 2,1 
exacerbations (sd 1.6); azithromycin: mean 0,8 exacerbations (sd 1.1) 49. The reduction in percentage 
is used for the determination of trial size.  
We used a poisson regression model to determine group size39. For type I error and type II error 0.05 
and 0.2 were used respectively. The hypothesis will be tested two sided. With a baseline exacerbation 
rate of 2.1 in the placebo group and an expected response rate ratio of 0.5 with an exposure time of 1 
year a total of 18 evaluable patients are required to be on each treatment arm.  
With a drop-out percentage of 30% we must include totally 48 (24 patients per group) patients10;22. 
Due to unforeseen reasons we initially include two extra patients per group. But after the interim 
analysis three extra patients will be included in the study, because the drop-off percentage is higher as 
expected in advance. Reason for discontinuation of the study is the intensive treatment and cleaning 
schedule of the inhaled study medication. So, with a total of 58 patients (29 per group) with 
bronchiectasis, and not the initially 52 patients (26 per group), we expect to achieve the intended 
effect size.

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5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
Tobramycin inhalation solution (TIS) 
This medication is used to treat people with cystic fibrosis (CF) and non-CF bronchiectasis who have a 
persistent lung infection with Gram-negative bacteria (H. influenzae, Klebsiella spp, E. coli, P. 
aeruginosa, e.g.). People with bronchiectasis often produce thick, sticky mucus that can plug up the 
tubes, ducts and passageways in the lungs. This can result in serious breathing problems and 
infections in the lungs. Tobramycin belongs to a class of drugs known as aminoglycoside antibiotics. 
Tobramycin inhalation solution works by stopping the growth of Gram-negative bacteria and S. aureus 
that commonly infects the lungs of people with bronchiectasis. This effect decreases lung infections 
and damage and helps to improve breathing. 
 
Placebo: Sodium chloride inhalation solution 0.9% (NaCl 0.9%) 
This medication is frequently used as a placebo. Each single-use plastic ampule contains sterile, non-
pyrogenic, preservative-free sodium chloride. There is no bacteriostatic agent or other preservative 
added. Sodium chloride inhalation solution 0.9% is well tolerated and no severe adverse effects or 
side effects were recorded.  
 
5.2 Use of co-intervention  
All co-medications are allowed, except for any oral (except for macrolides), IV or inhaled antibiotics 
within 1 month prior to the start of the study and any IV or IM corticosteroids or change in oral 
corticosteroids (> 10 mg) within 1 month prior to the start of the study. Immunosuppressive agents 
such as azathioprine, chemotherapeutic agents, and TNFα inhibitors are prohibited. Also, any 
change/start treatment regimens of macrolides, hypertonic saline, inhaled mannitol or other 
mucolytics, within 1 month prior to the start of the study are prohibited. Also, the use of loopdiuretics, 
mannitol or urea are prohibited. 
 
5.3 Escape medication  
In consultation with the own GP or respiratory physician the patient may use extra bronchodilators for 
relief of dyspnoea. In subjects who experience a pulmonary exacerbation, every effort should be made 
to continue their allocated inhaled study drug, unless the study drug is not tolerated, or the pulmonary 
exacerbation is believed to be related to study drug. All subjects who receive any study drug need to 
complete the visit 7 assessments. Subjects who are prematurely withdrawn from study drug will be 
encouraged to remain in the study and attend subsequent study visits; at a minimum, they should 
complete the visit 7 assessments as an early termination visit. 
 
 
 

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6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational product(s) 
Tobramycin Inhalation Solution USP37 
This medication is used to treat people with  (CF) and non-CF bronchiectasis who have a persistent 
lung infection with Gram-negative bacteria (e.g., H.influenzae, Klebsiella spp, E.coli, P. aeruginosa). 
People with bronchiectasis often produce thick, sticky mucus that can plug up the tubes, ducts and 
passageways in the lungs. This can result in serious breathing problems and infections in the lungs. 
Tobramycin belongs to a class of drugs known as aminoglycoside antibiotics. Tobramycin inhalation 
solution works by stopping the growth of a Gram-negative bacteria and S. aureus that commonly 
infects the lungs of people with bronchiectasis. This effect decreases lung infections and damage and 
helps to improve breathing. 
 
Sodium chloride inhalation solution 0.9% (NaCl 0.9%) 
This medication is frequently used as a placebo. Each single-use plastic ampule contains sterile, non-
pyrogenic, preservative-free sodium chloride. There is no bacteriostatic agent or other preservative 
added. Sodium chloride inhalation solution 0.9% is well tolerated and no severe adverse effects or 
side effects were recorded. 
 
6.2 Summary of findings from non-clinical studies 
 
6.2.1 Pharmacokinetics 
Tobramycin inhalation solution contains tobramycin, a cationic polar molecule that does not readily 
cross epithelial membranes38. The bioavailability of tobramycin inhalation solution may vary because 
of individual differences in nebulizer performance and airway pathology25. Following administration of 
tobramycin inhalation solution, tobramycin remains concentrated primarily in the airways. 
 
6.2.2 Sputum Concentrations 
Ten minutes after inhalation of the first 300 mg dose of tobramycin inhalation solution, the average 
concentration of tobramycin was 1237 mcg/g (ranging from 35 to 7417 mcg/g) in sputum37. 
Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the tobramycin inhalation 
solution regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 
mcg/g (ranging from 39 to 8085 mcg/g) in sputum. High variability of tobramycin concentration in 
sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 
14% of tobramycin levels at ten minutes after inhalation.  
 
6.2.3 Serum concentrations 
The average serum concentration of tobramycin one hour after inhalation of a single 300 mg dose of 
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on the tobramycin inhalation solution regimen, the average serum tobramycin concentration one hour 
after dosing was 1.05 mcg/mL37. 
 
6.2.4 Elimination 
The elimination half-life of tobramycin from serum is approximately 2 hours after intravenous (IV) 
administration. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin 
following IV administration, systemically absorbed tobramycin is eliminated principally by glomerular 
filtration. Unabsorbed tobramycin, following tobramycin inhalation solution administration, is probably 
eliminated primarily in expectorated sputum. 
 
 
 6.3 Summary of findings from clinical studies 
In present table all studies using TIS (all preparations) and outcomes are documented. 
 
 
 
TIS USP (TEVA) has only been studied in CF patients (two studies, unpublished)37.  In each study, 
tobramycin inhalation solution therapy resulted in a significant reduction in the number of P. 

