Double-blind, Placebo-controlled, Clinical Trial on Efficacy and Safety of 12-months Therapy With Inhaled Colistimethate Sodium in the Treatment of Subjects With Non-cystic Fibrosis Bronchiectasis Chronically Infected With P. Aeruginosa
Phase: PHASE3
Conditions: Non Cystic Fibrosis Bronchiectasis
Sponsor: Zambon SpA

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CLINICAL TRIAL PROTOCOL
A DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTRE, 
CLINICAL TRIAL TO INVESTIGATE THE EFFICACY AND SAFETY OF 12 
MONTHS OF THERAPY WITH INHALED COLISTIMETHATE SODIUM IN 
THE TREATMENT OF SUBJECTS WITH NON-CYSTIC FIBROSIS 
BRONCHIECTASIS CHRONICALLY INFECTED WITH PSEUDOMONAS 
AERUGINOSA (P. AERUGINOSA) 
Protocol Code 
Z7224L01 
Protocol Name  PROMIS I 
EudraCT Number  2015-002743-33 
Final Date 
22 Oct 2019 
Version Final 7.0 
Zambon SpA 
Via Lillo del Duca 10 
20091 Bresso - Milan – Italy 
THIS DOCUMENT IS ZAMBON'S SOLE PROPERTY AND OWNERSHIP. THIS 
DOCUMENT, AND ALL INFORMATION AND DATA CONTAINED HEREIN HAS TO BE 
CONSIDERED AND TREATED AS STRICTLY CONFIDENTIAL. THIS DOCUMENT SHALL 
BE USED ONLY FOR THE PURPOSE OF THE DISCLOSURE HEREIN PROVIDED. NO 
DISCLOSURE OR PUBLICATION SHALL BE MADE WITHOUT THE PRIOR WRITTEN 
CONSENT OF ZAMBON.  

Z7224L01 
APPROVAL PAGE 
Protocol Title: A double-blind, placebo-controlled, multi-centre, clinical trial to 
investigate the efficacy and safety of 12 months of therapy with inhaled 
colistimethate sodium in the treatment of subjects with non-cystic fibrosis 
bronchiectasls chronically infected with Pseudomonas aeruginosa (P. 
aeruginosa) 
Protocol Name: PROMIS I 
Protocol Code: Z7224L01 
Protocol Version and Date: Version 7.0; 22 Oct 2019 
EudraCT number: 2015-002743-33 
Author: 
, Zambon S.p.A. 
Sponsor Name and Address: Zambon S.p.A. 
Via Lillo del Duca 10 
20091 Bresso - Milan - Italy 
As agreed and approved by: 
Date (dd/mmNYYY) 
Dr. 
, Open 
R&D Global Head 
23 1 cc..~~.___ ________ 
_ 
Date (dd/mmNYYY) 
Final v.7.0, Date 22/0cU2019 
SOP C.03.02.06 - App. 1 
, Clinical 
Development Manager/Project 
Lead 
SIGNATURE 
SIGNATURE 
Page 2 of 61 
PPD
PPD
PPD
PPD
PPD

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ZAMBON CONTACT DETAILS 
Zambon S.p.A  
Via Lillo del Duca 10 
20091 Bresso - Milan (Italy) 
Phone: +39 02 665241 
Email: clinicaltrials@zambongroup.com 
Role 
Name 
Contact Data 
Medical Advisor 
 
 
 
CONTRACT RESEARCH ORGANISATION CONTACT DETAILS 
 
  
 
 
United States of America 
 
 
Role 
Name 
Contact Data 
Medical Monitor 
 
 
 
 
 
Contact for serious adverse 
event/pregnancy reporting 
 
 
 
 
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PPD
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OTHER INSTITUTIONS 
Role 
Name 
Contact Data 
Central Laboratory 
 
 
 
 
 
 
 
The Netherlands 
 
 
  
 
 
 
Singapore 
 
 
 
Electronic Patient Reported 
Outcome (eCOA) 
 
 
 
United Kingdom 
 
 
 
 
 
 
United States of America 
 
Interactive Web Response 
System (IWRS) 
 
 
 
Belgium 
 
Electronic Data Capture  
 
 
 
 
United Kingdom 
 
Investigational Medicinal 
Product (IMP) Packaging and 
Labelling; Logistics 
 
  
  
United Kingdom. 
 
 
 
 
Singapore, 
 
  
 
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Role 
Name 
Contact Data 
 nebuliser and 
 
Software 
 
 
  
  
 
United Kingdom 
 
 data analyser/I-
 
software 
 
 
 
 
West Sussex 
 
 
LIST OF COMMITTEES  
Not applicable.  
 
 
 
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SUMMARY OF CHANGE HISTORY 
Protocol Version 
Key Changes 
Protocol Version Final v.4.0; 18 Nov 2016 
The Protocol Versions from 1.0 to 3.0 were internal 
versions and were not submitted. Version 4.0 is the 
final version that was submitted to CAs in Europe. 
Protocol version Final v 4.1: 31 Jan 2017 (UK only) 
Amendment made to reflect changes requested by 
The East of England – Cambridge East Research 
Ethics Committee  
1. Section 8.2.2: detail on the need for contraceptive 
precautions/use of condoms/not taking part in 
sperm donation for male participants with female 
partners of child-bearing potential was added. 
2. Section 17.10: a longer follow-up period for 
pregnancy outcomes was added.  
Protocol Version Final v.4.1; 03 July 2017 (Portugal 
only) 
After the revision of the protocol by the CA in 
Portugal two sections of the protocol (Summary: 
Exclusion Criteria and Section 8.2.2 Exclusion 
Criteria) were modified to accommodate the request 
to 
adequately 
characterize 
the 
“severe 
cardiovascular disease” to be considered. 
Protocol Version Final v.5.0; 17 April 2018 
Global 
harmonization: 
protocol 
revised 
to 
harmonize the changes requested by EU EC/CAs 
and the second pivotal Phase 3 protocol (PROMIS 
II) following requests received from the US Food 
and Drug Administration (FDA) in particular 
regarding the endpoints and statistical analysis. The 
primary endpoint was amended to two co-primary 
endpoints of frequency of pulmonary exacerbations 
and number of exacerbation-free days, with a 
subsequent increase in sample size and number of 
countries/sites. 
Other 
comments 
were 
addressed 
and 
the 
opportunity has been taken to standardize and re-
format sections accordingly. In addition, any 
ambiguities in the text were amended for 
clarification purposes. 
Protocol Version Final v.6.0; 11 Dec 2018 
Protocol modified following agreement with the FDA 
during a Type C Meeting held on 31 Oct 2018 to 
revert to a single primary endpoint of frequency of 
pulmonary exacerbations, with 
 
 being included as a secondary endpoint, and 
(for Promis II) reducing the duration of the treatment 
period to 12 months. 
For additional information, please refer to the 
Summary of Key Changes document associated 
with this protocol version. 
Protocol Version Final v.7.0; 22 Oct 2019 
Amendment to reflect the transition in Contract 
Research 
Organisation 
from
 
 to 
 and amending the contact details 
accordingly. 
For additional information, including amendments 
to clarify inclusion and exclusion criteria, please 
refer to the Summary of Key Changes document 
associated with this protocol version. 
 
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TABLE OF CONTENTS 
 
APPROVAL PAGE ............................................................................................................ 2 
ZAMBON CONTACT DETAILS ......................................................................................... 3 
CONTRACT RESEARCH ORGANISATION CONTACT DETAILS ..................................... 3 
OTHER INSTITUTIONS ..................................................................................................... 4 
LIST OF COMMITTEES ..................................................................................................... 5 
Table of Contents .............................................................................................................. 7 
1. 
Abbreviations ......................................................................................................... 10 
2. 
Summary ............................................................................................................... 12 
3. 
Introduction and Rationale ..................................................................................... 16 
3.1. 
Evaluation of the Anticipated Risk/Benefit Ratio ............................................. 19 
4. 
Objectives .............................................................................................................. 20 
5. 
Ethics Requirements .............................................................................................. 20 
6. 
Design and Duration of the Clinical Trial ................................................................ 20 
6.1. 
Clinical Trial Design ........................................................................................ 20 
6.2. 
Duration of Clinical Trial .................................................................................. 21 
7. 
Clinical Trial Population ......................................................................................... 22 
7.1. 
Number of Subjects ......................................................................................... 22 
7.2. 
Selection of Subjects ....................................................................................... 22 
7.2.1. Inclusion Criteria .......................................................................................... 22 
7.2.2. Exclusion Criteria ......................................................................................... 22 
8. 
Overall Clinical Trial Schedule ............................................................................... 24 
8.1. 
Visit 1 - Screening Visit (Within 30 Days of Visit 2) ......................................... 24 
8.2. 
Visit 2 - Randomisation Visit (Day 0) ............................................................... 25 
8.3. 
Visit 3 (Day 28 ± 1 Week) ................................................................................ 25 
8.4. 
Visit 4 (3 Months ± 1 Week) to Visit 6 (9 Months ± 1 Week), inclusive ............ 26 
8.5. 
Visit 7 (12 Months ± 1 Week); End of treatment .............................................. 27 
8.6. 
Follow-up Phone Call (2 weeks ± 3 days after end of treatment) .................... 28 
8.7. 
Exacerbation Visit/Contact .............................................................................. 28 
9. 
Methodology .......................................................................................................... 29 
9.1. 
Methods of Assessment .................................................................................. 29 
9.1.1. Demography and Medical History ................................................................ 29 
9.1.2. Physical Examination ................................................................................... 29 

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9.1.3. Vital Signs .................................................................................................... 29 
9.1.4. Laboratory Evaluations ................................................................................ 30 
9.1.5. Efficacy Evaluations ..................................................................................... 31 
9.1.6. Safety Evaluations ....................................................................................... 33 
9.2. 
Adherence with IMP Dosing Regimen ............................................................. 35 
9.3. 
Pharmacodynamics ......................................................................................... 35 
9.4. 
Pharmacokinetics ............................................................................................ 35 
10. 
Prior and Concomitant Treatments ........................................................................ 35 
10.1. 
Rescue Medication .......................................................................................... 36 
11. 
Investigational Medicinal Product .......................................................................... 37 
11.1. 
Investigational Medicinal Product Supplies and Packaging ............................ 37 
11.2. 
Investigational Medicinal Product Dispensing and Administration ................... 37 
11.3. 
Randomisation ................................................................................................ 38 
11.4. 
Investigational Medicinal Product Accountability ............................................. 39 
12. 
Clinical Trial Amendments ..................................................................................... 39 
13. 
Deviations from the Clinical Trial Protocol ............................................................. 39 
13.1. 
Code Breaking ................................................................................................ 40 
14. 
Clinical Trial Withdrawals/Drop-outs ...................................................................... 40 
15. 
Stopping and Discontinuation Criteria for the Trial ................................................. 41 
16. 
Reporting Safety Information ................................................................................. 41 
16.1. 
Definition of Adverse Event ............................................................................. 41 
16.2. 
Definition of Adverse Event of Special Interest ............................................... 41 
16.3. 
Definition of Adverse Drug Reaction ............................................................... 42 
16.3.1. 
Definition of Unexpected Adverse Drug Reaction ..................................... 42 
16.3.2. 
Definition of Medical Device Malfunction and Incident .............................. 42 
16.4. 
Definition of Serious Adverse Events or Serious Adverse Drug Reactions ..... 42 
16.4.1. 
Definition of Serious Adverse Event or Serious Adverse Reaction ........... 42 
16.4.2. 
Definition of Suspected Unexpected Serious Adverse Reactions ............. 43 
16.5. 
Definition of Severity of Adverse Events ......................................................... 43 
16.6. 
Definition of Adverse Event Causality ............................................................. 43 
16.7. 
Adverse Event Recording ................................................................................ 44 
16.8. 
Adverse Event Reporting ................................................................................ 44 
16.8.1. 
Reporting Serious Adverse Events ........................................................... 44 
16.8.2. 
Reporting Adverse Events of Special Interest .......................................... 44 
16.9. 
Follow-up for Adverse Events ......................................................................... 45 
16.10. Pregnancy ....................................................................................................... 45 
17. 
Records ................................................................................................................. 45 
17.1. 
Case Report Forms, Source Data and Query Resolution ............................... 45 
17.2. 
Records Maintained by the Investigator .......................................................... 46 

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17.3. 
Trial Master File .............................................................................................. 46 
17.4. 
Trial Monitoring ............................................................................................... 46 
17.5. 
Confidentiality of Subject’s Information ........................................................... 46 
18. 
Biometrics .............................................................................................................. 47 
18.1. 
Data Management ........................................................................................... 47 
18.2. 
Study Variables ............................................................................................... 47 
18.3. 
Sample Size .................................................................................................... 48 
18.4. 
Statistical Analyses ......................................................................................... 49 
18.4.1. 
Trial Populations ....................................................................................... 49 
18.4.2. 
Efficacy Data ............................................................................................ 50 
18.4.3. 
Safety Data ............................................................................................... 52 
18.4.4. 
Handling of Missing Data .......................................................................... 54 
19. 
Informed Consent .................................................................................................. 54 
20. 
Ethics Committee Approval.................................................................................... 55 
21. 
Regulatory Requirements ...................................................................................... 55 
22. 
Quality Assurance .................................................................................................. 55 
23. 
Insurance ............................................................................................................... 55 
24. 
Clinical Trial Report ............................................................................................... 56 
25. 
Use of Information and Publication ........................................................................ 56 
26. 
References ............................................................................................................ 57 
27. 
Appendices ............................................................................................................ 59 
 
 
 
 

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1. ABBREVIATIONS 
  
  
ABPA 
Allergic bronchopulmonary aspergillosis 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP                   Alkaline phosphatase 
ALT                   Alanine aminotransferase 
AST                  Aspartate aminotransferase 
BUN 
Blood Urea Nitrogen 
CA 
Competent authority  
CBA                  Colistin Base Activity 
CF 
Cystic fibrosis 
CFU 
Colony forming units 
CI 
Confidence interval 
COPD 
Chronic obstructive pulmonary disease 
CRO 
Contract research organisation 
CT 
Computerised tomography 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
EC 
Ethics Committee 
ECG                  Electrocardiogram 
eCRF 
Electronic case report form 
eCOA 
Electronic  clinical outcome assessment 
EU 
European Union 
FAS 
Full analysis set 
FDA                  Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FOE                  Frequency Of Exacerbation 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT                  Gamma-Glutamyl transferase 
GLI                    Global Lung Function Initiative reference equations  
GMP  
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HRCT                High-resolution Computerised Tomography 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational medicinal product  
ITT 
Intention-to-treat 
IU 
International Unit 
IWRS 
Interactive web response system 
MedDRA  
Medical Dictionary for Regulatory Activities 
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MIC                   Minimum Inhibitory Concentration 
mITT                  modified Intention-to-treat 
MIU 
Million International Unit 
NCFB                Non-CF-Bronchiectasis 
NTM                  Non-Tuberculous Mycobacterial 
P. aeruginosa Pseudomonas aeruginosa 
PP 
Per-protocol population 
Q2                     Quarter two 
Q4 
Quarter four 
 
 
 
 
RAN 
Randomised population 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
 
 
SmPC 
Summary of product characteristics  
SOPs 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TMF 
Trial master file 
WHO-DD  
World Health Organization-Drug Dictionary  
 
 
 
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2. SUMMARY 
 
Title: 
 
A double-blind, placebo-controlled, multi-centre, clinical trial to investigate 
the efficacy and safety of 12 months of therapy with inhaled colistimethate 
sodium in the treatment of subjects with non-cystic fibrosis bronchiectasis 
chronically infected with Pseudomonas aeruginosa (P. aeruginosa) 
Protocol Code/Name: 
Z7224L01/Promis I 
Eudract Number: 
2015-002743-33 
Phase: 
III 
Test Product: 
Colistimethate sodium (Promixin®/Tadim®) – powder for nebuliser solution 
vials. 
Powder 1 million IU (approximately equivalent to 80 mg of colistimethate 
sodium/33 mg colistin base activity); vehicle 0.45% sodium chloride 
(saline) solution. 
Control Product/Placebo: 
Matching vial and 0.45% sodium chloride (saline) solution.  
Dosage: 
Subjects will administer the investigational medicinal product (IMP) twice 
daily (morning and evening) via the 
 
 Aerosol Delivery 
 System. 
The content of the vial is reconstituted with 1 mL of 0.45% sodium chloride 
(saline) solution and 1 mL of the medication placed in the
 device to 
fill the 0.3 mL nebulisation chamber to give a delivered dose of 10 mg 
colistin base activity (CBA). 
Objective: 
The primary objective of the trial is to investigate the effect of the use of 
inhaled colistimethate sodium, administered twice daily via the 
 for 
12 months, compared to placebo in subjects with non–cystic fibrosis 
bronchiectasis (NCFB) chronically infected with P. aeruginosa on the 
frequency of pulmonary exacerbations. 
Key secondary objectives are: 
 
 
 