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aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial 
density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were 
smaller in each successive cycle. Patients treated with longterm tobramycin inhalation solution were 
hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated 
with tobramycin inhalation solution required an average of 9.6 days of parenteral anti-pseudomonas 
antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 
40% of tobramycin inhalation solution patients and 53% of placebo patients were treated with 
parenteral anti-pseudomonas antibiotics. 
The relationship between in-vitro susceptibility test results and clinical outcome with tobramycin 
inhalation solution therapy is not clear. However, 4 tobramycin inhalation solution patients who began 
the clinical trial with P. aeruginosa isolates having MIC values ≥ 128 mcg/mL did not experience an 
improvement in FEV1 or a decrease in sputum bacterial density. 
Treatment with longterm tobramycin inhalation solution did not affect the susceptibility of the majority 
of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did 
exhibit increased tobramycin MICs. The percentage of patients with P. aeruginosa isolates with 
tobramycin MICs ≥ 16 mcg/mL was 13% at the beginning, and 23% at the end of 6 months of the 
tobramycin inhalation solution regimen. 
6.4 Summary of known and potential risks and benefits 
Maintenance use of TIS UPS is generally well tolerated as shown during two clinical studies in 258 
cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin inhalation 
solution in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic 
fibrosis therapy for a total of 24 weeks. No severe adverse effects were recorded. The most common 
side effects are coughing, sore throat, dysphonia and bronchospasm. Tinnitus (3%) was transient, 
resolved without discontinuation of the tobramycin inhalation solution treatment regimen, and were not 
associated with loss of hearing in audiograms. 
Nine (3%) patients in the tobramycin inhalation solution group and nine (3%) patients in the placebo 
group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the 
tobramycin inhalation solution group, creatinine decreased at the next visit. 
 
 
6.5 Description and justification of route of administration and dosage 
TIS UPS is produced and packed by TEVA Pharmaceuticals in accordance to the principles and the 
detailed guidelines of Good Manufacturing Practice for Medicinal Products and will be delivered at the 
pharmacy of Stichting Haarlemse Ziekenhuizen. All the public information about the investigational 
product is written in the SPC-document. TIS is packaged in small plastic ampules (miniplasco’s) of 5 
ml; each ampule contains one full dose of tobramycin (300mg). These ampules are packed in identical 
sealed boxes. The investigators will be blinded for the content of the boxes. The placebo is a plastic 
ampule of NaCl 0.9% 5ml. These ampules are also called miniplasco’s. The placebo is produced by 
Centrafarm B.V in accordance to the principles and detailed guidelines of Good Manufacturing 

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Practice for Medical Products. Also, these ampules will be delivered at the pharmacy of Haarlemse 
Ziekenhuizen. The shape of the ampules of the placebo (NaCl 0.9%) is different form the ampules of 
TIS, therefore the ampules will be packed in identical sealed boxes. The investigators will be blinded 
for the content of the boxes, in this way the blind will remain existent. 
Labelling will be done at the pharmacy of Haarlemse Ziekenhuizen. The ampules remain intact, and a 
new label is printed on the package in accordance with the guidelines Good Manufacturing Practice. 
The expiration date, reference code and batch code are printed on the ampules and sealed boxes. 
The 300mg dose of tobramycin inhalation solution (or placebo) is the same for patients regardless of 
age or weight. Doses should be inhaled as close to 12 hours apart as possible and not less than 6 
hours apart. In this study TIS is used once daily in the morning. The pharmacy of Haarlemse 
Ziekenhuizen is responsible for the labelling and packaging of the sealed boxes for both TIS and 
placebo. These labelled and sealed boxes are sent to the pharmacy of the Noordwest 
Ziekenhuisgroep, location Alkmaar. The transportation is under refrigeration at 2-8ºC/36-46ºF. The 
storage of the investigational product (TIS or placebo) is under refrigeration at 2-8ºC/36-46ºF with 2-
year shelf life at these circumstances. Temperature will be monitored continuously. 
Upon removal from the refrigerator, tobramycin inhalation solution USP pouches (opened or 
unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. Tobramycin 
inhalation solution USP should not be used beyond the expiration date stamped (totally of two years) 
on the ampule when stored under refrigeration (2-8ºC/36-46ºF) or beyond 28 days when stored at 
room temperature (25ºC/77ºF). TIS USP ampules should not be exposed to intense light. The solution 
in the ampule is transparent but may darken with age if not stored in the refrigerator; however, the 
color change does not indicate any change in the quality of the product  
 
The investigational product (TIS or placebo) is especially formulated to be used with an InnoSpire 
Deluxe compressor (Philips Respironics) with a SideSteam Plus nebulizer with mouthpiece. This 
compressor is produced by Philips Respironics and delivered by Mediq Romedic Netherlands. The air 
compressor is used with a nebulizer to turn the medicine into a fine spray. Before inhalation of TIS 
salbutamol is administered at a dose of 200mcg to prevent bronchial constriction. TIS (or placebo) 
while breathing through the mouthpiece the spray is inhaled into the airways. The nebulizer is used for 
about 5 minutes. The whole procedure; preparation of the nebulizer, inhalation and cleaning takes 
about 15 minutes to complete. Afterwards the patient should rinse their mouth three times.  
 
6.6 Dosages, dosage modifications and method of administration 
See 6.5 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
Randomisation will be done by the statistician at the Noordwest Ziekenhuisgroep. The randomisation 
list will be sent to the pharmacy of Haarlemse Ziekenhuizen. Labelling takes place at the pharmacy of 
the Haarlemse Ziekenhuizen in accordance to this randomisation list. This labelled and sealed boxes 

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are sent to the pharmacy of the Noordwest Ziekenhuisgroep. Storage will be done in the refrigerator at 
the department of pulmonology in accordance to the GCP guidelines. See also 6.5. 
 
 
6.8 Drug accountability 
Medication will be provided by TEVA Pharmaceuticals and delivered at the pharmacy of the 
Haarlemse Ziekenhuizen. After labelling and packaging, the investigational medication will be 
delivered at the pharmacy of the Noordwest Ziekenhuisgroep location Alkmaar. All medication is 
coded. The medication will be delivered by the investigator at all participating centres. Transportation 
will be at refrigeration at 2-8ºC/36-46ºF in special boxes. The medication will be stored at the 
participating centres under refrigeration at 2-8ºC/36-46ºF, according to the local arrangements. 
Medication will be provided at the patients during each out-patient visit, with the explanation to store 
the investigational product in the refrigerator at 2-8ºC/36-46ºF. Used ampules are returned in opaque 
sealed plastic bags during the out-patient visit. The used ampules are counted by an independent 
research nurse and will be recorded in an excel file. In this way the blind will remain existent and 
nevertheless compliance can be checked. The ampules will be destroyed by the local pharmacy of the 
relevant hospital. 
 
 
7. METHODS 
 
7.1 Study parameters/endpoints 
 
7.1.1 Main study parameter/endpoint 
The primary objective of the study is to determine whether maintenance use of TIS once daily (OD) as 
compared to placebo may reduce the number of exacerbations per year in patients with non-CF 
bronchiectasis.  
 
7.1.2 Secondary study parameters/endpoints (if applicable) 
The secondary objective of this study is to evaluate the effect of TIS treatment on time to next 
exacerbation, airflow limitation (FVC% predicted, FEV1% predicted), LRTI-VAS, Quality of Life-
Bronchiectasis (QOL-B), Leicester cough score, bacterial load in sputum and tobramycin resistance, 
including MIC values, depending on the capabilities of the microbiological laboratory. 
 
 
7.1.3 Other study parameters (if applicable) 
Other objectives of the study are age of the patients, sex, tobacco and alcohol use, number of patients 
with COPD or other etiologies, and the biomarkers like C-reactive protein level and leukocytes in 
serum, liver function and renal function. In addition to these objectives, it is also interesting how much 
patients withdrew from the study because of bronchospasm or other adverse effects, supplementary 
use of oral antibiotics due to an exacerbation, azithromycin maintenance and pseudomonas carriage. 
An exacerbation will be noticed bij using the diary card weekly. If there are any changes in medical 

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condition and compliance with medication, this will be noticed by using the diary card. In subjects who 
experience a pulmonary exacerbation, the own GP or respiratory physician will assess the severity of 
pulmonary symptoms and signs and prescribes antibiotics and/or medication e.g prednisolone, 
bronchodilators) . If so, the investigator will be informed. At least also an objective of the study is 
hospitalization and duration of the hospitalization.  
 
7.2 Randomisation, blinding and treatment allocation 
Randomisation will be done by Excel and SPSS statistics 20 with an allocation ratio of 1:1 between 
groups. Once a number is assigned to a patient, the investigator will open the treatment regimen 
assignment and the subject will receive treatment according to the assigned strategy.  The numbers 
are anonymous dispensed in closed envelopes and stored at department of pulmonary diseases of the 
Noordwest Ziekenhuisgroep location Alkmaar. The main-investigator will be responsible for 
maintaining the storage and allocation of the envelopes.  
 
7.3 Study procedures 
Patients with bronchiectasis and who fulfil the inclusion and exclusion criteria will be asked to 
participate in the study. After a run-in period of 4 weeks’ patients will be randomized to receive one of 
the two possible treatment regimens: TIS OD 300 mg daily or placebo. Administration will be 
continuous for the full 12 months. According to the parallel group design patients will be treated for 52 
weeks. After completing the intervention period patients will have a follow-up (wash out period) of 4 
weeks. This wash-out period was considered to be one month, in which time the antimicrobial effect of 
the antibiotic supposedly disappears, as suggested in earlier studies22. 
Subjects will be evaluated at run-in = visit 0 (week -4), visit 1 (day 1- start of the study), visit 2 (week 
13), visit 3 (week 26), visit 4 (week 39), visit 5 (week 52: end of treatment) and visit 6 (run-out; week 
56: end of the study). One week after start of treatment a phone call will be scheduled.  Clinical, 
laboratory, and bacteriology evaluations will be determined according the schedule (Figure 1: study 
schedule). Subjects who terminate treatment should be followed for the same period as those who 
complete the study, according to the study schedule. 
During the study any changes in medical condition and compliance with medication will be filed in the 
diary card.  
At visit 1, after randomisation, a tolerance test with either TIS or placebo (blinded acccording 
randomisation) will be performed. Before nebulizing TIS patients are treated with salbutamol 200mcg 
using an aerochamber. During tidal breathing patients inhale 300mg TIS or placebo (at room 
temperature) by using the Innospire Deluxe nebulizer with mouthpiece during approximately 5 
minutes. If patients develop a moderate-severe bronchial obstruction, patients are excluded from the 
study. The severity of bronchial obstruction and coughing is assessed by a specialized nurse, the 
respiratory physician or the own GP. An exacerbation is defined as the presence of three or more of 
the following symptoms or signs for at least 24 hours: increased cough, increased sputum volume, 
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or malaise, and the treating physician agreed that antibiotic  and/or prednisolone therapy was 
required. 
All participants are provided with 24-hour contact details (phone and mail) and invited to contact their 
respiratory physician or general practitioner and study staff at any time (including after hours) in the 
event of exacerbation symptoms, to ensure that these symptoms are evaluated prospectively. 
Participants will be instructed to ensure that antibiotic prescriptions will be provided by the own 
respiratory physician of the centres or the general practitioner. 
Criteria for protocol-defined pulmonary exacerbation (PDPE) will be adjudicated prospectively by the 
treating respiratory physician. Antibiotic and/ or prednisolone prescriptions are also directed by the 
treating respiratory physician or the general practitioner, and standardized according to microbiology 
and antibiotic tolerance. Deteriorations in respiratory symptoms that do not meet criteria for PDPEs will 
be termed non–protocol-defined PEs (non-PDPEs). In these circumstances, participants were advised 
that they did not require antibiotics and only if clinically indicated, determined by the treating physician 
or the general practitioner. 
 
 
 
Run-in (Visit 0, week -4) 
At the baseline visit (- 4 weeks), subjects will be deemed eligible for the study after the clinical 
diagnosis bronchiectasis has been made, and the study has been explained to them. The following 
procedures will be completed: 
- 
Verify inclusion/exclusion criteria 
- 
Obtain written informed consent (alternatively at visit 1) 
- 
Record medical history 
- 
Collection of demographic information, concurrent disease, concomitant medication use, and 
previous course(s) of antibiotic therapy in the preceding year  
- 
Physical examination (including sputum characteristics, cough, dyspnoea, pleuritic chest pain, 
chills or rigors, and lung sounds) and vital signs (respiratory rate, heart rate, blood pressure, body 
temperature and oxygen saturation) 
- 
Laboratory examination (CRP, Hb, WBC, Sodium, Potassium, Creatinin, eGFR, Liver Function 
Tests, extra blood sample(s) will be taken and frozen for future research) 
- 
Sputum culture (semi-quantitative)  
- 
Randomisation (or at visit 1) 
 