Design: 
Randomised, multi-centre, double-blind, placebo-controlled, parallel 
group trial. 
Subjects will be randomised to active or placebo in a 1:1 ratio. 
The study will consist of a total of 7 clinic visits with a follow-up phone call 
two weeks after discontinuation of treatment. Additional clinic visits, where 
feasible, and weekly phone calls will be conducted following pulmonary 
exacerbations until resolution. 
Number of patients: 
A total of 420 patients will be randomised to have 340 completed patients 
(170 for each treatment group). 
Trial duration: 
First subject in to last subject out: Q2 2017 to Q4 2020, inclusive. 
Duration of patient 
participation: 
Screening period up to 30 days, followed by 12 months treatment duration 
and a follow-up phone call two weeks after discontinuation of treatment. 
Participation Countries: 
Number of estimated countries: 15 
Number of Sites: 
Approximately 100 
Sample Size: 
A total of 420 randomised patients (210 per group) is foreseen assuming 
a withdrawal rate of approximately 20%, to achieve a total number of 
completed patients of 170 per group. For the primary endpoint of 
frequency of exacerbation (FOE), and a Poisson regression allowing for 
over-dispersion for FOE, with a two-sided significance level of 0.05, a 
treatment effect of 35% and a follow-up time of 1 year, with an FOE of 
1.09 in the placebo group, this sample size will provide a power of 90%. 
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If the treatment difference effect size is 30% between the colistimethate 
sodium and placebo groups, the power with 170 completed patients per 
group will be 80%. 
Population: 
Inclusion Criteria:  
Subjects are eligible if they:  
1. are able and willing to give informed consent following a detailed 
explanation of participation in the protocol and signed consent 
obtained; 
2. are aged 18 years or older of either gender; 
3. are diagnosed with NCFB by computerised tomography (CT) or high 
resolution CT (HRCT) as recorded in the subject’s notes and this is 
their predominant condition being treated; 
4. had at least 2 NCFB pulmonary exacerbations requiring oral or 
inhaled antibiotics or 1 NCFB pulmonary exacerbation requiring 
intravenous antibiotics in the 12 months preceding the Screening Visit 
(Visit 1) and had no NCFB pulmonary exacerbation with or without 
treatment during the period between Visit 1 and Visit 2; 
5. have a documented history of P. aeruginosa infection; 
6. are clinically stable and have not required a change in pulmonary 
treatment for at least 30 days before the Screening Visit (Visit 1); 
7. have pre-bronchodilator FEV1 ≥25% of predicted; 
8. had a positive sputum culture for P. aeruginosa from an adequate 
sample taken at the Screening Visit (Visit 1) or during the screening 
period.  
Exclusion Criteria:  
Subjects are not eligible if they have/are: 
1. known bronchiectasis as a consequence of cystic fibrosis (CF); 
2. known history of hypogammaglobulinaemia requiring treatment with 
immunoglobulin, unless fully replaced and considered immuno-
competent by the Investigator; 
3. myasthenia gravis or porphyria;  
4. severe cardiovascular disease such as severe uncontrolled 
hypertension, ischaemic heart disease or cardiac arrhythmia and any 
other conditions that would confound the evaluation of safety, in the 
opinion of the Investigator; 
5. had  major surgery in the 3 months prior to the Screening Visit (Visit 
1) or planned inpatient major surgery during the study period; 
6. receiving treatment for allergic bronchopulmonary aspergillosis 
(ABPA); 
7. had massive haemoptysis (greater than or equal to 300 mL or 
requiring blood transfusion) in the preceding 4 weeks before the 
Screening Visit (Visit 1) or between Visit 1 and Visit 2; 
8. respiratory failure that would compromise patient safety or confound 
the evaluation of safety or efficacy of the study in the opinion of the 
Investigator; 
9. current active malignancy, except for basal cell carcinoma or 
squamous cell carcinoma of the skin without metastases; 
10. taking immunosuppressive medications (such as azathioprine, 
cyclosporine, tacrolimus, sirolimus, mycophenolate, rituximab), 
and/or anti-cytokine medications (such as anti-IL-6 and anti-tumour 
alpha necrosis factor products) in the preceding year before the 
Screening Visit (Visit 1);  
11. known history of human immunodeficiency virus (HIV); 
12. current treatment for non-tuberculous mycobacterial (NTM) lung 
disease or tuberculosis; 
13. known or suspected to be allergic or unable to tolerate colistimethate 
sodium (intravenous or inhaled) or other polymixins, including 
previous evidence of bronchial hyper-reactivity following inhaled 
colistimethate sodium; 

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14. treatment with long term (≥ 30 days) prednisone at a dose greater 
than 15 mg a day (or equivalent dose of any other corticosteroid) 
within 6 months of the Screening Visit 1 (Visit 1); 
15. new maintenance treatment with any oral macrolides (e.g. 
azithromycin/erythromycin/clarithromycin) started within 30 days of 
the Screening Visit (Visit 1) or started between Visit 1 and Visit 2; 
16. use of any intravenous or intramuscular or oral or inhaled anti-
pseudomonal antibiotic (except chronic oral macrolide treatment with 
a stable dose) within 30 days prior to the Screening Visit (Visit 1) and 
between Visit 1 and Visit 2; 
17. pregnant or breast feeding or plan to become pregnant over the next 
year or of child-bearing potential and unwilling to use a reliable 
method of contraception for at least one month before randomisation 
and throughout their involvement in the trial; 
18. significant abnormality in clinical evaluations and/or laboratory tests 
(physical examination, vital signs, haematology, clinical chemistry, 
clinically relevant impaired renal function, defined as serum creatinine 
levels ≥2.0x upper limit of normal, ECG) endangering the safe 
participation of the patient in the study at the Screening Visit (Visit 1) 
and during the study; 
19. participated in another investigational, interventional trial within 30 
days prior to the Screening Visit (Visit 1); 
20. in the opinion of the Investigator not suitable for inclusion for whatever 
reason. 
Outcome measures: 
Primary Efficacy Variable: 
Mean annual pulmonary exacerbation rate. 
 
Secondary Efficacy Variables: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Variables: 
• 
incidence of treatment emergent adverse events (TEAEs); 
• 
absolute changes in percent-predicted FEV1 from baseline to 
each post-baseline visit; 
• 
number of subjects experiencing bronchospasm clinically or 
spirometrically determined following IMP administration; 
• 
 as determined by in-
vitro 
 
 
 
from 
Screening/Randomisation (Visit 1/Visit 2) to Visits 3, 5 and end of 
treatment (Visit 7) as well as on 
 from Exacerbation Visits 
and clinic visits due to pneumonia;  
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• 
from Screening (Visit 1) to End of Treatment 
(Visit 7); 
• 
haematology, clinical chemistry and renal function tests; 
• 
physical examination and vital signs data; 
• 
12-lead electrocardiogram. 
Statistical Analysis 
Primary analyses will be performed on the modified intention-to-treat 
(mITT) population with exclusions from the ITT defined and justified in the 
Statistical Analysis Plan (SAP). A supportive analysis will be conducted 
using a per-protocol (PP) population excluding subjects with major 
protocol deviations. 
Annual pulmonary exacerbation rates will be compared between 
treatment groups using a Poisson regression model allowing for over-
dispersion and also considering pooled site, use of stable concomitant 
therapy with oral macrolides and pulmonary exacerbation frequency in the 
12 months preceding Visit 2 as covariates.  
The primary analyses detailed above will be a comparison of 
colistimethate sodium against placebo at the end of the 12-month, double-
blind phase. Full details will be provided in the SAP. 
The secondary variable of the 
 
will be analysed using a log-rank test 
comparing two survival curves. The number of 
 will 
be analysed using an appropriate non-parametric test. 
The number of 
 will also be analysed 
using a binomial regression model. The absolute changes in
1 and the
 
 will be presented separately. 
 scores 
 will be analysed using linear 
mixed models.  
An analysis of covariance model on log10 transformed values fitting 
baselines will be used to compare 
 between 
treatment groups. 
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3. INTRODUCTION AND RATIONALE 
Background  
Bronchiectasis is a debilitating pathologic condition of the lung characterised by chronic 
inflammation, wall thickening and dilatation of the airways. Impaired mucociliary clearance 
renders the lungs susceptible to chronic infection which leads to chronic airway 
inflammation, progressive obstruction of the small airways and bronchial wall destruction 
[1]. 
To date, this vicious cycle of inflammation and infection is considered to arise from a 
number of causes either inherited or acquired. Thus, bronchiectasis is a final pathology 
emerging from a number of potential causes, which may require their own specific 
treatment. 
The most common inherited cause of bronchiectasis in Caucasian populations is cystic 
fibrosis (CF); however, there is increasing recognition of significant numbers of subjects 
presenting with bronchiectasis from a variety of causes [2]. 
In non-CF bronchiectasis (NCFB), subjects show symptoms of chronic cough, increased 
sputum production, dyspnoea and malaise [3, 4], which may occur following infection or 
toxic insult due to immune deficiency or excessive immune response after e.g. allergic 
bronchopulmonary aspergillosis (ABPA). Evidence for the disease can be sought 
radiologically via computerised tomography (CT), scanning the lungs for thickening and 
dilatation of the bronchi in subjects for whom CF has been reasonably excluded with sweat 
testing and / or genetic analysis.  
Reviews of NCFB reported a prevalence of bronchiectasis ranging from 4.2/100,000 for 
persons aged 18 to 34 years to 271.8/100,000 for those aged ≥75 years [5].  
Further, prevalence was higher among women than men at all ages and also much higher 
in poor countries where it is a major cause of morbidity and mortality [6]. 
The airways of subjects with NCFB commonly become chronically infected with bacteria, 
the most common being Haemophilus influenzae, Staphylococcus aureus, Streptococcus 
pneumoniae and Pseudomonas aeruginosa (P. aeruginosa). P. aeruginosa is associated 
with worsening of symptoms and disease status.  
A meta-analysis of 21 observational cohort studies with 3,683 NCFB patients [7] showed 
that chronic infection with P. aeruginosa was associated with a 6.6-fold increase in the rate 
of hospitalisation and a 3.0-fold increase in mortality compared with adult NCFB patients 
without chronic infection with P. aeruginosa.  
However, there is no conclusive data in the literature on whether the presence of P. 
aeruginosa is correlated with accelerated decline of lung function [8] or not [9]. 
 
Treatment 
Treatment approaches include a variety of pharmacotherapies, airway clearance and in 
selected cases surgery [3, 4].  
Generally, therapy aims to either treat the underlying cause or the already established 
bronchiectasis. 
Airway clearance techniques including postural drainage, active cycle breathing technique 
and chest wall percussion, have been used for many years to increase mucociliary 
clearance together with prevention of mucus retention and mucus plug formation. It allows 
a subject to expectorate sputum at a convenient time. However, evidence through 
controlled studies is limited to prove its objective usefulness in terms of disease 
modification or survival [3, 4]. 
Usage of mucolytics in NCFB is controversial. Human DNase does not appear to be as 
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pulmonary exacerbation and hospitalisation rates and antibiotic use [10]. Other approaches 
enhancing airway clearance and sputum yield include the use of osmotic agents like 
nebulised hypertonic saline and inhalation of dry powder mannitol. 
A wide range of antibiotic therapies is used in the management of bronchiectasis. They are 
either given as treatment for acute pulmonary exacerbations, generally administered orally, 
or as prophylactic long-term treatment (oral or nebulised) aiming to disrupt the vicious cycle 
of infection and inflammation. However, to penetrate scarred, thickened airway walls in 
bronchiectasis, normally high oral doses of antibiotics are required. To avoid such high 
doses, which potentially result in unacceptable side-effects, the nebulised route has been 
employed to achieve sufficient drug concentrations in the bronchial walls and their 
secretions. 
Studies of inhaled antibiotics for the prevention of pulmonary exacerbations have yielded 
mixed results and none of these antibiotics is currently approved for this indication [11, 12, 
13, 14, 15.]. 
 
Trial Rationale  
To date, no therapies have been shown to cure or to reverse the progression of the disease.  
In 2010, the British Thoracic Society published guidelines for the management of patients 
with NCFB [16]. The guidance recommends treating patients with NCFB, who are infected 
with P. aeruginosa, with chronic inhaled anti-pseudomonal antibiotics, namely gentamicin, 
tobramycin or colistimethate sodium.  
More recently, the European Respiratory Society has published similar guidelines [17]. The 
European Respiratory Society guidelines were developed by an international 
multidisciplinary team of medical experts and NCFB patients. The first goal of the 
management of bronchiectasis specified by this group is the reduction of pulmonary 
exacerbations. Acute pulmonary exacerbations should be treated with 14 days of 
antibiotics. European Respiratory Society guidelines suggest long-term treatment with an 
inhaled antibiotic for adults with NCFB and chronic P. aeruginosa infection and the currently 
available evidence supports continuous use of nebulised colistin or gentamicin. There are 
no official guidelines for the treatment of NCFB patients in the US. 
Colistimethate sodium is an antibacterial cationic cyclic polypeptide belonging to the 
polymyxin group; it is currently approved in Europe for both intravenous and inhaled 
administration and in the US for intravenous administration. In Europe, colistimethate 
sodium has been extensively used in clinical practice for over 30 years via the inhaled 
administration route, for the treatment of colonisation and infections of the lung by 
susceptible P. aeruginosa in patients with CF. The approved injectable forms of 
colistimethate sodium in the US are indicated for the treatment of acute or chronic infections 
due to sensitive strains of certain Gram-negative bacilli and are particularly indicated when 
the infection is caused by sensitive strains of P. aeruginosa. 
Colistimethate sodium (1 million International Units [MIU], equivalent to 33 mg CBA) 
powder for nebuliser solution has been authorized and marketed in Europe by the Zambon 
SpA UK affiliate (Profile Pharma Ltd) since 2003 under the brand names Promixin® and 
Tadim® for nebulised treatment of colonisation and infections of the lung by susceptible P. 
aeruginosa in patients with CF. Authorisation was granted based on a bibliographic 
submission. The licensed dose in adults, adolescents, and children ≥ 2 years is 1-2 MIU 
(equivalent to 33-66 mg CBA) two to three times per day (max 6 MIU/198 mg CBA per 
day). 
To date, 2 clinical studies with Promixin® (colistimethate sodium) have been completed and 
reported. One was a pharmacokinetic study in healthy subjects (
), investigating 
the amount of colistimethate sodium absorbed across the lungs. This study found that the 

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administration of colistimethate sodium by inhalation in healthy subjects resulted in much 
lower systemic exposure than following i.v. administration. The absolute bioavailability was 
calculated to vary between 5% and 18% depending on the nebuliser.  The administration 
of CMS by inhalation was well-tolerated and no safety concerns were identified. No Serious 
Adverse Events (SAEs) were reported. 
The second (
) was the predecessor to the current trial, investigating whether 
inhaled colistimethate sodium (Promixin®) increased the time to the next pulmonary 
exacerbation and improved the symptoms experienced by reducing the bacterial load in 
the lungs in subjects with NCFB infected with susceptible P. aeruginosa [13]. 
The 
 trial enrolled bronchiectasis patients with two or more positive respiratory 
tract cultures for P. aeruginosa in the preceding 12 months and who were within three 
weeks of completing a course of antipseudomonal antibiotics for the treatment of an 
exacerbation. P. aeruginosa also had to be cultured from a sputum sample taken at the 
screening visit. Participants were randomised to receive colistimethate sodium (1 MIU [33 
mg CBA]; n = 73) or placebo (0.45% saline; n = 71) via the 
 twice a day, for up to 6 
months. The primary endpoint was time to exacerbation. Secondary endpoints included 
 
  
Median time (25% quartile) to exacerbation was 165 versus 111 days in the colistimethate 
sodium and placebo groups, respectively (p=0.11). Thirty-six of 73 patients (49%) in the 
colistimethate sodium group and 42 of 71 patients in the placebo group (59%) experienced 
a pulmonary exacerbation. Among the most adherent 75% of patients (adherence ≥81%), 
27 of 54 (50%) of colistimethate sodium patients experienced an exacerbation compared 
to 39 of 54 (72%) in the adherent placebo group. The median time (25% quartile) to 
exacerbation was 168 days in the adherent colistimethate sodium group and 103 days in 
the adherent placebo group (p=0.028).  
The colistimethate sodium group had 
 
 
 compared with placebo (in the 
intention-to-treat [ITT] population and in the adherent population).  
There were no safety concerns. 14 SAEs have been reported in nine patients. The 
incidence of Adverse Events (AEs) leading to discontinuation was extremely low and 
similar between treatment groups. All AEs were mild to moderate in severity and no subject 
experienced significant bronchoconstriction whilst receiving study treatment. No Suspected 
Unexpected Serious Adverse Reactions (SUSARs) were reported. There were no concerns 
with respect to renal toxicity or neuropathy. There was no evidence that the use of 
nebulized colistimethate led to the development of colistin-resistant isolates of P. 
aeruginosa or overgrowth of other bacteria. 
On the basis of the outcome of the 
 study and the scientific advice received 
from the British Medicines and Healthcare products Regulatory Agency (MHRA), two 
Phase 3 trials (PROMIS I and II) were designed as a 12 months double-blind, placebo-
controlled treatment to investigate if nebulised colistimethate sodium increases the 
 
 in subjects with NCFB chronically infected with P. aeruginosa.   
The need to balance treatment groups for concomitant use of macrolides was also 
identified as a factor which could influence results and which has been controlled for in 
both studies by using an interactive web-based response system for treatment allocation.  
However, the Sponsor subsequently received advice from the FDA requesting co-primary 
endpoints of 
 and number of 
, 
extending the PROMIS II trial to 24-months placebo-controlled duration, as well as 
modifications to the study endpoints and other study aspects detailed in this amended 
protocol. This advice was following the FDA Advisory Committee reviews of 2 other 
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investigational treatments for NCFB, and what they considered to be more robust endpoints 
to assess efficacy.  
As a consequence, this PROMIS I protocol was updated accordingly, however, still 
maintaining a 12-months placebo-controlled duration, per MHRA guidance and given that 
the second Phase 3 study investigated the 24 month duration period. 
The change in primary endpoint resulted in an increase in study sample size and number 
of countries/sites; the Sponsor has extended the enrolment time and overall study duration 
accordingly. Following a Type C Meeting held with the FDA on 31st October 2018, it was 
agreed that a single primary endpoint of frequency of pulmonary exacerbations and 12-
months placebo-controlled treatment duration would be acceptable as detailed in this 
amended protocol. 
The safety profile of nebulised colistimethate sodium will also be evaluated over this period. 
3.1. 
EVALUATION OF THE ANTICIPATED RISK/BENEFIT RATIO 
Colistimethate sodium (commercially available as Promixin®/Tadim®) is indicated for the 
management of chronic pulmonary infections due to P. aeruginosa in adult and paediatric 
patients with CF.  
Colistimethate sodium has a well-established safety profile in subjects with CF (Promixin® 
Summary of Product Characteristics [SmPC] [18]). 
Patient exposure data for CF patients in key European markets using commercial 
colistimethate sodium drug product (Promixin®/Tadim®) delivered with the 
 nebulizer 
estimates the number of treatment days as 13,146,075 (March 2003 to 31st July 2017, 
inclusive), with a low level of spontaneous adverse drug reactions reported. 
Common side-effects of nebulisation include coughing and bronchospasm with the first 
administration, observed in approximately 10% of subjects. Other common side effects on 
the respiratory system include chest tightness and bronchoconstriction.  
During the trial, subjects will administer an inhaled short-acting bronchodilator (e.g. 
salbutamol/albuterol) provided by the Sponsor prior to each IMP administration in order to 
reduce the side-effects described above. If subjects prefer not to use the bronchodilator 
and tolerate IMP without it this is acceptable. To monitor subjects for bronchial 
hyperreactivity in response to inhaled colistimethate sodium which may develop with 
continued use, regular spirometric examinations are included in the trial schedule.  
Further side-effects observed include hypersensitivity reactions such as skin rash and 
cases of sore throat or sore mouth (also potentially due to superinfection with Candida 
species).  
High serum concentrations may lead to a reduction of pre-synaptic acetylcholine release 
and thus may prolong the effects of muscle relaxants and increase fatigue. In addition, high 
serum concentration may result in renal impairment; whilst this is highly unlikely during 
inhalation therapy, in the current protocol an evaluation of renal function will be performed 
at baseline and during treatment. 
Colistimethate sodium should be used with extreme caution in subjects with porphyria. 
It is anticipated that administration of colistimethate sodium, administered twice daily via 
the 
 for 12 months, may significantly reduce the frequency of pulmonary 
exacerbations compared to placebo in subjects with NCFB chronically infected with P. 
aeruginosa. Anticipated benefits to the subject randomised to colistimethate sodium 
include improved lung function and overall 
 