Day 1 (Visit 1) 
- 
Record medical history  
- 
Assessment of LRTI-VAS 
- 
Quality of Life-Bronchiectasis (QOL-B) questionnaire 
- 
Leicester cough score 
- 
Physical examination (including sputum characteristics, cough, dyspnoea, pleuritic chest pain, 
chills or rigors, and lung sounds) and vital signs (respiratory rate, heart rate, blood pressure, body 
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- 
Collection of demographic information, concurrent disease, concomitant medication use, and 
previous course(s) of antibiotic therapy in the preceding year 
- 
Spirometry according to the standard criteria of the European Respiratory Society  
- 
Concomitant medication monitoring 
- 
Study drug and Innospire deluxe dispensation  
- 
Inhalation tolerance test with either TIS or placebo (depending on randomisation) and first dose of 
study drug administered under supervision of study staff 
- 
Instructions on proper administration and return of study drug and proper care of the nebulizer 
- 
Diary card instruction 
 
Week 1 (Phone call) 
- 
AE assessment of site effects of study medication 
- 
Assessment compliance with medication and potential problems with nebulizer 
- 
Diary card check 
 
Week 13 (Visit 2) 
- 
Record medical history (exacerbation, antibiotics?) 
- 
Diary card check 
- 
Repeat laboratory examination (CRP, Hb, WBC, Sodium, Potassium, Creatinin, eGFR, Liver 
Function) 
- 
Potential side effects will be recorded 
- 
Dispense study medication 
- 
Remaining study drug is collected and/or is sent to Noordwest Ziekenhuisgroep, location Alkmaar 
 
Week 26 (Visit 3) 
- 
Record medical history (exacerbation, antibiotics?) 
- 
Assessment of LRTI-VAS 
- 
Quality of Life-Bronchiectasis (QOL-B) questionnaire  
- 
Leicester cough score 
- 
Physical examination (including sputum characteristics, cough, dyspnoea, pleuritic chest pain, 
chills or rigors, and lung sounds) and vital signs (respiratory rate, heart rate, blood pressure, body 
temperature and oxygen saturation) 
- 
Diary card check 
- 
Repeat laboratory examination (CRP, Hb, WBC, Sodium, Potassium, Creatinin, eGFR, Liver
 
Function) 
- 
Sputum examination for microbiologic assessment 
- 
Spirometry according to the standard criteria of the European Respiratory Society  
- 
Potential side effects will be recorded 
- 
Dispense study medication 
- 
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Week 39 (Visit 4) 
- 
Record medical history (exacerbation, antibiotics?) 
- 
Diary card check 
- 
Repeat laboratory examination (CRP, Hb, WBC, Sodium, Potassium, Creatinin, eGFR, Liver
 
Function) 
- 
Potential side effects will be recorded 
- 
Dispense study medication 
- 
Remaining study drug is collected and/or is sent to Noordwest Ziekenhuisgroep location Alkmaar 
 
Week 52 (Visit 5) 
- 
Record medical history (exacerbation, antibiotics?) 
- 
Assessment of LRTI-VAS 
- 
Quality of Life-Bronchiectasis (QOL-B) questionnaire 
- 
Leicester cough score 
- 
Physical examination (including sputum characteristics, cough, dyspnoea, pleuritic chest pain, 
chills or rigors, and lung sounds) and vital signs (respiratory rate, heart rate, blood pressure, body 
temperature and oxygen saturation) 
- 
Diary card check 
- 
Repeat laboratory examination (CRP, Hb, WBC, Sodium, Potassium, Creatinin, eGFR, Liver 
Function Tests, extra blood sample(s) will be taken and frozen for future research) 
- 
Sputum examination for microbiologic assessment 
- 
Spirometry according to the standard criteria of the European Respiratory Society 
- 
Potential side effects will be recorded 
- 
Remaining study drug, nebulizer, and compressor are collected 
 
Week 56 (run out, Visit 6) 
- 
Record medical history (exacerbation, antibiotics?) 
- 
Assessment of LRTI-VAS 
- 
Quality of Life-Bronchiectasis (QOL-B) questionnaire 
- 
Leicester cough score 
- 
Diary card check 
- 
Repeat laboratory examination (CRP, Hb, WBC, Sodium, Potassium, Creatinin, eGFR, Liver 
Function) 
- 
Sputum examination for microbiologic assessment 
- 
Spirometry according to the standard criteria of the European Respiratory Society 
 
7.4 Withdrawal of the individual subjects 
Subjects can quit the study at any time for any reason if they wish to do so without any consequences. 
The investigator/treating physician can decide to withdraw a subject from the study for urgent medical 
reasons. 

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7.5 Replacement of individual subjects after withdrawal 
We estimate a drop-out of 30% patients. The number of potentially lost patients has been added to the 
number patients required by sample size calculation.   
 
   7.6 Follow-up of subjects withdrawn from treatment 
Follow-up of patients withdrawn from treatment have an out-patient visit following the study schedule. 
These patients will be evaluated the same as the patients who complete the study. Subjects will be 
evaluated at run-in = visit 0 (week -4), visit 1 (day 1- start of the study), visit 2 (week 13), visit 3 (week 
26), visit 4 (week 39), visit 5 (week 52: end of treatment) and visit 6 (run-out; week 56: end of the 
study). One week after start of treatment a phone call will be scheduled. During an exacerbation the 
patient will contact his/her own GP or specialist.  
 
7.7 Premature termination of the study 
With the expertise of maintenance treatment in CF patients and non-CF patients it is not likely that 
side effects may be a reason for termination of the study. If the independent expert sees any issues 
with safety regarding this clinical trial the study may be suspended or terminated for further/interim 
analysis by an independent statician. If he has serious concerns about safety of study subjects he will 
report these to the METC. 
 

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8. SAFETY REPORTING 
 
8.1 Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and 
the reviewing accredited METC if anything occurs, on the basis of which it appears that the 
disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited METC, except in so 
far as suspension would jeopardise the subjects’ health. The investigator will take care that all subjects 
are kept informed.  
 
   8.2 AEs, SAEs and SUSARs 
 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the investigational product / the experimental intervention. All 
adverse events reported spontaneously by the subject or observed by the investigator or his staff will 
be recorded. Only AE’s related to study procedures or medication will be recorded and reported once 
a year.  
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any dose: Results in 
death; is life threatening (at the time of the event); requires hospitalisation or prolongation of existing 
inpatients’ hospitalisation; results in persistent or significant disability or incapacity; is a congenital 
anomaly or birth defect.  
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgement, the event may jeopardise the subject or may require an intervention to prevent 
one of the outcomes listed above. 
 
SAE will be reported by the participating centres, preferably by mail, as soon as possible to the 
coordinating investigator. 
The coordinating investigator will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 15 days after the coordinating investigator has first 
knowledge of the serious adverse events. 
 