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4. OBJECTIVES
The primary objective of the trial is to investigate the effect of the use of inhaled 
colistimethate sodium, administered twice daily via the 
 for 12 months, compared to 
placebo in subjects with NCFB chronically infected with P. aeruginosa on the frequency of 
pulmonary exacerbations. 
The secondary objectives of the trial are to investigate the effect of the use of inhaled 
colistimethate sodium, administered twice daily via the 
 for 12 months, compared to 
placebo in subjects with NCFB chronically infected with P. aeruginosa on: 
•
All the trial variables are described in Section 18.2. 
5. ETHICS REQUIREMENTS
This trial will be conducted in compliance with last version of Declaration of Helsinki; refer 
to 
the 
link 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/ , with International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), in particular E6(R2), with the applicable 
regulatory requirements and with Zambon and contract research organisation (CRO) 
standard operating procedures (SOPs). 
6. DESIGN AND DURATION OF THE CLINICAL TRIAL
6.1. 
CLINICAL TRIAL DESIGN 
This is a randomised, multi-centre, double-blind, placebo-controlled, parallel-group 
interventional trial in subjects with NCFB suffering from chronic infections with 
P. aeruginosa.
The trial will be conducted in approximately 100 sites in 15 estimated countries.
Please refer to Appendix 1 for a trial flow chart.
The study will consist of a total of 7 clinic visits (see Section 8) with a follow-up phone call 
two weeks after discontinuation of treatment. Additional clinic visits, where feasible, and 
weekly phone calls will be conducted following pulmonary exacerbations (or any episodes 
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of pneumonia) until resolution, and a clinic visit may also be required during a pulmonary 
exacerbation or pneumonia (Section 8.8).  
At Screening (Visit 1), subjects will be asked to provide Informed Consent prior to any trial 
related assessment and will be checked against inclusion and exclusion criteria. Their 
medical history will be recorded. Additionally, subjects will undergo 12-lead ECG, 
laboratory assessments and will provide sputum samples. These results will be available 
before Visit 2; if the Screening Visit sputum sample is negative for P. aeruginosa, up to two 
further samples may be collected and tested, within 30 days, after which, if all three are 
negative, the subject will be asked not to attend Visit 2 and will be deemed a Screen Failure 
(see Section 8.1).  
However, should the Investigator deem it preferable to repeat screening, the subject can 
be re-screened once within 2 months after Visit 1. In this case the subject must re-consent 
to participate and all screening assessments must be performed again.  
At Visit 2 (within 30 days after Visit 1), eligible subjects with P. aeruginosa cultured from 
their screening visit sputum sample will be randomised in a 1:1 ratio to receive either 
colistimethate sodium or placebo.  
It is planned to enrol 210 subjects into each treatment group. 
It is planned that subjects will attend for a further 5 visits at the sites at 1, 3, 6, 9, and 
12 months after Randomization (visit 2) (i.e. Visits 3, 4, 5, 6, and 7) and will have 1 follow-
up phone call at 12.5 months.  
Procedures performed at all clinical visits are detailed in Section 8.0 and will include 
documentation of concomitant medications and treatment emergent adverse events 
(TEAEs) as well as spirometry to determine forced expiratory volume in 1 second (FEV1) 
and forced vital capacity (FVC). Additionally, the subjects will be asked by the Investigator 
for information on any NCFB pulmonary exacerbations that were not reported.  
Further sputum samples will be collected at Visits 2, 3, 5 and 7, to be analysed 
 
. Sputum samples
collected at Screening (Visit 1) and at the end of treatment (Visit 7) will have isolates
retained by the central laboratory for later analysis 
At Visits 2, and at each post-baseline study visit, 
 will be assessed using 
the 
. 
In case subjects feel that they are experiencing a NCFB pulmonary exacerbation (as 
defined in Section 18.2), they should contact the investigational site immediately to discuss 
their symptoms and, if feasible, to arrange an Exacerbation Visit (which should take place 
within 2 working days of the exacerbation starting, if possible). The Investigator will check 
whether the pulmonary exacerbation meets the criteria defined in this Clinical Trial Protocol 
(CTP), will decide on an appropriate course of action (including systemic antibiotic 
treatment, if required) and will perform the assessments defined in the Section 8.8.  
6.2. 
DURATION OF CLINICAL TRIAL 
The overall study duration (from first patient first visit to last patient last visit) is expected to 
be from Q2 2017 to Q4 2020.  
The maximum expected duration of participation in this trial for an individual subject, from 
Visit 1 (Screening) to the follow-up phone call is 13.5 months. Treatment duration will be 
12 months. 
The start of the trial is defined as first subject in, i.e. Visit 1 for the first subject. 
p
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The end of the trial is defined as the last subject out, i.e. when the last subject had the 
follow-up phone call. The end of the trial for the purposes of the primary statistical analysis 
is defined as the last subject completing the trial. 
If the trial is prematurely stopped, please refer to Section 15. 
7. CLINICAL TRIAL POPULATION 
7.1. 
NUMBER OF SUBJECTS 
A total of 420 subjects (210 in each treatment group) are planned to be enrolled into the 
trial. The enrolment is competitive among sites.  
For a description of sample size calculation, please refer to Section 18.3. 
7.2. 
SELECTION OF SUBJECTS 
7.2.1. 
INCLUSION CRITERIA 
Subjects can be included in the trial if they meet all the inclusion criteria listed below: 
1) 
are able and willing to give informed consent, following a detailed explanation of 
participation in the protocol and signed consent obtained; 
2) 
are aged 18 years or older of either gender; 
3) 
are diagnosed with NCFB by computerised tomography (CT) or high resolution CT 
(HRCT) as recorded in the subject’s notes and this is their predominant condition 
being treated; 
4) 
had at least 2 NCFB pulmonary exacerbations requiring oral or inhaled antibiotics 
or 1 NCFB pulmonary exacerbation requiring intravenous antibiotics in the 12 
months preceding the Screening Visit (Visit 1) and had no NCFB pulmonary 
exacerbation with or without treatment during the period between Visit 1 and Visit 
2; 
5) 
have a documented history of P. aeruginosa infection; 
6) 
are clinically stable and have not required a change in pulmonary treatment for at 
least 30 days before the Screening Visit (Visit 1); 
7) 
have pre-bronchodilator FEV1 ≥25% of predicted; 
8) 
had a positive sputum culture for P. aeruginosa from an adequate sample taken at 
the Screening Visit (Visit 1) or during the screening period.  
7.2.2. 
EXCLUSION CRITERIA 
Subjects are not eligible for the trial if they meet one or more of the exclusion criteria listed 
below: 
1) 
known bronchiectasis as a consequence of cystic fibrosis (CF); 
2) 
known 
history 
of 
hypogammaglobulinaemia 
requiring 
treatment 
with 
immunoglobulin, unless fully replaced and considered immuno-competent by the 
Investigator;  
3) 
myasthenia gravis or porphyria;  
4) 
severe cardiovascular disease such as severe uncontrolled hypertension, 
ischaemic heart disease or cardiac arrhythmia and any other conditions that would 
confound the evaluation of safety, in the opinion of the Investigator; 
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5) 
had major surgery in the 3 months prior to the Screening Visit (Visit 1) or planned 
inpatient major surgery during the study period; 
6) 
receiving treatment for allergic bronchopulmonary aspergillosis (ABPA); 
7) 
had massive haemoptysis (greater than or equal to 300 mL or requiring blood 
transfusion) in the preceding 4 weeks before the Screening Visit (Visit 1) or 
between Visit 1 and Visit 2; 
8) 
respiratory failure that would compromise patient safety or confound the evaluation 
of safety or efficacy of the study in the opinion of the Investigator; 
9) 
current active malignancy, except for basal cell carcinoma or squamous cell 
carcinoma of the skin without metastases; 
10) taking immunosuppressive medications (such as azathioprine, cyclosporine, 
tacrolimus, sirolimus, mycophenolate, rituximab), and/or anti-cytokine medications 
(such as anti-IL-6 and anti-tumour alpha necrosis factor products) in the preceding 
year before the Screening Visit (Visit 1); 
11) known history of human immunodeficiency virus (HIV); 
12) current treatment for non-tuberculous mycobacterium (NTM) lung disease or 
tuberculosis. 
13) known or suspected to be allergic or unable to tolerate colistimethate sodium 
(intravenous or inhaled) or other polymixins, including previous evidence of 
bronchial hyper-reactivity following inhaled colistimethate sodium; 
14) treatment with long term (≥ 30 days) prednisone at a dose greater than 15 mg a 
day (or equivalent dose of any other corticosteroid) within six months of the 
Screening Visit (Visit 1);  
15) new 
maintenance 
treatment 
with 
any 
oral 
macrolides 
(e.g. 
azithromycin/erythromycin/clarithromycin) started within 30 days of the Screening 
Visit (Visit 1) and between Visit 1 and Visit 2; 
16) use of any intravenous or intramuscular or oral or inhaled anti-pseudomonal 
antibiotic (except chronic oral macrolide treatment with a stable dose) within 30 
days prior to the Screening Visit (Visit 1) and between Visit 1 and Visit 2; 
17) pregnant or breast feeding or plan to become pregnant over the next year or of 
child-bearing potential and unwilling to use a reliable method of contraception for 
at least one month before randomisation and throughout their involvement in the 
trial; 
18) significant abnormality in clinical evaluations and/or laboratory tests (physical 
examination, vital signs, haematology, clinical chemistry, clinically relevant 
impaired renal function, defined as serum creatinine levels ≥2.0x upper limit of 
normal, ECG) endangering the safe participation of the patient in the study at the 
Screening Visit (Visit 1) and during the study; 
19) participated in another investigational, interventional trial within 30 days prior to the 
Screening Visit (Visit 1); 
20) in the opinion of the Investigator not suitable for inclusion for whatever reason. 
 
Contraceptive methods 
Safety in human pregnancy has not been established. Animal studies do not indicate a 
teratogenic potential. However, there is evidence that colistimethate sodium crosses 
the placenta and, consequently, there is potential for foetal toxicity if administered 
during pregnancy.  Colistimethate sodium should only be given during pregnancy if the 
benefits outweigh any potential risk. 
Female subjects can be enrolled if they are either post-menopausal for at least 2 years, 
or surgically sterilized or have undergone hysterectomy.  
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Female subjects of child-bearing potential must be willing to avoid pregnancy. They are 
required to have a negative pregnancy test at inclusion (see Section 9.1.4), and should 
use highly effective methods of birth control for 1 month prior to randomisation, 
throughout the trial duration and up to 1 month after the last dose of IMP, which include: 
• combined (oestrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal or transdermal)
• progestogen-only hormonal contraception associated with inhibition of ovulation
(oral, injectable or implantable)
• intrauterine device
• intrauterine hormone-releasing system
• surgical sterilization (e.g. bilateral tubal ligation or occlusion)
• male sterilization (vasectomised partner)
• sexual abstinence.
Throughout the course of the study male participants with female partners of child-
bearing potential must abstain from sexual intercourse, use condoms or use effective 
contraceptive precautions. Male participants must also not take part in the donation of 
sperm whilst enrolled on the study. 
8. OVERALL CLINICAL TRIAL SCHEDULE
The current trial will include 7 planned clinical visits at the investigational site and 1 follow-
up telephone call. A detailed flow chart showing the procedures performed is given in 
Appendix 1. The following sections outline the procedures to be performed at the individual 
visits. 
8.1. 
VISIT 1 - SCREENING VISIT (WITHIN 30 DAYS OF VISIT 2) 
At Visit 1 (Screening), the following procedures will be performed: 
•
obtain written Informed Consent;
•
documentation of medical history and subject demographic data;
•
documentation of previous and concomitant medications (including long term
antibiotic use for NCFB pulmonary infection prophylaxis, and in particular oral
azithromycin/erythromycin/clarithromycin administration in the last 12 months, and
any prior use of nebulised colistin or colistimethate sodium or other inhaled/oral
antibiotic);
•
check number of NCFB pulmonary exacerbations in the preceding year;
•
check of inclusion/exclusion criteria;
•
assessment of vital signs (Section 9.1.3);
•
physical examination (including chest auscultation);
•
12-lead ECG in the supine position after 5 minutes of rest (evaluation by local
medical staff) in order to verify the subject’s eligibility (Section 9.1.6);
•
blood samples for clinical laboratory assessments (haematology, clinical chemistry
and renal function tests). (Section 9.1.4);
•
dip-stick pregnancy test for women of child-bearing potential.
•
spirometry (if not done in the 30 days beforehand); pre-bronchodilator FEV1 must be
≥30% of predicted for the patient normal value (determined using Global Lung
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• collection of 
 
(results have to be available by Visit 2; if negative, the subject will be asked to return 
to the clinic for a repeat sputum sample prior to Visit 2 - if this second sample is also 
negative, one further sample may be collected for analysis; thereafter, the subject 
will be a screen failure and will not be required to attend Visit 2); 
• instruction of subjects on actions to be taken in case of NCFB pulmonary 
exacerbations. 
The Investigator will arrange an appointment for Visit 2 within 30 days. 
8.2. 
VISIT 2 - RANDOMISATION VISIT (DAY 0) 
At Visit 2 (Randomisation), the following procedures will be performed: 
• check if subject is still eligible according to inclusion and exclusion criteria and check 
of screen failure criteria for Visit 2; 
• documentation of concomitant medications (including azithromycin/erythromycin/ 
clarithromycin use) or treatments; 
• record details of any AEs since the Screening Visit (Visit 1); 
• training and completion of 
 on electronic clinical 
outcome assessment (eCOA) device before other study procedures; 
• dip-stick pregnancy test for women of child-bearing potential. 
• collection of 
; 
• randomisation by Interactive Web Response System (IWRS) and treatment kits 
assignment;  
• dispensing of, and subject training on, 
 device including the use of the 
 disc;  
• subject training on IMP preparation, inhaled bronchodilator use and subject’s card 
dispensing; 
• first IMP administration under clinical supervision (at least 10 minutes after 
inhalation of short-acting bronchodilator; if the patient prefers not to use a 
bronchodilator this should be documented and the lack of bronchial hyper-reactivity 
after IMP administration documented); 
• spirometry, including assessment of FEV1 and FVC pre-bronchodilator and 30 ± 10 
minutes post-IMP dose (Note: in case of a >15% decrease - not due to poor 
technique - in FEV1 from pre-bronchodilator baseline after first IMP intake, or 
clinically determined bronchospasm, the subject will be immediately withdrawn from 
the trial); 
• dispensing of sufficient IMP kits and inhaled bronchodilator for the treatment period 
until Visit 3; 
• instruction of subjects on actions to be taken in case of 
 
. 
The Investigator will arrange an appointment for Visit 3 (28 days ± 1week).  
In addition, the Investigator will call the subject after 1 week to ensure that there are no 
problems with the mixing of IMP, the use of the nebuliser device and will also ask about 
any AEs, including any 
 due to 
 
, and any medical device malfunctions and/or incidents (see Section 16.3.2). 
8.3. 
VISIT 3 (DAY 28 ± 1 WEEK) 
At Visit 3, the following procedures will be performed: 
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• documentation of concomitant medications (including azithromycin/erythromycin/ 
clarithromycin use) or treatments; 
• check for occurrence of 
 not reported by the subject 
(Note: whether an unreported 
 occurred will be assessed 
retrospectively by the Investigator by asking about the prescription of antibiotics by 
other physicians; if yes, the 
 and its duration will be recorded in the 
electronic Case Report Forms [eCRF]); 
• record details of any AEs since previous visit; 
• record details of any medical device malfunction and/or incidents since previous visit 
(Section 16.3.2); 
• record of 
 and days of 
 due to 
 