SAEs that result in death or are life threatening should be reported expedited. The expedited reporting 
will occur not later than 7 days after the responsible investigator has first knowledge of the adverse 
event. This is for a preliminary report with another 8 days for completion of the report.  
 

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8.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product related to 
any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
the event must be serious (see chapter 9.2.2); there must be a certain degree of probability that the 
event is a harmful and an undesirable reaction to the medicinal product under investigation, regardless 
of the administered dose the adverse reaction must be unexpected, that is to say, the nature and 
severity of the adverse reaction are not in agreement with the product information as recorded in: 
Summary of Product Characteristics (SPC) for an authorised medicinal product or Investigator’s 
Brochure for an unauthorised medicinal product. 
 
The coordinating investigator will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
 
SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 
SUSARs that have arisen in other clinical trials of the same sponsor and with the same medicinal 
product, and that could have consequences for the safety of the subjects involved in the clinical trial 
that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every 
half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine, 
accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as notification 
to the competent authority. All participating centres receive SUSARSs once a month by mail. 
 
The expedited reporting will occur not later than 15 days after the coordinating physician has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days 
for a preliminary report with another 8 days for completion of the report.  
 
In summary, patients report potential adverse effect/ event (AE) of the study drug to their own 
respiratory physician as well in their diary chart. The respiratory physician reports this adverse 
effect/event to the coordinating investigator within one week and in SAE (e.g. hospital admission) as 
soon as possible. The coordinating investigator will inform the METC as described before. 
 
The list of randomisation will be stored at the department of Pulmonology of the Noordwest 
Ziekenhuisgroep, location Alkmaar. Breaking the code will only be performed by the coordination 
physician.  
 

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8.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout the 
clinical trial, a safety report to the accredited METC, competent authority, and competent authorities of 
the concerned Member States. 
This safety report consists of: a list of all suspected (unexpected or expected) serious adverse 
reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered 
by organ system, per study; a report concerning the safety of the subjects, consisting of a complete 
safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
8.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. Depending 
on the event, follow up may require additional tests or medical procedures as indicated, and/or referral 
to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol.  
 
8.5 Safety Committee/ Independent expert 
The safety committee consist of one member, called the independent expert who is independent of the 
set-up and execution of the trial. This independent expert will receive the definite protocol and all 
revisions. The independent expert will convene every three to six months and review the results, i.e. 
results split by experimental and control arms. The independent expert has the power to recommend 
termination of the study based on the evaluation of these results. There are typically three reasons an 
independent expert might recommend termination of the study: safety concerns, outstanding benefit, 
and futility. The primary mandate of this independent expert is to protect patient safety. If adverse 
events of a particularly serious type are more common in the experimental arm compared to the 
control arm, then the independent expert would have to strongly consider termination of the study. 
This evaluation has to be made in consideration of risk/benefit. In many cases, the experimental arm 
could cause serious adverse events, but the resulting improvement in survival could outweigh these 
adverse events. 
The idependent expert should inform the findings or conclusions to the study investigators by mail or 
e-mail. If there is any dispute between the independent expert and study investigators, the 
independent expert should notify the METC Noord-Holland.    
 
The independent expert is: 
Casper de Graaff longarts, Heiloo 
Email: cgraaff0@gmail.com 
 

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9. STATISTICAL ANALYSIS 
 
9.1 Calculation of study numbers 
  
See 4.4. sample size calculation 
We used the Poisson regression model for the power analysis39: 
 
Numeric Results when X1 is Binomial with Proportion = 0,5 And Phi (Over-Dispersion Parameter) = 
1,0000 
                       Mean  R-Squared          
              Sample   Response    Baseline  Exposure  X1 vs       Two-   
              Size        Rate             Rate        Time         Other X's  Sided  
Power      (N)       Ratio            Exp(B0)   (MuT)       (R2)          Alpha        Beta 
0,80000     36       0,5000         2,1000      1,0000      0,0000     0,05000    0,20000 
 
The hypothesis is that prolonged treatment with tobramycin reduces the number of exacerbations per 
patient by 50%. This reduction seems clinical relevant and is based on the assumption that 
maintenance treatment with TIS OD as well as intermittent TIS BID is comparable to that of 
azithromycin treatment. This assumption is derived from the data of the BAT trial (placebo: mean 2,1 
exacerbations (sd 1.6); azithromycin: mean 0,8 exacerbations (sd 1.1))49. The reduction in percentage 
is used for the determination of trial size.  
We used a poisson regression model to determine group size39. For type I error and type II error 0.05 
and 0.2 were used respectively. The hypothesis will be tested two sided. With a baseline exacerbation 
rate of 2.1 in the placebo group and an expected response rate ratio of 0.5 with an exposure time of 1 
year a total of 18 evaluable patients are required to be on each treatment arm.  
With a drop-out percentage of 30% we have to include totally 48 (24 patients per group) patients10;22. 
Due to unforeseen reasons we initially include two extra patients per group. But after the interim 
analysis three extra patients will be included in the study, because the drop-off percentage is higher as 
expected in advance. Reason for discontinuation of the study is the intensive treatment and cleaning 
schedule of the inhaled study medication. So with a total of 58 patients (29 per group) with 
bronchiectasis, and not the initially 52 patients (26 per group), we expect to achieve the intended 
effect size.  
 
 
9.2 Randomisation method  
Randomisation will be done by SPSS, statistics 20 with an allocation ratio of 1:1 between groups. 
Once a number is assigned to a patient, the investigator will open the treatment regimen assignment 
and the subject will receive treatment according to the assigned strategy.  The numbers are 
anonymous dispensed in closed envelopes and stored at department of pulmonary diseases Medical 
Center Alkmaar. The main-investigator will be responsible for maintaining the storage and allocation of 
the envelopes.  
 

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9.3 Analysis populations 
9.3.1 Clinical Intent-To-Treat analysis (ITT) 
All randomized patients with non CF-bronchiectasis will be included in the final ITT-population. 
 
9.3.2 Modified Intent-To-Treat analysis (mITT) 
The patients who are randomised but dropped out from the study directly after the tolerance test due 
to a moderate-severe bronchial obstruction or a severe cough, are excluded from the mITT analysis. 
So the mITT population includes the patients who passed the tolerance test with TIS or placebo 
according to the randomisation. 
 
9.3.3 Per protocol Treatment analysis (PTT) 
All randomized patients who received and completed treatment according to study protocol will be 
included in the per protocol analysis. Patients will be considered as non-evaluable if they do not 
complete a total treatment for at least 9 months. Termination of the study or incomplete data collection 
is also defined as non-evaluable.  
 
9.4 Methods of analysis 
9.4.1 General statistical considerations 
All data will be collected and analysed using SPSS statistics 20.  
Statistical analysis will be performed on an intent-to-treat basis by the investigator and an independent 
statistician. All continuous variables will be tested for normal distribution with the Kolmogorov-Smirnov 
test for normal distribution. The Student-t test will be used for normally distributed variables, the Mann-
Whitney U test for not normally distributed variables and the χ2 test for dichotomous variables. The 
software package SPSS 20 for Windows (IBM-SPSS Inc., Chicago, Illinois, USA) is available for 
statistical analysis. A value of p<0.05 will be considered significant. 
 
9.4.2 Comparison of baseline characteristics  
Baseline comparison of the treatment groups with regard to demographic variables will be compared 
with general used tests.  
 
9.4.3 Primary study parameter(s) 
A poisson regression model was used to analyse the primary outcome measure, evaluating both 
events and exposure (person-time), employing a quasilikelihood factor (with overdispersion 
correction), and incorporating the following covariables: treatment assignment, age, sex, smoking 
history, and presence of P aeruginosa and azithromycin maintenance use at baseline. 
 

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9.4.4 Secondary study parameter(s)  
Time to first exacerbation during the treatment period, as well as during the wash-out period, will be 
assessed using Cox proportional hazards regression and reported graphically using Kaplan-Meier 
estimates. 
Statistical significance in change of FEV1 (percent of predicted) and FVC (percent of predicted) 
attributable to treatment will be calculated with a linear mixed-model analysis. The effect of time on 
outcome variables will be checked for linearity by means of plots and model Proportional hazards 
assumptions will be tested with log-minus-log plots. Time will be entered as an interval variable, with 
the number of intervals depending on the frequency of follow-up visits at which the outcome will be 
measured. Predefined confounders are entered stepwise as fixed effects. Predictors remain in the 
regression equation if the model fit increases significantly. Thereafter, random effects will be explored 
for intercept (patients) and slope (time and patients). If random effects do not change the model fit 
significantly, a fixed effect will be assumed. Change in quality of life was analyzed using linear mixed-
model analysis as well. The minimal important difference (MID) in bronchiectasis was reported only for 
the Quality Of Life-Bronchiectasis questionnaire (QOL-B), with a minimal important difference (MID) 
for the Respiratory symptoms scale of 8 points represent clinical relevance46. The MID for the leicester 
cough questionnaire in chronic cough is 1.3 points in total and represent clinical relevance47. The 
Leicester cough questionnaire was initially developed for patients with chronic cough, but has been 
validated in patients with bronchiectasis. Consequently, the minimal important difference of 1.3 points 
will be used in this study and represent clinical relevance. Secondary to these questionnaires the 
LRTI-VAS questionnaire will be used. This questionnaire is a validated and reliable tool for symptom 
measurement in non-CF bronchiectasis48. 
 
9.4.5 Other study parameters 
Baseline comparison of the treatment groups with regard to demographic variables (such as age, 
gender, number of co-morbidities, smoking, alcohol use, etc.) and time of TIS treatment. These 
parameters will be assessed by using the Student-t test for normally distributed variables, and the 
Mann-Whitney U test for not normally distributed variables.  
 
9.4.6 Interim analysis  
After inclusion and follow up of 50% of the randomized patients an interim analyses will be conducted. 
A poisson regression model  is used for our power analysis; See chapter 9.1.  
The interim analysis is used to calculate the predetermined effect size, and whether more patients 
should be included depending on this effect size. Depending on the frequency of exacerbations at 
baseline and the effect size, a power analyses will be done by using the poisson regression model. 
 
 
 
10.ETHICAL CONSIDERATIONS 
 

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10.1 Regulation statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Conference on Harmonization (ICH) guidelines and the most recent version of the 
Declaration of Helsinki. 
All amendments to the protocol and informed consent forms must be reviewed by the local 
Independent Ethics Committee for approval before being implemented. In the event of any deviation 
from the protocol, the investigator must document the nature of and rationale for the deviation. 
Informed consent must take place prior to any study specific procedure or test. Written signed and 
dated informed consent will be obtained from each subject (or his/her legally acceptable 
representative) in accordance with GCP and with local regulatory and legal requirements. The 
completed informed consent will be retained by the investigator as part of the study records. 
 
10.2 Recruitment and consent 
Patients will be asked to participate in this study by their own physician or the investigator at the time 
of the hospital visit or are contacted by phone. All patients receive the patient information letter and 
informed consent form during this visit or this information will be provided by mail.  
Within one week the patient will be contacted. Any questions will be answered. If the patient is willing 
to participate to the study, an appointment at the outpatient department will be made. During this visit 
informed consent will be signed by both the patient and sub-investigator. 
 
10.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable.  
 
10.4 Benefits and risks assessment, group relatedness 
Low risk study according to the risk-classification as designed by the Dutch Foundation of University 
Medical Centres. The full risk classification (in Dutch) can be found in Appendix 4. 
 
10.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 9 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research 
in Humans of 23th June 2003). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. 
- 
€ 650.000, -- (i.e. zes hundred and fifty thousand Euro) for death or injury for each subject 
who participates in the Research; 
- 
€ 5.000.000, -- (i.e. five million Euro) for death or injury for all subjects who participate in the 
Research;  

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- 
€ 7.500.000, -- (i.e. seven million five hundred thousand Euro) for the total damage incurred 
by the organisation for all damage disclosed by scientific research for the Sponsor as 
‘verrichter’ in the meaning of said Act in each year of insurance coverage. 
 
The insurance applies to the damage that becomes apparent during the study or within 4 years after 
the end of the study. 
 
10.6 Incentives (if applicable)  
Not applicable. 
 
 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
All data will be collected by the researcher on the electronic Case Report Form (e-CRF). The data will 
be entered into a database, where subjects will be assigned a study number. Their personal 
information will not be entered into the database. A separate subject identification list, the Investigator 
Site File, will be kept by the investigator at the study site in case the study data needs to be linked to 
individual subjects.  
All study data will be kept for 15 years. Blood samples and sputum samples will be stored for 3 years.  
 
11.2 Monitoring and Quality Assurance  
The conduct of the study and data entries will be monitored by an external monitor, J. Doodeman. He 
will select a sample of cases and check them for irregularities. If any are found, the monitor may 
choose to select a larger sample or review all available data. He will report the irregularities to the 
sponsor who is responsible for correcting any mistakes.  
All adverse events will be analysed periodically by the statistician of the DSMB. If SAE’s or SUSARs 
are more common in the experimental arm compared to the control arm he will inform the sponsor and 
other members of the DSMB which may then take actions as described in chapter 8.5. All serious 
adverse events will be reported to the accredited METC.  
 