; 
• completion of 
 on the eCOA device before other 
study procedures; 
• dip-stick pregnancy test for women of child-bearing potential; 
• blood samples for renal function tests (Section 9.1.4); 
• collection of 
 
 
• spirometry, including assessment of FEV1 and FVC; 
• review of 
 data using the data analyser provided to sites for the ongoing 
assessment of adherence (and re-training of subjects, if appropriate); 
• IMP collection and accountability (used/unused vials), including check of 
bronchodilator use and dispensing of sufficient IMP kits and inhaled bronchodilator 
for the treatment period until Visit 4; 
• instruction of subjects on actions to be taken in case of NCFB pulmonary 
exacerbations. 
The Investigator will arrange an appointment for Visit 4 (within 2 months ± 1week). 
8.4. 
VISIT 4 (3 MONTHS ± 1 WEEK) TO VISIT 6 (9 MONTHS 
± 1 WEEK), INCLUSIVE 
At Visit 4 to Visit 6, inclusive, the following procedures will be performed: 
• documentation of concomitant medications (including azithromycin/erythromycin/ 
clarithromycin use) or treatments; 
• check for occurrence of 
 not reported by the subject 
(Note: whether an unreported 
 occurred will be assessed 
retrospectively by the Investigator by asking about the prescription of antibiotics by 
other physicians; if yes, the 
 and its duration will be recorded in the 
eCRF); 
• record details of any AEs since previous visit; 
• record details of any medical device malfunctions and/or incidents since previous 
visit (Section 16.3.2); 
• record of 
 and days of 
 due to 
 
 since the previous visit; 
• blood samples for clinical laboratory assessments (haematology, clinical chemistry 
and renal function tests) at Visit 5 only (Section 9.1.4); 
• completion of 
 on eCOA device before study 
procedures; 
• dip-stick pregnancy test for women of child-bearing potential; 
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• collection of 
 
; 
• spirometry, including assessment of FEV1 and FVC; 
• review of 
 data using the data analyser provided to sites for the ongoing 
assessment of adherence (and re-training of subjects, if appropriate); 
• IMP collection and accountability (used/unused vials), including check of 
bronchodilator use and dispensing of sufficient IMP kits and inhaled bronchodilator 
for the treatment period until the subsequent visit; 
• instruction of subjects on actions to be taken in case of NCFB pulmonary 
exacerbations. 
The Investigator will arrange an appointment for the subsequent visit. 
8.5. 
VISIT 7 (12 MONTHS ± 1 WEEK); END OF TREATMENT 
At Visit 7, the following procedures will be performed: 
• documentation of concomitant medications (including azithromycin/erythromycin/ 
clarithromycin use) or treatments; 
• check of occurrence of 
 not reported by the subject 
(Note: whether an unreported 
 occurred will be assessed 
retrospectively by the Investigator by asking about the prescription of antibiotics by 
other physicians; if yes, the 
 and its duration will be recorded in the 
eCRF); 
• record details of any AEs since previous visit; 
• record details of any medical device malfunctions and/or incidents since previous 
visit (See section 16.3.2); 
• record of 
 and days of 
 due to 
 
 since previous visit; 
• completion of 
 on eCOA device before any study 
procedures; 
• assessment of vital signs (Section 9.1.3); 
• physical examination (including chest auscultation); 
• 12-lead ECG in the supine position after 5 minutes of rest (with evaluation by local 
medical staff, Section 9.1.6); 
• dip-stick pregnancy test for women of child-bearing potential; 
• blood samples for clinical laboratory assessments (haematology, clinical chemistry 
and renal function tests, Section 9.1.4);  
• collection of 
 
; 
• last IMP administration under clinical supervision (at least 10 minutes after inhalation 
of short-acting bronchodilator); 
• spirometry, including assessment of FEV1 and FVC pre-bronchodilator and 30 ± 10 
minutes post-IMP dose; 
• collection of
 device and disc (to be transferred to 
 for download); 
• IMP collection and accountability (used/unused vials) and collection of 
bronchodilator. 
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8.6. 
FOLLOW-UP PHONE CALL (2 WEEKS ± 3 DAYS AFTER END OF 
TREATMENT) 
A follow-up phone call will be performed at 2 weeks ± 3 days after the discontinuation of 
IMP.  
The following procedures will be performed during the call:  
• documentation of concomitant medications; 
• AE monitoring. 
If the result of the susceptibility test at the end of treatment (Visit 7) suggests the subject is 
resistant to colistin, he/she will be called for an extra visit with sputum collection for analysis 
of 
. 
8.7. 
EXACERBATION VISIT/CONTACT 
Subjects will be trained by the Investigator to recognise signs and symptoms of NCFB 
pulmonary exacerbations.  
At each post-randomisation visit the patient will be reminded about how to recognise 
symptoms of a NCFB pulmonary exacerbation and instructed to contact the site as soon 
as they have experienced these symptoms for 24 hours. If feasible, the subject will be 
asked to attend the clinic at their earliest convenience. If it is not practical for the subject to 
make an additional clinic visit then relevant information will be collected via phone and the 
subject will be asked to send a sputum sample to the clinic. 
Any episodes of pneumonia during the trial should be considered as severe pulmonary 
exacerbations and will also require a clinic visit, if feasible. 
The Investigator will decide if symptoms represent a NCFB pulmonary exacerbation 
meeting the protocol-defined criteria or not and on the appropriate course of action.  
It will be clinically determined if the subject requires systemic antibiotic therapy (oral or 
intravenous) in addition to IMP administration or whether IMP administration should be 
temporarily interrupted (see below). Treatment of a NCFB pulmonary exacerbation will 
follow current treatment regimens used in the respective participating trial site.  
If subjects need to be admitted to hospital for intravenous antibiotics, they should be visited 
by the research staff for an assessment within 72 hours of admission (where possible). If 
the subject is admitted to a hospital that is not the investigational site, the assessments 
should be carried out (where possible) by the admitting hospital under the direction of the 
investigational site. These assessments will include those collected during exacerbation 
visits/contacts and will include details regarding any interruption of IMP administration. In 
these circumstances, every effort should be made to complete all assessments although it 
is recognised that this might not be possible.  
Telephone calls will be made to patients on a weekly basis during a NCFB pulmonary 
exacerbation until resolution to assess the progression of symptoms to and to determine 
whether systemic antibiotic treatment is ongoing. A telephone script will be provided to sites 
and responses to standardised questions will be collected in relevant eCRFs. 
Resolution of a NCFB pulmonary exacerbation is defined as the date of completion of the 
required course of systemic antibiotic treatment or the Investigator’s judgement that the 
NCFB pulmonary exacerbation has resolved, whichever is later. Exacerbations occurring 
less than 14 days after the end of a course of systemic antibiotics for a NCFB pulmonary 
exacerbation will be considered as a single event (see Section 9.1.5).  
IMP administration may be temporarily interrupted during the time of systemic antibiotic 
treatment due to a pulmonary exacerbation based on the Investigator’s judgement; 
thereafter, the study treatment should restart as soon as possible. Stop date and re-start 
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date will be recorded in the relevant eCRF. The occurrence of a pulmonary exacerbation 
does not mandate the discontinuation of the subject from the trial, unless it occurs between 
Visit 1 and Visit 2 and /or the Investigator believes discontinuation is in the subject’s best 
interest. 
The following assessment will be performed at an Exacerbation Visit or Phone contact, and 
all details of the pulmonary exacerbation have to be recorded: 
• start date and duration of all symptoms since the start; 
• all symptoms present which support the NCFB pulmonary exacerbation diagnosis; 
• all concomitant medications, especially systemic antibiotics; 
• physical examinations and vital signs (if attending the clinic); 
• date of 
 and/or days of 
 (if any); 
• measurement and recording of FEV1 and FVC (if feasible); 
• pulmonary exacerbation as AE/SAE according to protocol and followed until 
resolution, including weekly follow-up phone calls as detailed above; 
• collection of 
 
for other antibacterial panels. If 
subjects are unable to attend the clinic then suitable arrangements will be made to 
obtain an additional 
, if feasible. 
9. METHODOLOGY 
9.1. 
METHODS OF ASSESSMENT 
9.1.1. 
DEMOGRAPHY AND MEDICAL HISTORY 
At Visit 1 (Screening) the subjects’ demographic data will be documented, (including age, 
ethnicity, gender, height, weight as well as smoking history and alcohol use), date of 
diagnosis of NCFB and if known, the underlying cause of the bronchiectasis. Body weight 
will also be measured at Visit 7.  
Further, the subjects’ medical history will be documented, i.e. relevant past and/or currently 
ongoing conditions. This includes details regarding pulmonary exacerbations in the last 12 
months and the collection of a report on CT/HRCT results, to confirm the diagnosis of NCFB 
as per inclusion criterion 3 (see Section 7.2.1).  
Any relevant worsening in ongoing conditions during the trial (i.e. since Visit 1) are required 
to be recorded as AEs in the eCRF (see Section 16). 
9.1.2. 
PHYSICAL EXAMINATION 
At Visit 1 and Visit 7, a physical examination of general body systems will be performed 
according to current medical standard and site practice. The examination has to include a 
chest auscultation. Any relevant worsening regarding physical examination results of a 
subject since Visit 1 should be recorded as AEs in the eCRF (see Section 16). 
9.1.3. 
VITAL SIGNS 
At Visit 1 and Visit 7, vital signs will be recorded according to site practice and before 
spirometry testing. This will include heart rate, systolic/diastolic blood pressure (measured 
after at least 5 minutes in the supine position), respiratory rate, and body temperature. 
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Automatic or manual devices may be used, but the same device should be used for any 
given subject throughout the trial. The same arm should be used for all measurements. 
The Investigator will perform an overall evaluation for safety purposes and the recording 
will be reported as “normal”, “abnormal clinically significant” or “abnormal not clinically 
significant”. Abnormalities of clinical significance will be reported as AEs.  
Any clinically relevant worsening of vital signs of a subject since Visit 1 should be recorded 
as AEs in the eCRF (see Section 16). 
9.1.4. 
LABORATORY EVALUATIONS 
Routine laboratory evaluations will be performed at the Screening Visit (Visit 1), Visit 5 and 
Visit 7. The haematology and clinical chemistry parameters detailed in Table 1 will be 
analyzed at the central laboratory using standard, validated laboratory methods.  
Renal function will be monitored by laboratory tests (creatinine, Blood Urea Nitrogen [BUN]) 
performed at the Screening Visit (Visit 1) and during the treatment: at Day 28 of treatment 
(Visit 3), after 6 months (Visit 5) and at the end of treatment (Visit 7).  
Subjects with clinically relevant impaired renal function (as defined by serum creatinine 
levels ≥2.0x upper limit of normal) will be discontinued. 
Note that at Visit 1 and Visit 7 the blood samples for these assessments must be collected 
after the 12-lead ECG assessments have been performed.  
A dipstick urine pregnancy test for women of child-bearing potential will be performed at 
the investigational site at the Screening Visit (Visit 1) and at all scheduled study visits 
thereafter.  
Female subjects who become pregnant during the trial must be withdrawn from the trial 
without delay and will be followed up to determine the outcome of the pregnancy. The 
Investigator is required to inform the Sponsor of a subject’s pregnancy and the estimated 
date of delivery. Reporting requirements are outlined in Section 16.10.  
Clinical laboratory tests will be reviewed for results of potential clinical significance before 
Visit 2 to confirm patient’s eligibility and during the trial, as appropriate. Clinically significant 
laboratory abnormalities arising from Visit 2 onwards are considered to be AEs. Where 
possible, a diagnosis should be ascribed to the abnormal lab test. 
If the Investigator determines a laboratory abnormality to be clinically significant, it 
constitutes an AE, excluding abnormalities detected at Screening Visit (Visit 1). 
 
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Table 1 CLINICAL LABORATORY EVALUATIONS 
Hematology: at the Screening Visit (Visit 1), Visit 5 and Visit 7 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell count and differential (neutrophils, lymphocytes, monocytes, eosinophils and basophils) 
Clinical Chemistry at the Screening Visit (Visit 1), Visit 5 and Visit 7 
BUN*  
Chloride  
AST 
Creatinine* 
Uric acid 
ALT 
Sodium 
Amylase 
GGT 
Potassium 
ALP 
Bilirubin (direct and total) 
Calcium 
 
 
 
 
 
Pregnancy Test: 
 
Urine β-hCG (dipstick) at the Screening Visit (Visit 1) and at all visits thereafter 
* These evaluations will also be performed at Visit 3 
9.1.5. 
EFFICACY EVALUATIONS 
 
Pulmonary Exacerbations 
The primary efficacy assessment for an individual subject is the frequency of pulmonary 
exacerbations. 
 
A pulmonary exacerbation is defined as the presence concurrently of at least 3 of the 
following 8 symptoms/signs for at least 24 hours: 
• increased cough; 
• increased sputum volume and/or consistency; 
• increased sputum purulence; 
• new or increased  haemoptysis; 
• increased wheezing; 
• increased dyspnoea; 
• increased fatigue/malaise; 
• episodes of fever (temperature ≥38°C). 
And: 
it is clinically determined that the subject requires and is prescribed systemic antibiotic 
therapy.  
The start date of a protocol-defined pulmonary exacerbation will be taken as the first day 
that at least 3 of the pre-defined 8 symptoms/signs occurred concurrently for at least 24 
hours, as determined by the Investigator.  
Resolution of a pulmonary exacerbation is defined as the date of completion of the required 
course(s) of systemic antibiotic treatment and/or the Investigator’s judgment that the NCFB 
pulmonary exacerbation has resolved, whichever is the later of the two dates. The 
exacerbation end date will be reported at the next scheduled visit or by phone. 
A new pulmonary exacerbation is only considered to occur if there are at least 14 days 
between the end of the course of systemic antibiotics and the onset of new qualifying 
symptoms. If the subject is not better at the end of an initial 14-day course of systemic 
antibiotics, then the antibiotic should be continued for an additional standard treatment 
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The treatment of pulmonary exacerbations will follow current treatment regimens used at 
the respective participating investigational site. 
Procedures to be followed in case a subject experiences symptoms suggestive of a 
pulmonary exacerbation are described in Section 8.8 (Exacerbation Visit/Contact).  
 
 
In this trial, 
  
The 
 is a validated 50-item symptom questionnaire developed to measure health 
status and QoL in subjects with obstructive airway diseases [19, 20].  
 
. Scores will be collected for these 3 domains and the Total 
score will be produced. 
The 
 is a validated self-administered, patient reported outcome measure assessing 
 for subjects with NCFB [21, 22].  
 
and was developed 
for use in clinical trials and routine clinical practice.  
The questionnaires will be completed by the subjects at Visit 2 (Randomisation), and at 
each subsequent study visit prior to any study procedures using an eCOA device, i.e. 
SITEpro Tablet. The device will be provided by 
. and is 
an electronic data collection system used to collect data at sites.  
During Visit 2, appropriate training will be provided to the subjects on how to correctly 
complete the questionnaires on the device.  
To utilise the device, the Investigator has to enter the screening number. Then the device 
will present the questionnaires for completion by the subject. To ensure that all visits are 
completed as defined in this CTP, the Investigator will select the appropriate visit number 
from the options on the screen before handing the device to the subject. 
After completing the assessments as instructed, the subject will return the device to the 
Investigator who will then complete a data transfer to record the subject data in the trial 
database. To ensure that sites are not compromised with respect to the study blinding, the 
Investigator will not be able to view the responses provided by the subject.  
The data transfer will be performed every time a subject completes the questionnaires on 
the eCOA device.  
 
  
For the purposes of subject eligibility only, two discrete 
 (of 2.5 mL each) 
may be collected with the first sample being sent to the local laboratory and the second 
sample sent refrigerated to 
 or 
 on the day of collection. 
These may be collected by the patient at home in the morning of the visit and brought to 
clinic. After collection, the samples should be kept refrigerated (2oC to 8oC) as much as 
possible. 
This is only permitted if the local laboratory is able to analyse 
 
. The Institution must provide 
copies of the relevant laboratory accreditations (ISO 15189 Medical Laboratories, ISO/IEC 
17025, or equivalent) prior to local positive results being considered acceptable for 
enrolment. If results are disparate (and the local result is positive but the central result 
negative) sites need to contact the Sponsor for confirmation that the subject can be 
enrolled. 
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Subsequently, 
 will be collected at each visit with the exception of 
Visits 4 and 6 as well as at any Exacerbation Visit (including episodes of pneumonia). Two 
samples may be taken during the clinic visit or at home on the morning of the visit, with the 
 only being sent for analysis. They will be sent refrigerated 
on the day of collection for analysis to 
, specialized in 
microbiological analyses. 
 will be responsible for all aspects of the 
 
analyses, including preparation of laboratory kits to be provided to investigational sites and 
will perform laboratory data management activities.  
For analysis of 
 these 
 will be collected in sterile 
transport tubes and shipped refrigerated to the microbiological laboratory by selected 
courier to preferably arrive at the laboratory within 48 hours after collection.  
Results of this quantitative analysis for 
 will be presented as colony 
forming units (CFU) count per gram. Additionally, results from Visit 1 (Screening) and Visit 
7 (End of Treatment) will be made available to the Investigator in the form of laboratory 
reports via fax/email for the subjects’ following visit/contact and transferred to the trial 
database according to pre-defined criteria. Results from other visits will not be reported 
directly to the Investigator in order not to bias safety and efficacy evaluations. The 
 will also be evaluated at specific visits from the 
samples (see Section 9.1.6). 
More details on laboratory analyses and logistics can be found in the laboratory manual.  
 