11.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited METC 
has been given. Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor. All amendments will be notified to 
the METC that gave a favourable opinion.  
 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or to the 
protocol or any other supporting documentation, that is likely to affect to a significant degree:  
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 

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- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the competent authority, 
but will be recorded and filed by all other amendments and will be notified to the METC that gave a 
favourable opinion.  
 
11.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse events/ 
serious adverse reactions, other problems and amendments.  
 
11.5 End of study report 
The investigator will notify the accredited METC of the end of the study within a period of 8 weeks. The 
end of the study is defined as the last patient’s last visit.  
In case the study is ended prematurely, the investigator will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final study report with 
the results of the study, including any publications/abstracts of the study, to the accredited METC.  
 
11.6 Public disclosure and publication policy 
The results will be published within a year after completing the study. The study is completed after the 
follow up of a year of the last person. The main article will be published in an international respiratory 
journal with a high impact factor. Due tot the CCMO-guidelines the Sponsor acknowledges the 
importance of public disclosure/publication of information collected or generated by the Institution or 
Principal Investigator, under the condition that public disclosure/publication takes place under the 
provisions of article 8 of the Clinical Trial Agreement, called the onderzoekscontract BATTLE. 
 
 
 

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12. STRUCTURED RISK ANALYSIS  
 
12.1 Potential issues of concern 
 
a. Level of knowledge about mechanism of action  
The vicious cycle hypothesis of bronchiectasis argues that bacterial colonization of the normally sterile 
respiratory tract provokes and perpetuates airway inflammation. According to this hypothesis, if 
bacteria are the primary drivers of airway inflammation, bacterial clearance through the use of short- or 
long-term antibiotic therapy would be expected to reduce airway inflammation, allow airway healing, 
and modify the long-term course of the disease. There is strong evidence from  CF bronchiectasis to 
support this view, with data suggesting that bacterial colonization is associated with airway 
inflammation and that antibiotic treatment during stability and at exacerbation can reduce markers of 
inflammation40-43. Extrapolation from CF to non-CF bronchiectasis is difficult because the 
pathophysiology is different and the failure of recombinant DNase treatment to provide benefit in non-
CF bronchiectasis demonstrates that responses to treatment can be very different in CF compared  
with non-CF bronchiectasis6. Another point of uncertainty is the different pharmacokinetics in CF 
patients particularly for aminoglycosides and b-lactam-antibiotics when compared with normal 
individuals. The higher body clearance due to increased renal and non renal elimination demands that 
higher antibiotic doses are administered more frequently44. However, differences between CF-patients 
and non-CF individuals in this context do not seem to be as large as used to be thought and may have 
been exaggerated by the lack of properly matched controls for clinical studies44. 
However numerous studies in CF patients have shown that TIS has a positive effect on lung function, 
quality of life and in some on the number of exacerbations. There are limited studies evaluating the 
effect of bacterial clearance in non-CF bronchiectasis. From earlier studies we know that bacterial load 
(e.g. P.aeruginosa) can be reduced by TIS. Bacterial killing effects markers of airways and systemic 
inflammation inpatients with bronchiectasis and therefore decreases clinical symptoms such as cough, 
dyspnoea and sputum production. The reduction of these symptoms has a positive effect on the health 
related quality of life. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar biological 
mechanism 
There is tremendous experience with TIS as chronic treatment in CF-patients. In general practice it is 
well tolerated. Only few studies have been performed in non-CF bronchiectasis patients (see section 
6.2 and 6.3). Although not registered, numerous patient are already treated with TIS (TOBI® and 
Bramitob®). These patients are tolerating TIS well and nebulizing this drug seems very effective 
(personal experiences of Dutch pulmonologists). 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell 
material?   
Not applicable. 
 

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d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Not applicable. 
 
e. Analysis of potential effect 
see section 6.1, 6.2 and 6.3. 
 
f. Pharmacokinetic considerations 
see section 6.1 and 6.2. 
 
g. Study population 
non-CF bronchiectasis. 
 
h. Interaction with other products 
Combination with furosemide, ureum or mannitol should be avoided because of potential nephro- 
and/or ototoxicity. Especially, nephrotoxicity may occur in combination with IV prescribed 
aminoglycosides, amphotericin B, cephalosporins, polymyxins, ciclosporin, tacrolimus and platinum 
containing drugs. A combination with botulinetoxine or anticholinesterases (e.g., neostigmine, 
pyridostigmine) may induce a prolonged neuromuscular blockade. 
 
i. Predictability of effect 
Effect can possibly be measured by biomarkers (inflammation), lung function and bacterial load in 
sputum. 
 
j. Can effects be managed? 
Not applicable. 
 
12.2 Synthesis 
Because of the previous experience with TIS in CF patients, but also in non-CF patients there is low 
risk of toxicity. First dose of study drug administered under supervision of study staff may give 
information of the tolerance. A number of safety measurements are included: phone call after one 
week, other outpatient visits, serial laboratory testing, dairy card, and safety checks by the 
independent expert. 
 
 
 
 
 
 
 
 

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 (38)  Neu HC, Bendush CL. Ototoxicity of tobramycin: a clinical overview. J Infect Dis 1976; 134 
Suppl:S206-S218. 
 (39)  Signorini D. Sample size for Poisson regression. Biometrika 1991; 78(2):446-450. 
 (40)  Sagel SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET. Sputum biomarkers of 
inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care 
Med 2012; 186(9):857-865. 
 (41)  Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway inflammation in children with 
cystic fibrosis and healthy children assessed by sputum induction. Am J Respir Crit Care Med 
2001; 164(8 Pt 1):1425-1431. 
 (42)  Downey DG, Brockbank S, Martin SL, Ennis M, Elborn JS. The effect of treatment of cystic 
fibrosis pulmonary exacerbations on airways and systemic inflammation. Pediatr Pulmonol 
2007; 42(8):729-735. 
 (43)  Downey DG, Martin SL, Dempster M, Moore JE, Keogan MT, Starcher B et al. The 
relationship of clinical and inflammatory markers to outcome in stable patients with cystic 
fibrosis. Pediatr Pulmonol 2007; 42(3):216-220. 
 (44)  Doring G, Conway SP, Heijerman HG, Hodson ME, Hoiby N, Smyth A et al. Antibiotic therapy 
against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 
2000; 16(4):749-767. 
 
 (45)  Orriols R, Rosana Hernando, Adelaida Ferrer, Sonia Terradas, Bruno Montoro. Eradication 
Therapy againgst Pseudomonas aeruginosa in Non-Cystic Fibrosis Bronchiectasis. Respir J 
2015;90:299-305. 
 
 (46) Quittner AL, O'Donnell AE, Salathe MA, Lewis SA, Li X, Montgomery AB, O'Riordan TG, 
Barker AF. Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and 
determination of minimal important difference scores. Thorax. 2015 Jan;70(1):12-20. doi: 
10.1136/thoraxjnl-2014-205918.  
 
 (47) Arietta Spinou, Konstantinos C Fragkos, Kai K Lee, Caroline Elston, Richard J Siegert, 
Michael R Loebinger, Robert Wilson, Rachel Garrod, Surinder S Birring. The validity of health-
related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis 
Thorax 2016 doi:10.1136/thoraxjnl-2015-207315. 
 

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 (48) Altenburg J, Wortel K, de Graaff CS, et al. Validation of a visual analogue score (LRTI-VAS) in 
non-CF bronchiectasis. Clin Respir J 2014. Published Online First: 8 Aug 2014. 
doi:10.1111/crj.12198  
 
 (49) Altenburg, de Graaff CS, Wim G. Boersma et al. Effect of AzithromycinMaintenance 
Treatment on Infectious Exacerbations Among Patients With Non–Cystic Fibrosis 
Bronchiectasis. The BAT Randomized Controlled Trial. JAMA. 2013 Mar 27;309(12):1251-9.   
 
 
 
 
 
Appendix 1. Lower Respiratory Tract Infection Visual Analogue Scale (LRTI-
VAS) -Dutch edition- 
 
KLACHTEN SCHAAL        Randomisatie nr.   
DAG:                                                                  
  Naam:               
 
Zet a.u.b. een kruisje op de volgende lijnen: 
 
1. 
KORTADEMIGHEID 
 
 
 
2.  
VERMOEIDHEID 
 
 
 
3. 
HOEST 
 
 
 
4.     WAT VOOR SPUTUM GEEFT U OP? 
 
 
 
5. 
PIJN 
 
 
 
Ik heb de ergst 
denkbare 
kortademigheid 
Ik ben 
helemaal 
niet 
kortademig 
Ik ben 
helemaal 
niet moe 
Ik heb de ergst 
denkbare 
moeheid 
Ik heb de ergst 
denkbare 
hoest
Ik hoest 
helemaal 
niet 
Donker groen  
sputum 
Wit sputum 

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Appendix 2. Leicester Cough Questionnaire -Dutch edition- 
 
 
 
 
 
 
 
 
 
HOEST VRAGENLIJST  
Deze vragenlijst is ontworpen om de gevolgen van het hoesten op diverse aspecten van uw leven 
te meten. Lees iedere vraag aandachtig en OMCIRKEL het antwoord dat de afgelopen twee 
weken het meest op u van toepassing is (slechts één antwoord per vraag). Beantwoord a.u.b. alle 
vragen, en zo eerlijk mogelijk. 
 
In de afgelopen twee weken… 
altijd  
meesta
l  
heel 
vaak  
regelm
atig 
af en 
toe 
zelden 
nooit 
1. 
had u door het hoesten 
last  van pijn op de 
borstkas of in de maag? 
1 
2 
3 
4 
5 
6 
7 
2. 
had u door het hoesten 
last van slijm 
ophoesten? 
1 
2 
3 
4 
5 
6 
7 
3. 
bent u door het hoesten 
vermoeid geraakt? 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
 
 
 
 
In de afgelopen twee weken… 
nooit 
zelden 
af en 
toe 
regelm
atig 
heel 
vaak 
meesta
l 
altijd 
4. 
had u het idee het 
hoesten onder controle 
te hebben? 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
 
 
 
 
In de afgelopen twee weken… 
altijd  
meesta
l  
heel 
vaak  
regelm
atig 
af en 
toe 
zelden 
nooit 
5. 
hoe vaak schaamde u 
zich voor het hoesten? 
1 
2 
3 
4 
5 
6 
7 
6. 
werd u ongerust door 
het hoesten? 
1 
2 
3 
4 
5 
6 
7 
7. 
verstoorde het hoesten 
uw werk of andere 
dagelijkse bezigheden? 
1 
2 
3 
4 
5 
6 
7 
8. 
bemerkte u dat het 
hoesten het plezier in 
het leven vergalde? 
1 
2 
3 
4 
5 
6 
7 
9. 
moest u hoesten van 
verflucht of andere 
prikkelende luchtjes? 
1 
2 
3 
4 
5 
6 
7 
Ik heb de ergst 
denkbare pijn 
Geen pijn 
Naam: 
 
Geboortedatum 
 
Bezoeknummer: 
 
Datum:

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10. 
hoe vaak werd uw 
nachtrust verstoord door 
het hoesten? 
1 
2 
3 
4 
5 
6 
7 
11. 
hoe vaak hoestte u op 
een dag? 
1 
2 
3 
4 
5 
6 
7 
12. 
voelde u zich 
gefrustreerd door het 
hoesten 
1 
2 
3 
4 
5 
6 
7 
13. 
was u het hoesten zat? 
1 
2 
3 
4 
5 
6 
7 
In de afgelopen twee weken… 
altijd  
meesta
l  
heel 
vaak  
regelm
atig 
af en 
toe 
zelden 
nooit 
14. 
was u hees door het 
hoesten? 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
 
 
 
 
In de afgelopen twee weken… 
nooit 
zelden 
af en 
toe 
regelm
atig 
heel 
vaak 
meesta
l 
altijd 
15. 
zat u vol energie? 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
 
 
 
 
In de afgelopen twee weken… 
altijd  
meesta
l  
heel 
vaak  
regelm
atig 
af en 
toe 
zelden 
nooit 
16. 
was u bezorgd dat uw 
hoest door een ernstige 
ziekte veroorzaakt 
werd? 
1 
2 
3 
4 
5 
6 
7 
17. 
was u bezorgd dat 
anderen dachten dat u 
wat ernstigs mankeerde, 
door uw hoesten? 
1 
2 
3 
4 
5 
6 
7 
18. 
verstoorde uw hoest uw 
praten of een 
telefoongesprek? 
1 
2 
3 
4 
5 
6 
7 
19. 
meende u dat het 
hoesten vervelend is 
voor uw partner, familie 
of vrienden? 
1 
2 
3 
4 
5 
6 
7 
Gebaseerd op de Leicester Cough Questionnaire © Birring 
 
 
 
 

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Appendix 3.  Quality of Life Questionnaire Bronchiectasis (QOL-B) -Dutch 
edition- 
 

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Appendix 4. Risico-classificatie investigator initiated onderzoek -Dutch edition- 
 
 

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