 Download 
The subjects will administer the IMP via the 
 device twice daily which is activated 
by a disc provided with the 
. Subjects will receive appropriate training on the use of 
the 
 device (including written instructions) and on preparation of the IMP to be used 
in the 
. Subjects will perform the first administration of IMP under supervision of the 
site personnel during Visit 2 and they will be informed that the device will log their IMP 
usage. When subjects self-administer the IMP via the 
 device, the time of day, length 
of nebulisation and amount of IMP administered are stored in the device. 
During the trial, adherence will be assessed on-site by the Investigator on an ongoing basis 
by downloading the data from the 
 into a data analyser installed in laptops provided 
by the Sponsor. In addition, drug accountability, assessing the amount of IMP used and 
not used by a subject (see Section 11.4) will be performed. The data remains on the 
 
so it can be fully analysed at the end of the study.  
After the end of treatment, i.e. Visit 7, the device use data from the 
 will be downloaded 
to the laptop using instructions provided to the site personnel. The data can then be sent 
electronically to the CRO or 
 as per instructions. Alternatively, the device can be 
stored and returned to 
 with returned IMP. 
 will then send the device on to 
 (the 
 manufacturer) who will download the data and send it on to the CRO. As 
the 
 system records all information on the doses of IMP taken, these data will be used 
to determine overall adherence.  
9.1.6. 
SAFETY EVALUATIONS 
Adverse Events  
AEs will be recorded by the Investigator in the appropriate eCRF Section starting with the 
date of informed consent until the follow-up phone call. At each contact (i.e. clinical visit or 
phone call), subjects will be asked in a non-leading manner if they experienced any AEs.  
All AEs occurring from the day of the first IMP administration, i.e. Visit 2, until the end of 
the trial, i.e. follow-up phone call, will be considered as TEAEs.  
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(Note: A pulmonary exacerbation will be reported as an AE or serious AE [SAE]; 
pulmonary exacerbations will also be captured as efficacy assessments). 
For definitions and reporting of AEs and SAEs, see Section 16. 
 
Lung Function by Means of Spirometry 
Spirometry measurements of FEV1 and FVC (predicted values will be as per GLI reference 
equations [23]) will be performed at Visit 1 (if not performed in the preceding 30 days) to 
verify the eligibility of the subject (see inclusion criteria in Section 7.2.1), and at Visit 2 
through Visit 7.  
Lung function measurement and daily calibration of the spirometer will be performed 
according to the standardised methods described by the American Thoracic 
Society/European Respiratory Society. It is suggested that, in each centre, the model of 
the spirometer used does not change during the study. 
Lung function measurements will be done at approximately the same time of the day during 
clinic visits (dependent on IMP administration) with subjects either standing or sitting (for 
each subject, this should be consistent throughout the trial) with the nose clipped after at 
least 10 minutes rest. Calibration of the spirometer must be performed preferably by the 
same Investigator at each visit prior to spirometry measurements and the reports must be 
kept with the source trial documents.  
For FEV1 and FVC the highest value from 3 technically satisfactory attempts will be 
considered (irrespective of the curve they come from). 
At Visit 2 and Visit 7, FEV1 and FVC will be measured and recorded prior to the inhaled 
short-acting bronchodilator (e.g. salbutamol/albuterol) administration (pre-dose) and 30 ± 
10 minutes post-IMP. Note: the IMP will always be administered 10-15 minutes after 
bronchodilator. In case a subject’s FEV1 decreases by >15% - not due to poor technique - 
at the post-dose reading and/or in the case of clinically determined bronchospasm, the 
subject will be withdrawn from the trial (see exclusion criteria in Section 7.2.2). 
At all other visits, FEV1 and FVC will be measured as above. 
 
 and Other Species 
Besides 
 analysis (see Section 9.1.5), 
 
 will be evaluated from 
 collected at 
each visit. The 
 testing will be done using a minimal inhibitory concentration 
(MIC) method. Testing of 
 with other antibacterial panels will also be 
conducted for samples collected during pulmonary exacerbations.  
If 
 is detected and/or any isolate shows a significant rise in 
MIC (i.e. showing greater than a four-fold change in colistimethate sodium MIC) genotyping 
studies on 
 isolates may be conducted to determine if the change in MIC was 
due to microbiological recurrence or re-infection. 
 collected at Screening (Visit 1) and at the end of treatment (Visit 7) will 
have isolates retained by the central laboratory for later analysis for 
 
as well as the emergence of 
 and any developing resistance. 
More details on laboratory analyses and logistics can be found in the laboratory manual. 
 
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12-lead Electrocardiogram  
Computerized 12-lead ECG recordings will be obtained at each study centre using site 
machines at the Screening Visit (Visit 1) to verify the eligibility of the subject, and at Visit 
7/End of Treatment. 
ECGs will be performed after obtaining vital signs. Prior to recording, the subject should be 
at rest for at least 5 mins.  
ECGs will be evaluated by the Investigator/local medical staff and the recording will be 
reported in the eCRF as “normal”, “abnormal clinically significant” or “abnormal not clinically 
significant”.  
If abnormalities of clinical significance are recorded at Visit 1, the subject will be excluded 
from the trial (see exclusion criteria in Section 7.2.2); abnormalities of clinical significance 
recorded at Visit 7 will be reported as AEs.  
Repeat measurements will be performed if needed. 
9.2. 
ADHERENCE WITH IMP DOSING REGIMEN 
 
The Investigator will assess the subjects’ adherence with the IMP dosing regimen on an 
ongoing basis by the data downloaded from the 
device into a data analyser installed 
in laptops provided by the Sponsor.  
Information on data download from the 
 logging system is given in Section 9.1.5.  
The Investigator will also assess the amount of IMP dispensed, used (i.e. returned open 
vials) and not used (i.e. returned, unopened vials) at all clinical visits, starting with Visit 2 
(first dose) up to the day of the last dose (Visit 7/End of Treatment).  
IMP inventory and accountability records will be maintained within IWRS. 
In the event that adherence is less than approximately 80% at any visit, adherence will be 
discussed with the subject and appropriate re-training will be given by site staff. 
9.3. 
PHARMACODYNAMICS 
Not applicable.  
9.4. 
PHARMACOKINETICS 
Not applicable.  
10. PRIOR AND CONCOMITANT TREATMENTS 
At Visit 1 (Screening), all prior and concomitant medications, including antibiotics, and over-
the-counter products used by an individual subject within 1 month prior to the Screening 
Visit (Visit 1) will be documented in the eCRF.  
In particular, any prior use of inhaled colistimethate sodium or colistin or other inhaled 
antibiotic, if stopped within 1 month prior to Visit 1, must be documented. 
The following will be recorded: 
• Dates of administration including start and end dates; 
• Dosage information including dose and frequency; 
• Reason for use. 
 
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During all subsequent clinical visits, the Investigator will document any changes in 
concomitant medications or use of rescue medication.  
The following chronic treatments are permitted during the trial: 
• oral macrolides (e.g. azithromycin/erythromycin/clarithromycin); Note: the decision 
whether concomitant antibiotic therapy should be administered to a subject will have 
been taken at least 30 days prior to Screening [Visit 1]; it is recommended to 
maintain a stable dose and continue the treatment throughout the trial; 
• inhaled long-acting bronchodilators; 
• inhaled short or long-acting muscarinic antagonists; 
• inhaled corticosteroids;  
• oral prednisone at a stable dose less than or equal to 15 mg a day or equivalent 
dose of any oral corticosteroid; 
• methylxanthines at stable unchanged doses; 
• leukotriene receptor antagonists; 
• roflumilast; 
• mucoactive treatments (nebulised hypertonic saline, nebulised isotonic saline, dry 
powder mannitol, nebulised dornase alpha, nebulised N-acetylcysteine) and oral 
mucolytics or expectorants, provided they had been a regular medication for at least 
30 days. 
 
The following medications may be used concomitantly with caution: 
• non-depolarising muscle relaxants; 
• other 
nephrotoxic 
or 
neurotoxic 
medications 
(e.g. 
cephalothin 
sodium, 
aminoglycosides, non-depolarising muscle relaxants) including those administered 
intravenously or intramuscularly; 
For non-permitted medications, please see Exclusion Criteria (Section 7.2.2).  
10.1. RESCUE MEDICATION 
Rescue medication for NCFB pulmonary exacerbations allowed in the study include: 
• acute and/or short-term administration of oral/intravenous bronchodilators and 
corticosteroids, if required; 
• systemic (oral or intravenous) antibiotics according to current treatment regimens 
used at the participating sites; 
• acute and/or short-term administration of oxygen therapy/ventilator assistance. 
 
At each visit subjects will be asked about any rescue medications they have taken to self-
treat at home.  
Rescue medication prescribed by the Investigator for a pulmonary exacerbation will be 
documented. 
The following will be recorded: 
• Dates of administration including start and end dates; 
• Dosage information including dose and frequency; 
• Reason for use. 

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11. INVESTIGATIONAL MEDICINAL PRODUCT 
11.1. INVESTIGATIONAL MEDICINAL PRODUCT SUPPLIES AND 
PACKAGING 
Colistimethate sodium and placebo will be supplied in 30-vial packs with the 
 device 
containing a disc to activate the aerosol device. 
Colistimethate sodium is supplied as sterile powder in a glass vial. Each vial contains 
1,000,000 International Units (1 MIU) which weighs about 80 mg (equivalent to about 33 
mg colistin base activity). The product is manufactured by 
 
. 
Identical sterile vials for placebo will be manufactured by 
. All 
vials will be masked with white plastic sleeves so that the contents are not visible. The 
weight of the powder is insignificant compared to the glass vial. 
The vehicle will be 0.45% sodium chloride sterile solution provided in plastic ampoules 
sealed in aluminium pouches containing a deliverable 1.0 mL of 0.45% NaCl manufactured 
by 
.  
No special precautions for storage are required for the IMP. 
All IMP, vehicles, inhaled short-acting bronchodilator (e.g. salbutamol/albuterol), and 
 
devices will be shipped to sites by 
 where 
 is in charge of 
masking vials, packaging and labelling.  
IMPs will be labelled according to Good Manufacturing Practice (GMP) and country specific 
regulations as required by the regulatory agencies in the countries where the trial is 
conducted. Labels will be printed in a booklet with all local languages or as a single panel 
label. Allocation of IMP will be managed through the IWRS used for the trial. 
The 
 system will be provided as the commercially available devices. 
The inhaled short-acting bronchodilator (e.g. salbutamol/albuterol) will be provided as non-
IMP to all subjects and labelled properly for clinical trial use only.  
11.2. INVESTIGATIONAL MEDICINAL PRODUCT DISPENSING AND 
ADMINISTRATION 
Subjects will administer the first dose of the IMP at the investigational site under the 
supervision of the site staff, and will be instructed by the Investigator or a delegated person 
how to prepare and self-administer the IMP at home via the
 
 system, twice daily (morning and evening) over a period of 12 months. At least 10 
minutes prior to each administration, an inhaled short-acting bronchodilator (e.g. 
salbutamol/albuterol) should be taken to improve tolerability. When the first dose is 
administered at the investigational site, subjects will have their FEV1 monitored pre-
bronchodilator and 30 ± 10 minutes post-IMP dose to investigate if there is any evidence 
of bronchospasm (defined as a decrease >15% in FEV1 – not due to poor technique - from 
pre-bronchodilator baseline).  
Subjects experiencing a decrease in FEV1 >15% from pre-bronchodilator baseline and/or 
clinically determined bronchospasm after receiving their first dose of IMP, will be withdrawn 
from the trial. 
The subject will administer the IMP at home twice daily (morning and evening) about at 
least 10 minutes after inhaled short-acting bronchodilator administration. If the patient does 
not wish to use the bronchodilator and tolerates the IMP without it, this is acceptable but 
should be documented appropriately.   
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The IMP must be reconstituted by carefully removing the red plastic cap on top of the vial 
and the attached aluminium collar seal, and injecting the 1 mL saline through the rubber 
stopper into the vial using a syringe provided by the CRO to each site. The vials must not 
be shaken but gently rolled between both hands to facilitate the dissolving of the powder. 
After 5 minutes of rest, the stopper can be opened and all of the solution transferred into 
the 
 chamber (with a 0.3 mL dosing chamber). Active treatment and placebo solutions 
are identical so that neither the Investigator nor the subject can recognize the identity of 
the product.  
The instructions for preparation and administration of the IMP through the 
 device will 
be described in detail in an information leaflet for participating subjects. 
The Investigator must instruct the subject to use the 
 device only for this study and 
only with the IMP provided. The IMP must not be diluted with any other solution or product.  
At each visit, the subjects will be provided with sufficient IMP for treatment until the following 
visit including additional spare vials.  
Subjects must be instructed to return the empty used and unused vials to the site at the 
respective visits. Subjects will be requested to bring their 
 to each clinic visit for the 
ongoing assessment of IMP adherence via the data analyser installed in the laptop 
provided by the Sponsor for this purpose. 
11.3. RANDOMISATION 
 
Each subject will receive a screening number as soon as site staff enters the IWRS, 
provided by 
, after they have signed the Informed Consent Form (ICF) at Visit 1.  
The screening number will consist of a country number (2 digits), a site number (3 digits) 
and a unique, sequential number for a subject at an individual site (3 digits), e.g. 01-001-
001. Every subject who signs the ICF must be entered into the IWRS system regardless of 
eligibility. 
At Visit 2, eligible subjects will be randomised using the IWRS according to a pre-specified 
randomisation scheme such that they either receive colistimethate sodium or placebo. Site 
and use of stable concomitant therapy with oral macrolides (azithromycin or erythromycin 
or clarithromycin) (Yes/No) will be considered for balancing randomisation. Thus, within 
each site, subjects with azithromycin or erythromycin or clarithromycin use will be 
randomised independently from subjects without use of azithromycin or erythromycin or 
clarithromycin, to receive colistimethate sodium or placebo in a 1:1 ratio.  
The randomisation within each site and nested level of azithromycin or erythromycin or 
clarithromycin use will be done with blocks to guarantee a good balance between 
colistimethate sodium and placebo at any stage of the enrolment. 
Note: according to Exclusion Criterion 17, the decision on whether stable concomitant 
antibiotic therapy with any oral macrolides (e.g. azithromycin/erythromycin/clarithromycin) 
will be administered to a subject or not will have been made at least 30 days prior to 
Screening (Visit 1). The treatment with oral macrolides should be continued throughout the 
trial in order not to jeopardize the study results.  
The allocation to the treatment will be stored within the IWRS database until unblinding of 
the trial is requested. Unblinding may be performed through the IWRS directly by the 
Investigators only in case of SAE of life-threating significance where knowledge of 
treatment assignment is essential for the future management of patient care (see Section 
13.1).  
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11.4. INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY 
IMP inventory and accountability records will be maintained within IWRS. The following 
rules are to be followed: 
a) 
The Investigator will keep IMP in a pharmacy, or a locked and secure storage facility, 
accessible only to those individuals authorised by the Investigator to dispense the 
IMP. 
b) 
The inventory will be maintained by the Investigator or pharmacist or other nominated 
individual. A Site Inventory Summary Report will be printed from IWRS and signed by 
the Investigator or pharmacist and Clinical Research Associate (CRA) and filed in the 
Investigator Site File and/or Pharmacy Site File. 
c) 
The IWRS includes details of IMP received and a clear record of when they were 
dispensed and to which subject and returned IMP and when returned. The IWRS shall 
indicate the quantity and description of all IMPs on hand at any time during the course 
of the clinical trial. 
d) 
At the conclusion or termination of the clinical trial, the Investigator agrees to conduct 
a final IMP inventory and to record the results of the inventory on an appropriate form 
provided by the CRO/IWRS (Investigational Product Return Form). The pharmacist, 
if applicable, may assist with this. The monitor will check that IMP accountability was 
correctly performed. According to instructions, the Investigator will return all original 
IMP containers, whether empty or containing test preparations, to 
 for final 
reconciliation and destruction. 
e) 
The IMP can be dispensed to subjects only by the Investigator/pharmacist who agrees 
not to supply IMP to any person except those named as Investigators/Co-
Investigators/study coordinators as detailed in the Site Signature/Delegation Log, and 
to subjects in this trial. 
12. CLINICAL TRIAL AMENDMENTS 
Changes to the CTP can only be made by preparing written amendments to be agreed and 
signed by the Investigator and Sponsor. No substantial amendment can be implemented 
without a favourable opinion of the EC and CA, unless the changes consist of urgent safety 
measures to protect trial subjects. 
Amendments which are non-substantial amendments as defined by current regulations can 
be sent to the EC/CA for notification as applicable per local requirements, and may be 
implemented at the site before EC notification according to local rules.  
13. DEVIATIONS FROM THE CLINICAL TRIAL PROTOCOL 
Any major or critical deviation which may have an impact on study results and/or the safety 
of the subjects should be immediately reported to the CRO and a decision will be taken 
together with the Sponsor whether or not the subject (for whom the deviation from the CTP 
took place) is to continue in the trial. A deviation log will be maintained to track actual 
deviations and decisions taken, including all deviations which occurred. All deviations will 
be reported to the EC and CA according to ICH-GCP and local requirements. 
In case of an emergency deviation from the CTP applicable only when an emergency 
situation has to be faced for a subject, this deviation will only be applied to that individual. 
In such an emergency the Investigator must contact the CRO by telephone as soon as 
possible.  

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13.1. CODE BREAKING 
The code for any individual subject will not be broken by the Investigator during the course 
of the trial except in the circumstance of an SAE where knowledge of treatment assignment 
is essential for the management of patient care. 
In case of emergency, unblinding of the treatment code will be done through IWRS. The 
treatment group will be disclosed and confirmation will follow (by fax and/or notification 
email). The IWRS will be designed to send a confirmation (by fax and/or notification email) 
to the site for every transaction performed by the site users. Site users will be provided with 
usernames and passwords to access the IWRS. Unblinding of the study treatment must be 
done in case of an emergency situation, where the Investigator considers it essential to 
know what treatment the subject was taking. Access to the unblinding option will be granted 
only to the Investigators and sub-Investigators at the sites. The IWRS will promptly notify 
the Sponsor and the CRA whenever a treatment code is unblinded. If the treatment code 
has been disclosed, this must be recorded in the eCRF.  
Users from 
 and Sponsor Pharmacovigilance will have their own passwords 
to unblind subjects in case of suspected unexpected serious adverse reactions (SUSARs) 
to be reported to the CA and ECs. 
14. CLINICAL TRIAL WITHDRAWALS/DROP-OUTS 
Subjects will be withdrawn from the trial for one of the following reasons: 
• subject may withdraw from the study at any time at his/her own request;  
• subject may withdraw from the study due to an AE including subjects experiencing a 
decrease in FEV1 >15% from pre-bronchodilator baseline and/or clinically 
determined bronchospasm after receiving their first dose of IMP;  
• subject may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural, compliance or administrative reasons; 
• subject may be withdrawn due to lack of adherence to study medication regimen. 
• subjects who become pregnant should be withdrawn from the trial (subject’s follow-
up should be performed in accordance with Section 16.9);  
• non-emergency unblinding of study treatment allocation;  
• lost to follow up: before a subject is deemed lost to follow up, the Investigator or 
designee must make every effort to regain contact with the participant (where 
possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts should 
be documented in the participant’s medical record. Should the participant continue to 
be unreachable, he/she will be considered to have withdrawn from the study;  
• Sponsor, CA, or EC, terminate the trial or participation of an individual site.  
The reason for removal of a subject from the trial or premature discontinuation of treatment 
must be fully documented in the eCRF as well as in respective source documents. Follow-
up for withdrawn subjects follows the procedures described in Section 16.8 and Section 16.9. 
If possible, the subject should return to the clinic for an early End of Study Visit. The subject 
must return the medications, 
, and details regarding AEs (including exacerbations) and 
concomitant medications will be collected.  
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15. STOPPING AND DISCONTINUATION CRITERIA FOR THE 
TRIAL 
The trial may be prematurely terminated or placed on temporary hold for the following 
reasons: 
• the Sponsor feels that the number and/or severity of AEs justifies discontinuation of the 
trial; 
• the Sponsor considers the applied doses of the IMP to be no longer relevant; 
• data not known before become available and raise concern about the safety of the IMP 
so that continuation would pose potential risks to the subjects. 
Premature termination of the trial must be reported to the EC and CA according to 
applicable laws; generally within 15 days. A detailed written explanation of the reason 
should be given and alternative procedures for subjects under treatment specified.  
However, trial results have to be reported according to the requirements outlined in this 
CTP as far as applicable. 
If, after the termination of the trial, the risk/benefit analyses have changed, the new 
evaluation should be provided in case it will have an impact on the planned follow-up of the 
subjects who have participated in the trial. If possible, the subject should return to the clinic 
for an early End of Treatment Visit. 
16. REPORTING SAFETY INFORMATION 
16.1. DEFINITION OF ADVERSE EVENT 
An AE is "any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this 
treatment". 
AEs include: 
• worsening (change in nature, severity or frequency) of conditions present at the 
onset of the trial; 
• subject deterioration due to the primary illness; 
• intercurrent illnesses; 
• drug interactions; 
• events related or possibly related to concomitant medications; 
• abnormal laboratory values, as well as significant shifts from baseline within the 
range of normal, which the Investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, 
whether or not considered related to the IMP. 
16.2. DEFINITION OF ADVERSE EVENT OF SPECIAL INTEREST  
No AEs of special interest are defined for this trial.  

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16.3. DEFINITION OF ADVERSE DRUG REACTION 
An adverse drug reaction (ADR) is “any untoward and unintended response to an IMP 
related to any dose administered and which implies an AE with at least a reasonable 
possibility of a causal relationship with the use of the product (i.e. there is evidence or 
arguments to suggest a causal relationship). 
The definition also covers medication error and uses outside what is foreseen in the CTP, 
including misuse and abuse of the IMP. 
All AEs judged by either the reporting Investigator or the Sponsor as having a reasonable 
causal relationship to a medicinal product qualify as suspected ADRs. 
16.3.1. 
DEFINITION OF UNEXPECTED ADVERSE DRUG REACTION 
An unexpected ADR is: “An adverse reaction, the nature, or severity of which is not 
consistent with the applicable product information”. 
The reference safety information for evaluation of AE expectedness in this trial will be 
Section 7.5.9 of the Investigator’s Brochure for colistimethate sodium in line with relevant 
information of the current EU SmPC Promixin® 1 MIU powder for nebuliser solution. In this 
patient population, pulmonary exacerbations (including pneumonia) are also considered as 
expected adverse events. 
16.3.2. 
DEFINITION OF MEDICAL DEVICE MALFUNCTION AND INCIDENT 
A medical device malfunction is the failure of a device to meet performance specifications 
or to perform as intended. A medical device incident is any malfunction or deterioration in 
the characteristics and/or performance of a device, as well as any inadequacy in the 
labelling or instructions for use which, directly or indirectly, might lead to or might have led 
to the death of a patient, a user, or other persons, or to a serious deterioration in their state 
of health. A medical device complaint meeting the criteria of a potential medical device 
incident is reportable.  
Subjects will also be monitored for any medical device malfunction or incident and, if these 
occur, details will be recorded as for ADRs. 
16.4. DEFINITION OF SERIOUS ADVERSE EVENTS OR SERIOUS 
ADVERSE DRUG REACTIONS 
16.4.1. 
DEFINITION OF SERIOUS ADVERSE EVENT OR SERIOUS ADVERSE 
REACTION 
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is any untoward 
medical occurrence or effect that at any dose: 
• results in death; 
• is life-threatening (i.e. the subject was at risk of death at the time of the event/reaction; 
it does not refer to an event/reaction which hypothetically might have caused death if 
it were more severe); 
• requires inpatient hospitalisation or prolongation of existing hospitalisation; 
• results in persistent or significant disability/incapacity (where disability is defined as a 
permanent or substantial disruption of ability to carry out normal life functions, either 
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• is a congenital anomaly/birth defect; 
• is an important medical event that may not result in death, be life-threatening, or 
require hospitalisation but, according to appropriate medical judgement, it may 
jeopardise the subject and may require medical or surgical intervention to prevent any 
of the outcomes listed in the definition above. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, and 
blood dyscrasias or convulsions that do not result in hospitalisation, or development 
of drug dependency or drug abuse.  
Any suspected transmission via a medicinal product of an infectious agent is also 
considered an SAE. 
A Serious Adverse Reaction (SAR) is any SAE judged by either the reporting Investigator 
or the Sponsor as having a reasonable causal relationship to a medicinal product. 
16.4.2. 
DEFINITION OF SUSPECTED UNEXPECTED SERIOUS ADVERSE 
REACTIONS 
 
A Suspected, Unexpected Serious Adverse Reaction (SUSAR) is a subset of SAEs/SARs 
that, although foreseeable, are potentially related to the IMP and not identified in the 
reference safety information and will be reported to the appropriate regulatory authorities 
and Investigators following local and global guidelines and requirements. 
16.5. DEFINITION OF SEVERITY OF ADVERSE EVENTS 
The term “severe” is used to describe the intensity (severity) of a specific event: 
• Mild: causing no limitation of usual activities; the subject may experience slight 
discomfort; 
• Moderate: causing some limitation of usual activities; the subject may experience 
annoying discomfort; 
• Severe: causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
16.6. DEFINITION OF ADVERSE EVENT CAUSALITY 
Causality shall be determined according to the definition of ADRs as given in Section 16.3. 
All AEs judged by either the Investigator or the Sponsor as having a reasonable suspected 
causal relationship to an IMP qualify as suspected ADRs. The causality assessment given 
by the Investigator should not be downgraded by the Sponsor. 
The following binary decision for causality will be used: 
• reasonable possibility that the IMP caused the event; 
• no reasonable possibility that the IMP caused the event. 
Features supportive of an association include: 
• temporal plausibility; 
• pharmacological properties of the drug or of the drug substance class; 
• course of the AE after dechallenge and, if applicable, after rechallenge; 
• specific tests indicating involvement of the drug in the occurrence/worsening of the 
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• alternative explanations. 
16.7. ADVERSE EVENT RECORDING 
Each AE occurring to a subject, either spontaneously revealed by the subject or observed 
by the Investigator, whether believed by the Investigator to be related or unrelated to the 
IMP, must be recorded by the Investigator on the AE information page of the eCRF. Also, for 
SAEs, information must be recorded in the eCRF (see Section 16.8.1).  
The Investigator performs an evaluation with respect to seriousness and causality of the AEs 
and records it on the appropriate section of the eCRF. 
16.8. ADVERSE EVENT REPORTING 
The Investigator must report to the CRO all AEs which occur during the trial, regardless of 
their relationship to IMP. All AEs are recorded by the Investigator on the AE information page 
of the eCRF. 
In addition, any SAE will have to be reported according to the following detailed procedure. 
16.8.1. 
REPORTING SERIOUS ADVERSE EVENTS 
Investigators must report SAEs within 24 hours of first becoming aware of the event. 
The SAE must be reported through the eCRF to the CRO’s Pharmacovigilance group as 
given in the contact details provided in the "List of Zambon/CRO personnel" at the 
beginning of this CTP. 
If there is any issue with the electronic reporting process, such as internet failure or 
database issues, this must not delay SAE reporting. The back-up procedure is to send the 
back-up paper SAE Form to the CRO’s Pharmacovigilance group by email or fax using the 
following contact details: 
Email: 
 
Fax: 
 
Note: Any reports submitted on paper must be retrospectively added to the eCRF as soon 
as possible. 
The community standards of confidentiality must always be maintained and any relevant 
national legislation on data protection must be followed. 
SAEs are reportable from the time a subject signs the informed consent to the follow-up 
phone call 2 weeks after the last dose of IMP. 
If the Investigator becomes aware of any SAE occurring to a subject within the follow-up 
window established in this CTP, he/she will report the SAE as above. The SAE will be also 
reported in the eCRF. 
If the Investigator becomes aware of any SAE outside the follow-up window established in 
this CTP, it is the Investigator’s responsibility to report the SAE to the CRO. The 
Investigator might use the eCRF, as described above. However, the SAE is not an event 
which occurred within the trial period. 
16.8.2. 
REPORTING ADVERSE EVENTS OF SPECIAL INTEREST  
No specific provisions relate to reporting of AEs of special interest.  
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16.9. FOLLOW-UP FOR ADVERSE EVENTS 
All AEs requiring the subject’s discontinuation and SAEs will be followed up until they are 
resolved or closed. 
Resolution of an AE is defined as the return to pre-treatment status or stabilisation of the 
condition with the expectation that it will remain chronic.  
The Investigator must respond to any request for follow-up information (e.g. additional 
information, outcome and final evaluation, specific records where needed) and answer any 
question that the Sponsor or designee may have regarding the AE.  
Regarding SAEs, the timelines and procedure for follow-up reports are the same as those 
for the initial reports for SAEs. 
This is necessary to permit a prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations. 
If follow-up information on SAEs is available, a follow-up eCRF form will be filled-in by the 
Investigator and sent to the CRO as described above, under Section 16.8.1.  
16.10. PREGNANCY 
Subjects must be instructed that known or suspected pregnancy occurring during the trial 
should be confirmed and reported to the Investigator, who must then withdraw the subject 
from the trial without delay. This also applies in case the partner of a male subject becomes 
pregnant at any time during the whole course of the study (in this event a specific ICF for 
the subject’s partner will be obtained). 
In the event that a subject is subsequently found to be pregnant after inclusion in the trial, 
then the subject will be withdrawn from the study and the pregnancy will be actively followed 
up to term and the status of mother and child will be reported by the Investigator to the 
CRO through the appropriate pregnancy report provided by the CRO.  
The Investigator will send pregnancy reports within the timeframes of SAEs. 
If pregnancy results in an abnormal outcome that the Investigator and/or the Sponsor 
considers to be due to the IMP, this will be treated as an expedited ADR report. 
17. RECORDS
17.1. CASE REPORT FORMS, SOURCE DATA AND QUERY 
RESOLUTION 
The Investigator must ensure that the clinical data required by the CTP are carefully 
reported in the eCRF. He/she must also check that the data reported in the eCRF 
correspond to those in the official files (source documentation).  
Data entered directly into the eCRF comprises all data recorded via the eCOA devices for 
 assessment, though an electronic copy of the subject’s 
 data must be stored as 
source data at the investigational site at the end of the trial. If available, spirometry and 
ECG measurement results must be printed and signed by the Investigator and kept as 
source data on site after entering details into the eCRF. Adherence data from the 
 
logging system will not be present at the investigational site as source data as they will be 
transferred into the eCRF from the sources directly. The Investigator will receive the results 
from the central lab by means of a laboratory report, and this should be signed by the 
Investigator, and stored as source data in the subject’s file. 
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All other data has to be documented in the subject file as source data first and then entered 
into the eCRF.  
Data must be entered into eCRFs in English by the designated site personnel as soon as 
possible after a subject visit, and monitors will have access to data recorded. These data 
will be reviewed versus source documents by trial monitors for completeness and 
acceptability during monitoring visits.  
If data correction is required for an eCRF after initial entry, the site personnel can make 
necessary corrections on their own or as a response to an auto generated query by the 
eCRF system. The CRA and Clinical Data Manager review the eCRF for accuracy and can 
also generate queries to the investigational staff for resolution.  
Any correction to the eCRFs' entries must be carried out by the Investigator or a designated 
member of staff. Corrections are recorded in an audit trail that records the old information, 
the new information, and identification of the person making the changes, date of correction 
made and reason for the change. In the interests of completeness of data acquisition, the 
questions which are repeated in each section of the eCRFs should be answered in full, 
even if there are no changes from a previous examination. A reasonable explanation must 
be given by the Investigator for all missing data. The Investigator or his/her designees 
named in the clinical staff list will review the eCRF for accuracy and completeness. The 
Investigator must electronically sign and date the eCRF pages as indicated. 
17.2. RECORDS MAINTAINED BY THE INVESTIGATOR 
A copy of all trial records (any documents sent or received from the Sponsor/CRO, 
correspondence with EC and any other institution or authority and relevant approvals, 
subjects' source data and subjects' identification documentation) must be maintained by 
the Investigator for at least 5 years (according to EU directive 2005/28/EC), or for a longer 
period, where so required by other applicable requirements or by an agreement between 
the Sponsor and the Investigator. 
17.3. TRIAL MASTER FILE 
The Trial Master File (TMF) will be maintained electronically by the CRO according to the 
respective CRO SOPs with direct access for all CRO and Sponsor personnel.  
At the end of the trial, the TMF will be transferred to the Sponsor, where it will be archived 
according to specific Sponsor SOPs. A copy of the Investigator files will be left on site after 
the end of the study. 
17.4. TRIAL MONITORING 
The trial will be monitored by means of regular visits and telephone calls according to 
specific and pre-defined SOPs and trial-specific monitoring guidelines. Details of the visits 
will be recorded in appropriate Monitoring Report forms to be submitted regularly to the 
Sponsor. Any relevant protocol deviation must be promptly communicated to designated 
Sponsor’s personnel.  Monitoring will be performed by personnel of the CRO, 
 
.  
17.5. CONFIDENTIALITY OF SUBJECT’S INFORMATION 
The Investigator has the responsibility to maintain the anonymity of subjects in compliance 
with the Italian data protection law. In all trial documents, subjects are associated to a code 
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which does not reveal the subject’s identity. Only at the site, the Investigator holds the 
subject’s identity on a Subject Identification Log under his/her responsibility. The 
Investigator will maintain this for the longest period allowed by his/her own institution and, 
in any case, until further communication from the Sponsor. 
The site and the Sponsor shall process personal data of subjects involved in the clinical 
trial as data controllers and in compliance with the Italian data protection law, each of them 
in its area of competence and in accordance with the responsibilities provided by GCP, 
only in relation to the trial performance and for pharmacovigilance purposes. 
Any contracted organisation as data processor including the CRO, the central laboratory, 
eCOA provider, and IWRS provider, will act in compliance with the terms and conditions 
agreed with the Sponsor. All data will be handled in compliance with Regulation (EU) 
2016/679 of the European Parliament and of the Council on the protection of natural 
persons with regard to the processing of personal data. 
18. BIOMETRICS 
18.1. DATA MANAGEMENT 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, and releasing) will be maintained and stored 
at the CRO. 
Electronic systems that may be used to process and/or collect data in this study will include 
the following: 
• IWRS system – randomisation, study drug supply 
• Electronic Data Capture - eCRF  
• eCOA device - 
 data capture 
• Statistical Analysis System (SAS®) – statistical review and analysis 
• Pharmacovigilance safety database 
Subject data will be captured in an eCRF system and reviewed by the CRA in order to 
check CTP adherence and to detect any data inconsistency or discrepancy (data validation 
step). 
Medical/surgical history and underlying diseases and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) latest version current at trial start and which 
will be maintained during the trial. 
Previous and concomitant medications will be coded using the World Health Organization-
Drug Dictionary (WHO-DD).  
Actual versions of coding dictionaries used will be stated in the Clinical Trial Report (CTR).  
The final data file will be transferred to the Sponsor in the agreed format as soon as possible 
after the trial is completed. 
18.2. STUDY VARIABLES 
 
Primary Efficacy Variable: The primary variable for this trial is the mean annual NCFB 
pulmonary exacerbation rate. 
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Secondary Efficacy Variables 
•
Safety Variables 
•
incidence of TEAEs;
•
absolute changes in percent-predicted FEV1 from baseline (Visit 2) to end of treatment
(Visit 7);
•
number of subjects experiencing bronchospasm clinically or spirometrically
determined following IMP administration at the start and end of treatment;
•
 from Screening/Randomisation (Visit 1/Visit 2) to Visits 3, 5 and
end of treatment (Visit 7) as well as on 
 from Exacerbation Visits and clinic
visits due to pneumonia;
•
emergence of other bacterial colonies and any developing resistance in 
 from
Screening (Visit 1) to End of Treatment (Visit 7);
•
haematology, clinical chemistry and renal function tests;
•
physical examination and vital signs data;
•
12-lead electrocardiogram.
18.3. SAMPLE SIZE 
The sample size has been calculated considering the results from the previous trial 
, relevant literature and the clinically meaningful benefit the treatment should 
provide. A treatment difference of 
 between the colistimethate sodium and placebo 
groups 
 
 
For the purpose of the power calculation, a simulation of exacerbations has been carried 
out by randomly assigning a patient a value 
 according to the 
treatment group they are in and then generating a 
 event rate using this parameter. 
This 
 leads to two negative binomials with the following parameter 
values: 
 
. 
These are rates per year. Note that, since the variances are greater than the mean, this 
means that there is mild over-dispersion. 
Under these assumptions, a Poisson regression allowing for over-dispersion for frequency 
of exacerbation (FOE), with a two-sided significance level of 0.05, a treatment effect of 
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, and a follow-up time of 
, assuming a frequency of 
 pulmonary 
exacerbations per annum for the FOE, a sample size of 170 completed subjects per group 
will provide a power of
 
 
  
Assuming a drop-out rate of about 20%, the total sample size should be 210 subjects per 
treatment group (420 total subjects). 
18.4. STATISTICAL ANALYSES 
The statistical analysis will be performed by the CRO and it will be carried out according to 
ICH guidelines ICH E9: “Statistical Principles for Clinical Trials” (CPMP/ICH/363/96 
September 1998) and ICH E10 “Choice of Control Group in Clinical Trials” 
(CPMP/ICH/364/96 January 2001). 
All the statistical analyses and outputs will be produced using SAS release 9.2 or later (SAS 
Institute, Inc. Cary, NC, USA). 
The data from all countries and all sites will be pooled and summarised. Unless stated 
otherwise, all available data from withdrawn subjects will be included in the analysis up to 
the time of withdrawal. 
Descriptive statistics will be used to present all efficacy and safety results: number of 
observations, mean, standard deviation, median, minimum, maximum for continuous data 
and frequency and percentage for categorical data. Statistics will be displayed by treatment 
group.  
The analysis of the trial is on a comparative basis. Two-sided p-values <0.05 will be 
considered statistically significant and 95% two-sided confidence intervals (CIs) will be 
presented, where appropriate. Any adjustment for multiplicity will be detailed in the 
Statistical Analysis Plan (SAP).  
More details about the statistical analysis will be provided in the SAP. The plan might be 
reviewed and updated as a result of the blind review of the data and will be finalised before 
breaking the blind. Any deviations from the SAP which occurred after breaking the blind 
will be documented and justified in the final CTR and deviations will be clearly marked as 
‘post hoc’ analysis. 
18.4.1. 
TRIAL POPULATIONS 
There will be 4 analysis populations defined for the trial analyses: 
Intention-To-Treat (ITT) Population The Intention-To-Treat Population will include all 
subjects who provided informed consent and received a patient number (randomisation 
number) whether or not they receive IMP. 
 
Modified Intention-To-Treat Population The Modified ITT (mITT) Population will comprise 
all subjects who provided informed consent, were randomised and received at least 1 dose 
or partial dose of the IMP.  
Primary analyses will be performed on the mITT population with exclusions from the ITT 
defined and justified in the SAP.  
Following the ITT principle, subjects will be analysed according to the treatment they have 
been assigned to at randomisation. 
The mITT will be used to produce summaries of baseline subject characteristics and for 
the analysis of all efficacy variables. 
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Safety Population 
The Safety Population will comprise all subjects who provide Informed Consent and 
received at least 1 dose or partial dose of IMP.  
Subjects will be analysed according to the treatment they actually received.  
The Safety Population will be used to produce summaries of all safety-related variables 
and demography. 
 
Per-Protocol Population 
The Per-Protocol Population (PP) will include all mITT subjects who were compliant with 
study drug administration (i.e. had a compliance of at least 80%) and who had no major 
protocol deviations that were considered as potentially impacting the efficacy results. Major 
protocol deviations might include, but are not limited to, subjects taking a non-permitted 
concomitant medication, the IMP not being administered during the trial as defined in the 
protocol, subjects receiving a treatment different than the one assigned by randomisation; 
others will be defined in the SAP.  
Results of the primary and secondary efficacy analyses conducted in the PP will be 
considered as supportive. 
Exclusion of subjects from the PP analyses will be decided jointly by the CRO and 
Sponsor’s Medical Monitor, Clinical Trial Manager and Statistician prior to unblinding of the 
randomisation code and database release.  
The subjects or observations to be excluded, and the reasons for their exclusion will be 
documented and approved by the above-mentioned persons prior to database release. The 
documentation will be filed together with the remaining trial documentation. 
The number of subjects in each analysis population will be reported. Violations excluding 
subjects from any particular population will be described, reporting the number of protocol 
violators for each criterion. All protocol violations, minor ones included, will be listed. 
18.4.2. 
EFFICACY DATA 
The primary analysis will be performed on the mITT population. Analyses conducted using 
the PP will be considered supportive. 
 
Primary Endpoint 
In order to investigate whether the use of inhaled colistimethate sodium reduces the 
frequency of pulmonary exacerbations compared to placebo in subjects with NCFB 
chronically infected with P. aeruginosa, the following hypothesis will be tested:  
- 
Null hypothesis A: there is no difference between inhaled colistimethate sodium and 
placebo as regards the effect on the pulmonary exacerbation rate against Alternative 
hypothesis A: inhaled colistimethate sodium reduces the pulmonary exacerbation 
rate. 
The null hypothesis must be rejected for the efficacy of inhaled colistimethate sodium to be 
considered demonstrated.  
A 
 analysis will be conducted using an alternative definition of NCFB pulmonary 
exacerbation. The re-classification of exacerbations will be conducted in a blinded fashion 
(before database lock). The alternative definition of pulmonary exacerbations used will be 
deterioration in three or more of the following key symptoms for at least 48 hours: 
- 
Cough  
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- 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Mean Annual Pulmonary Exacerbation Rate 
The number of NCFB pulmonary exacerbations during the treatment period will be 
analysed using a Poisson regression model allowing for over-dispersion including 
treatment, pooled sites and use of stable concomitant therapy with oral macrolides as fixed 
effects and log-time on trial as an offset.  
The number and the percentage of subjects with NCFB pulmonary exacerbations, the 
number of pulmonary exacerbations and the total follow-up time in years will be 
summarised by treatment group. The adjusted yearly mean exacerbation rates in each 
treatment group and the adjusted rate ratio with their 95% CIs will be estimated by the 
model.  
For the analysis, 2 pulmonary exacerbations will be considered as a single episode in cases 
where the second exacerbation starts less than 14 days after the end of the antibiotic 
therapy (oral or intravenous) for the first pulmonary exacerbation. 
If the null hypothesis will be rejected, additional investigation of proportionality of the hazard 
will be implemented in a secondary analysis. Additional details on the analysis will be 
provided in the SAP. 
A corresponding two-sided p-value of <0.05 will be considered statistically significant. 
 
Secondary Endpoints 
Summary statistics and analyses of the secondary efficacy/pharmaco-economic endpoints 
will be conducted for the mITT (main analysis) and the PP, as follows. 
 
 
 
will be calculated as the time in days from the date of the first dose 
of IMP
 
A log-rank sum test will be 
used to compare the treatment groups. Subjects completing the trial without 
 
 or who are discontinued prematurely 
, will 
be considered as censored at the time of their last follow-up.  
 
 
 will also be presented by treatment 
group. An appropriate non-parametric test will be used that makes allowing for the effect 
of prognostic covariates possible. This will be finalised in the SAP. 
 
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The number and the percentage of subjects
 
 
 
 
 
 
 
 
 
 
 
 
 
The 
 total score and domain scores 
 will be 
summarised at each visit by treatment group using descriptive statistics. Changes from 
baseline (Visit 2) will also be summarised for each post-baseline visit by treatment group. 
Scores will be computed according to the 
 manual [20].  
Multiple entries and missing data will be dealt with as described in the same manual. 
 will be analysed using a linear mixed model for repeated measures 
including treatment, visit, treatment-by-visit interaction, use of stable concomitant therapy 
with oral macrolides and pooled sites as fixed effects and baseline value as covariate. An 
unstructured covariance matrix will be assumed and the Kenward-Roger adjustment will 
be used for the degrees of freedom. The least square means in each treatment group, the 
least square mean differences between treatments, their 95% CIs and associated p-values 
at each visit will be estimated by the model.  
The 
 will be summarised and analysed similarly to 
the 
 Algorithm of scoring and methods for handling with multiple 
imputations and missing data will be performed according to the questionnaire instructions 
[21, 22]. 
 
The 
 as determined by the mean change in 
 from 
baseline (Visit 2) to Day 28 (Visit 3), as well as to Visits 5 and 7, will be compared between 
the treatment groups by an analysis of covariance model including treatment, pooled site 
and use of stable concomitant therapy with oral macrolides as fixed effects and baseline 
value as covariate. Least square means in each treatment group, least square mean 
difference between treatments, their 95% CIs and associated p-values will be estimated. 
Sensitivity analyses may be conducted to assess the robustness of conclusions. 
Summary statistics of the 
 
 and change from 
baseline (Visit 2) will be provided by treatment group for each trial visit. 
 
 
Absolute and relative frequency of subjects 
 
 
 will be presented by treatment group along with the summaries for the 
. Total number 
of days of 
 due to 
 per follow-up month will 
be collected during the study and described by treatment group. 
18.4.3. 
SAFETY DATA 
All safety endpoints will be summarised and analysed using the Safety Population. 
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Incidence of Treatment Emergent Adverse Events 
The number and the percentage of subjects reporting TEAEs, treatment emergent SAEs, 
severe TEAEs, TEAEs leading to discontinuation and TEAEs leading to death will be 
presented by treatment group, along with the number of events occurring.  
TEAEs will also be summarised by System Organ Class and Preferred Term according to 
MedDRA; they will additionally be summarised by severity and relationship to treatment. A 
separate summary table will be provided for SAEs. 
Only TEAEs, i.e. events with an onset date on or after the date of IMP start, will be included 
in the summary tables. Individual data listings will include all AEs recorded; a separate 
listing will be provided for treatment-emergent SAEs. 
 
Number of Subjects experiencing Bronchospasm Clinically or Spirometrically Determined 
following IMP Administration  
The number of subjects experiencing bronchospasm spirometrically determined (a >15% 
decrease in FEV1  - not due to poor technique - from pre-bronchodilator baseline in the 30 
minutes post-IMP), or clinically determined, will be summarised by treatment. Percentages 
of subjects in each treatment group and the relative risk for colistimethate sodium 
group/placebo group will be provided with 95% CI. Treatment differences will be assessed 
using a Fisher Exact test. 
The number and the percentage of subjects experiencing a bronchospasm following IMP 
administration as clinically determined will also be reported by clinical visit. 
In addition, the results for FEV1 and FVC at each visit will be summarised by treatment. 
Descriptive statistics for absolute and percentage changes from baseline, i.e. Visit 2 (pre-
dose measurement) will be reported. 
 
 
The number and percentage of subjects whose 
 
 at the end of treatment (at 12 months [Visit 7]) will be 
presented by treatment, overall and by status of previous usage of colistimethate 
sodium/colistin.  
 
Vital Signs 
Descriptive statistics for vital signs at Visit 1 and Visit 7 will be presented overall and by 
treatment.  
 
Physical examination data 
Descriptive statistics for physical examination data at Visit 1 and Visit 7 will be presented 
overall and by treatment.  
 
Haematology, clinical chemistry and renal function tests  
Haematology, clinical chemistry and renal function test results at Visit 1, Visit 5 and Visit 7 
will be converted to standard international units and summarised by treatment group using 
descriptive statistics for continuous variables. Summaries for change from Visit 1 at Visit 5 
and Visit 7 will also be provided. Renal function tests will also be summarised at Visit 3. 
Frequency of subjects with values appearing outside the central laboratory normal range 
will be reported by visit for each treatment group. All values appearing outside the 
laboratory normal range will be highlighted in listings. 
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12-lead Electrocardiogram 
Descriptive statistics for ECG results will be presented overall and by treatment. 
 
Adherence and Exposure 
Subject adherence will be analysed based on the data collected by the 
 logging 
system.  
Adherence will be summarised by treatment group presenting descriptive statistics and 
percentages of adherent subjects, i.e. with at least 80% adherence.  
The total number of doses of IMP taken by each subject, as recorded as part of the 
 
logging system will be summarised as well. 
18.4.4. 
HANDLING OF MISSING DATA 
Generally, there will be no imputation of missing values and only observed data will be 
included in the analyses.  
If an AE has a partial or fully missing date, and it is unclear whether the AE is treatment-
emergent, it will be assumed that it is. In the AEs analysis, when relationship to study drug 
is missing for a TEAE it will be imputed to be drug related. 
Additional details of handling of missing data for each type of analyses will be provided in 
the SAP. 
19. INFORMED CONSENT 
Written informed consent will be obtained by the Investigator or other authorised person 
from all subjects or their legally acceptable representative.  
The Investigator is responsible for correctly obtaining the informed consent in accordance 
with the applicable regulatory requirement(s), GCP and the ethical principles that have their 
origin in the Declaration of Helsinki. 
Prior to the beginning of the trial, the Investigator must have received the EC written 
approval of the ICF. 
Informed consent must be obtained prior to the initiation of any procedures specific to the 
trial. The record of the informed consent must be available to be audited/inspected by the 
Sponsor/CRO designees and by CA(s), whenever requested.  
The informed consent documentation must be personally dated and signed by the trial 
subjects, to confirm that consent is based on information that has been understood, and by 
the Investigator. 
Neither the Investigator, nor the trial staff, should coerce or unduly influence a subject to 
participate or to continue to participate in a trial. 
Before informed consent may be obtained, the Investigator or other authorised person, 
should provide the subject ample time and opportunity to inquire about details of the trial 
and to decide whether or not to participate in the trial. All questions about the trial should 
be answered to the satisfaction of the subject. 
The subject should receive a copy of the signed and dated ICF and any other written 
information provided to him/her, and updates. 
According to Directive 2001/20/EC, if the subject is not able to write, a verbal consent can 
be obtained. At least 1 impartial witness must be present during the obtaining of verbal 
informed consent. 
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Further, in case the subject and his/her legal representative are unable to read, informed 
consent will be obtained in the presence of an impartial witness, i.e. a person independent 
of the trial who will read the ICF and the written information for the subject. 
20. ETHICS COMMITTEE APPROVAL 
This trial will be undertaken only after written and dated approval from an appropriate EC 
has been received by the Investigator and by the Sponsor for the CTP, all its appendices, 
ICF, and subjects recruitment procedures (i.e. advertisement), if applicable. 
In addition to the documents mentioned above, the EC will be provided with the 
Investigator’s Brochure and any other documents that the EC may need to fulfil its 
responsibilities. 
During the trial, on regular basis, the Investigator will have to submit written summaries of 
the trial status (i.e. recruitment rate) to the EC, if requested. 
21. REGULATORY REQUIREMENTS 
The trial is to be conducted in compliance with the European legislations (Directive 
2001/20/EC and Directive 2005/28/EC) and the European Regulation 536/2014 and any 
applicable local regulations. 
Selection of subjects will not start prior to the approval of the EC has been obtained and 
the trial notified to or authorised by CAs.  
22. QUALITY ASSURANCE 
This CTP has been audited by the Sponsor’s Quality Assurance department. The Audit 
Plan for the study includes site audits. Audits will be planned and conducted according to the 
Sponsor’s SOPs. 
23. INSURANCE 
The Sponsor is concerned with the safety of the subjects in the clinical trial and wishes to 
protect the Investigator (and, as applicable per local regulations, the site, the monitor and 
all the Investigator’s staff involved in the trial) in the event of claims or lawsuits alleging 
injury as a result of administration of a study drug. 
In consideration of undertaking a human trial in subjects according to this CTP the Sponsor 
will:  
• indemnify the Investigator and hold him without liability for claims for damages 
arising out of the above described investigation in excess to those covered by his/her 
own professional liability insurance; 
• defend the Investigator against any claims or lawsuits initiated by, or on behalf of, 
subjects who seek damages for bodily injury alleged to have been sustained as a 
result of administration of the study drug; 
• pay any settlements of judgement resulting therefrom, providing that for all of the 
aforementioned cases, the study drug was administered under the Investigator's 
supervision and in strict accordance with accepted medical practice, the CTP, and 
the precautions, indications, and other instructions, provided by the Sponsor; 
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Indemnification is not valid for claims for damages arising from malpractice and/or 
negligence on the part of the Investigator or those under the Investigator's supervision. 
The protection afforded by this policy does not take the place of the Investigator's 
professional liability insurance, but covers damages in excess of such insurance protection. 
Further, this indemnity is conditional upon the Investigator giving the Sponsor information as 
soon as reasonably practicable and upon the Investigator assisting the Sponsor and its 
authorised representatives in the investigation and defence of any suit for which coverage is 
provided. 
24. CLINICAL TRIAL REPORT 
A CTR of the trial will be prepared and written by the CRO according to ICH topic E3 
(CPMP/ICH/137/95). A summary of the report will be sent to Investigators/EC/Regulatory 
Authorities according to current regulations. 
25. USE OF INFORMATION AND PUBLICATION 
The Investigator agrees to inform Zambon in advance about his/her intention to divulge any 
data, results concerning the Confidential Information and/or the trial subject to this 
agreement. As a consequence hereof, Investigator hereby undertakes to submit to 
Zambon, at least with a 60 days (30 days in case of abstracts) prior written notice, the text 
and/or the content of the concerned publication, sufficient to allow Zambon to 
properly assess that such proposed publication respects and/or is not in conflict with 
Zambon’s rights to preserve and protect its intellectual property rights and any 
confidentiality imposed to Zambon by the prevailing rules of the country where the trial is 
conducted. 
Further, without any prejudice to Investigator’s right to divulge and save information for 
purposes stated herein-above, Investigator intends to seek Zambon opinion and advice on 
and prior to the intended publication and/or disclosure, in consideration also of the 
contractual relationship in force between Zambon and Investigator and the nature of the 
trial hereto. 
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26. REFERENCES
1. Cole PJ. Inflammation. A two-edged sword—the model of bronchiectasis. Eur J
Respir Dis Suppl. 1986;147:6–15.
2. Bilton D. Update on non-cystic fibrosis bronchiectasis. Curr Opin Pulm Med.
2008;14:595-9.
3. McDonnell MJ, Ward C, Lordan JL, Rutherford RM. Non-cystic fibrosis
bronchiectasis. Q J Med. 2013;106:709-15.
4. Kim C, Kim DG. Bronchiectasis. Tuberc Respir Dis. 2012;73:249-57.
5. Weycker D, Edelsberg J, Oster G, and Tino G. Prevalence and Economic Burden of
Bronchiectasis: Clin Pulm Med. 2005;12:205-9.
6. Hacken NT, Kerstjens H, and Postma D. Bronchiectasis. Clin Evid (Online).
2008;1507. Published online 02 Jan 2008.
7. Finch S, McDonnell MJ, Abo-Leyah H, Aliberti S, Chalmers JD. A Comprehensive
Analysis of the Impact of Pseudomonas aeruginosa Colonization on Prognosis in
Adult Bronchiectasis. Ann Am Thorac Soc, 2015;12(11):1602-11.
8. Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The effect of Pseudomonas
aeruginosa on pulmonary function in patients with bronchiectasis. Eur Respir J.
2006;28:974-9.
9. Martinez-Garcia MA, Soler-Cataluña JJ, Perpiñá-Tordera M, Román-Sánchez P,
Soriano J. Factors associated with lung function decline in adult patients with stable
non-cystic fibrosis bronchiectasis. Chest. 2007;132:1565-72.
10. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis
with aerosolised recombinant human DNase I. rhDNase Study Group. Chest.
1998;113:1329–34.
11. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD,
Greening AP, Haslett C, Hill AT. A randomised controlled trial of nebulized
gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med.
2011;183(4):491-9.
12. Drobnic ME, Suñe´ P, Montoro JB, Ferrer A, Orriols R. Inhaled tobramycin in non-
cystic ﬁbrosis patients with bronchiectasis and chronic bronchial infection with
Pseudomonas aeruginosa. Ann Pharmacother. 2005;39:39-44.
13. Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D. Inhaled Colistin in
Patients with Bronchiectasis and Chronic Pseudomonas aeruginosa Infection. Am J
Respir Crit Care Med. 2014: 189(8),975–82.
14. Anthony De Soyza et al., RESPIRE 1: a phase III placebo-controlled randomised
trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis
European Respiratory Journal 2018 51: 1702052; DOI: 10.1183/13993003.02052-
2017
15. Timothy Aksamit et al. RESPIRE 2: a phase III placebo-controlled randomised trial
of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis
European Respiratory Journal 2018 51: 1702053; DOI: 10.1183/13993003.02053-
2017.
16. Pasteur MC, Bilton D, Hill AT. British Thoracic Society Bronchiectasis non-CF
Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis.
Thorax. 2010;65(Suppl. 1):i1–58.
17. Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society
guidelines for the management of adult bronchiectasis. Eur Respir J
2017;50:1700629.
18. Promixin (colistimethate sodium), UK Summary Of Product Characteristics, 2019.
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19. Wilson CB, Jones PW, O'Leary CJ, Cole PJ, Wilson R. Validation of the
AJRCCM 1997;156:536-41.
20. Jones P.
, Version 2.3. Division of 
Cardiac and Vascular Science, St George’s, University of London.
21. Q uittner AL, O’Donnell AE, Salathe MA, et al.
ﬁnal psychometric analyses and determination of minimal important 
difference scores. Thorax. 2015;70:12-20 (accessed 19 Feb 2018).
22.
- Bronchiectasis manual. Available from: 
http://www.psy.miami.edu/qol_b/scoring.phtml
23. Quanjer PH, Stanojevic S, Cole T, Baur X, Hall GL, Culver BH, et al, the ERS Global 
Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3–95-yr 
age range: the global lung function 2012 equations. Eur Respir J. 2012; 40:1324-
43.
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27. APPENDICES 
 
Appendix 1: Trial Flow Chart  
Appendix 2: Investigator Signature Page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1: Trial Flow Chart 
 
ACTIVITIES 
(See sections 8 & 9 
 for details) 
Visit 1 
Screening/ 
Rescreening 
Visit 2 
Randomisation 
 
Phone 
call  
 
 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Visit 7 
EoT 
 
Follow-up 
phone call 
Exacer-
bation  
Visit 
 
Within 30 Days of 
Visit 2 
Day 0 
 
Day 7 
Day 28 
± 1 week 
3 months 
± 1 week 
6 months 
± 1 week 
9 months 
± 1 week 
12 months 
± 1 week 
2 weeks  
± 3 days 
after EoT 
------ 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Medical history/demography 
X 
 
 
 
 
 
 
 
 
 
Verify eligibility for randomisation 
X 
X 
 
 
 
 
 
 
 
 
Previous/concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
AE monitoring including pulmonary exacerbations not otherwise 
reported 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Pregnancy test  
X 
X 
 
X 
X 
X 
X 
X 
 
 
Vital signs 
X 
 
 
 
 
 
 
X 
 
X 
Physical examination  
X 
 
 
 
 
 
 
X 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
Obtain blood samples: Haematology and clinical chemistry/Renal 
Function 
X 
 
 
Xa 
 
X 
 
X 
 
 
Collect 
 sample 
X 
X 
 
X 
 
X 
 
X 
 
X 
Spirometry: FEV1 and FVC 
X 
Xb 
 
X 
X 
X 
X 
Xb 
 
X 
 training, dispensing/collection 
 
X 
 
 
 
 
 
X 
 
 
Review of IMP administration &
 use (adherence) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Study medication: Dispense/accountability  
 
X 
 
X 
X 
X 
X 
X 
 
 
Record of 
 and days of 
 due to 
pulmonary exacerbations 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Weekly follow-up phone calls to determine end of pulmonary 
exacerbations 
 
 
 
 
 
 
 
 
 
 
X 
 
a 
Renal function test only. 
b 
FEV1 and FVC to be measured pre-bronchodilator and 30 ± 10 minutes post-IMP dose. 
 
 
 
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Appendix 2: Investigator Signature Page 
I have read the attached protocol:  A double-blind, placebo-controlled, multi-centre, clinical 
trial to investigate the efficacy and safety of 12 months of therapy with inhaled colistimethate 
sodium in the treatment of subjects with non-cystic fibrosis bronchiectasis chronically 
infected with Pseudomonas aeruginosa (P. aeruginosa). 
I agree to comply with the current International Council for Harmonisation Guidelines for 
Good Clinical Practice and the laws, rules, regulations, and guidelines of the community, 
country, state, or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the sponsor 
or a partnership in which the sponsor is involved.   
I will immediately disclose it in writing to the sponsor if any person who is involved in the 
study is debarred or if any proceeding for debarment is pending or, to the best of my 
knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be 
disclosed to anyone other than the recipient study staff and members of the EC.   
I agree to ensure that this information will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of the 
sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
 
 

SOP C.03.02.06 – App. 3 Page1 of 5
PROTOCOL AMENDMENT
A DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTRE, CLINICAL 
TRIAL TO INVESTIGATE THE EFFICACY AND SAFETY OF 12 MONTHS OF 
THERAPY WITH INHALED COLISTIMETHATE SODIUM IN THE TREATMENT 
OF SUBJECTS WITH NON-CYSTIC FIBROSIS BRONCHIECTASIS 
CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA
(P. AERUGINOSA)
Protocol Code:
Z7224L01
Protocol Name: Promis I
EudraCT Number: 2015-002743-33
Date 18 Nov 2016 - Version Final 4.0
Date 31 Jan 2017 – Version Final 4.1 (UK only)
Date 03 July 2017 – Version Final 4.1 (Portugal only)
Date 17 Apr 2018 – Version Final 5.0
Date 12 Dec 2018 – Version Final 6.0
DATE/VERSION OF THE AMENDMENT: Version Final 7.0/22 Oct 2019
Zambon Spa
Via Lillo del Duca 10
20091 Bresso - Milan - Italy
THIS DOCUMENT IS ZAMBON'S SOLE PROPERTY AND OWNERSHIP. THIS DOCUMENT, AND ALL 
INFORMATION AND DATA CONTAINED HEREIN HAS TO BE CONSIDERED AND TREATED AS STRICTLY 
CONFIDENTIAL. THIS DOCUMENT SHALL BE USED ONLY FOR THE PURPOSE OF THE DISCLOSURE 
HEREIN PROVIDED. NO DISCLOSURE OR PUBLICATION SHALL BE MADE WITHOUT THE PRIOR WRITTEN 
CONSENT OF ZAMBON. 

 
PPD
PPD
PPD
PPD

Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 3 of 9 
Summary of Key Changes 
Section Number & Title 
Description of Change 
Brief Rationale 
Throughout 
Minor administrative and formatting changes have been made to 
improve the quality of the overall study protocol document. 
Throughout 
References to 
. have been 
amended to 
 (the transitioning Contract Research 
Organisation [CRO]). 
Zambon Contact Details 
The Medical Advisor details 
have been amended from Luca 
 to 
 
 has left Zambon 
SpA. 
Contract Research Organisation 
Contact Details 
The CRO details have been 
amended from 
 
 to 
 
, along with the 
associated Medical Monitors 
and contact details for Serious 
Adverse Event (SAE)/pregnancy 
reporting. 
The CRO for the management 
of the study has been 
transferred from 
 
. to 
 
. This decision has been 
made following concerns 
regarding the ongoing 
management of the study and in 
order to improve audit 
preparedness. 
Other Institutions 
The details for 
 
 have been 
deleted. 
Central laboratory operations for 
Promis I do not include this 
division. 
The details for 
 
 have been deleted. 
The Investigational Medicinal 
Product (IMP) Packaging and 
Labelling operations for Promis I 
do not include this division. 
Section 2: Summary; Trial 
Duration 
The anticipated quarter for last 
subject out has been revised. 
The date for last subject out has 
been amended to Q4 2020 to 
reflect the increased recruitment 
period required to achieve the 
required sample size. 
Section 2: Summary; Population 
Inclusion criteria #3 has been 
amended from “diagnosed with 
NCFB by computerised 
tomography (CT) or high-
resolution CT (HRCT) as 
recorded in the subject’s notes” 
to “are diagnosed with NCFB by 
computerised tomography (CT) 
or high-resolution CT (HRCT) as 
recorded in the subject’s notes 
and this is their predominant 
condition being treated”. 
Amended to emphasize and 
clarify that NCFB should be the 
predominant condition 
experienced by the study patient 
requiring treatment (as opposed 
to, for example, chronic 
obstructive pulmonary disease. 
Inclusion criteria #4 amended to 
allow patients experiencing 2 
NCFB pulmonary exacerbations 
requiring inhaled antibiotics to 
be enrolled. 
Discussions with sites have 
indicated that inhaled antibiotics 
are routinely being used at 
several sites and not just oral 
antibiotics as routine 
management for patients with 
NCFB pulmonary exacerbations. 
Inclusion criteria #7 has been 
amended to allow patients with 
a pre-bronchodilator FEV1 ≥25% 
(as opposed to ≥30%). 
The FEV1 level has been 
adjusted downwards after 
consultation with experts in the 
field who agree this cut off level 
 
PPD
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Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 4 of 9 
would not negatively impact the 
study in terms of safety but 
would help with recruitment. 
Inclusion criteria #8 has been 
amended to reflect the fact that 
any positive result for one of the 
three potential sputum samples 
collected during the periods 
between Visit 1 and Visit 2 
allows for patient inclusion. 
Amended to reflect the sputum 
sample collection details 
documented in relevant sections 
of the study protocol. 
Exclusion criteria #3 has been 
amended to remove the 
reference to myeloproliferative 
disease. 
This was an exclusion criterion 
in the Zambon phase 2 trial but 
has not been an exclusion 
criteria in similar phase 3 trials. 
Removal of this exclusion 
criteria will have no negative 
impact on the safety of the trial 
or efficacy assessments. There 
are no known confounding 
factors with NCFB and 
myeloproliferative disease. 
Other exclusion criteria will 
ensure patient safety; in 
particular exclusion criteria #20 
(as renumbered). 
Exclusion criteria #8 has been 
deleted in its entirety. 
The amendment to inclusion 
criteria #3 detailed above makes 
this exclusion criterion 
redundant. 
Exclusion criteria #8 (as re-
numbered) has been amended 
from “respiratory failure requiring 
long-term domiciliary oxygen 
therapy or non-invasive 
ventilation” to “respiratory failure 
that would compromise patient 
safety or confound the 
evaluation of safety or efficacy 
of the study in the opinion of the 
Investigator.” 
The intention of the criteria was 
to exclude patients with 
respiratory failure who may not 
be fit enough to take part in a 
one-year trial. The use of 
oxygen or ventilation was a way 
of defining respiratory failure. 
Experience has shown that this 
is, in fact, confusing and 
patients using oxygen or night-
time ventilation without 
respiratory failure were 
unnecessarily being excluded. 
Exclusion criteria #9 (as re-
numbered) has been amended 
to include squamous cell 
carcinoma. 
Localised squamous cell skin 
cancer (like basal cell 
carcinoma) does not pose a risk 
to the safety or efficacy 
assessments of the study. 
Exclusion criteria #10 (as re-
numbered) has been amended 
to remove methotrexate. 
Methotrexate does not have 
significant immunosuppressive 
properties. 
Exclusion criteria #12 (as re-
numbered) has been amended 
from “current diagnosis or 
current treatment for non-
tuberculous mycobacterial 
(NTM) pulmonary infection or 
tuberculosis” to “current 
treatment for non-tuberculous 
Clarification of the intent of the 
exclusion criterion: amended for 
alignment with the ATS 
guidelines and the clinical study 
protocol for Promis I. 
 

Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 5 of 9 
mycobacterial (NTM) lung 
disease or tuberculosis”. 
Exclusion criteria #14 (“known to 
be intolerant to inhaled beta-2 
agonists (bronchodilators”) has 
been deleted. 
This has been removed as 
Zambon have removed the 
absolute requirement to use a 
bronchodilator before each IMP 
administration. Zambon have 
removed this requirement due to 
feedback that, as many patients 
can tolerate the IMP without it, 
then the mandated use is an 
unnecessary burden on patients 
who would prefer not to use it. 
The use of the bronchodilator is 
to aid tolerability not to improve 
efficacy. 
Exclusion criteria #13 (as re-
numbered) has been amended 
from “known or suspected to be 
allergic or unable to tolerate 
colistimethate sodium or other 
polymixins (intravenous or 
inhaled) including evidence of 
bronchial hyperreactivity” to 
“known or suspected to be 
allergic or unable to tolerate 
colistimethate sodium 
(intravenous or inhaled) or other 
polymixins, including evidence 
of bronchial hyper-reactivity 
following inhaled colistimethate 
sodium”. 
Clarification of exclusion 
criterion. 
Section 2: Summary; Outcome 
Measures 
The safety variable relating to 
bronchospasm has been 
extended to relate to any 
episode following IMP 
administration and not just at the 
end of treatment. 
Clarification of the intention of 
the safety variable for the 
determination of any adverse 
effects. 
Testing for 
 
 has been extended to 
all clinic visits at which 
 
samples are collected. 
As some subjects may be 
considered eligible for the study 
based on local laboratory results 
for the presence of 
, additional central 
analyses at Visit 2 may capture 
some additional pre-existing 
resistance data. 
At Visit 3 we will also look at the 
susceptibility of 
 to 
colistin sulphate. This is to 
identify if a pre-existing resistant 
strain present before 
commencement of IMP is 
growing preferentially if the IMP 
is suppressing the growth of 
susceptible strains.  This will 
help differentiate from emergent 
resistance that may develop 
 
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Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 6 of 9 
throughout the course of the 
study. 
Section 3.1: Evaluation of the 
Anticipated Risks and Benefits 
A statement has been added to 
allow patients to continue in the 
study without pre-bronchodilator 
use prior to IMP administration. 
As stated above, this 
requirement has been removed 
due to feedback that, as many 
patients can tolerate the IMP 
without it, then the mandated 
use or a short-acting inhaled 
bronchodilator prior to IMP 
administration is an 
unnecessary burden on patients 
who would prefer not to use it. 
The use of the bronchodilator is 
to aid tolerability not to improve 
efficacy. 
Section 6.1: Clinical Trial Design 
The section has been amended 
to emphasize that any episodes 
of pneumonia should be 
followed up with clinic/’phone 
calls as per any pulmonary 
exacerbations. 
As requested by the FDA, any 
episodes of pneumonia will be 
considered and followed-up in 
the same manner as pulmonary 
exacerbations. 
Section 6.2: Duration of Clinical 
Trial 
The anticipated quarter for last 
subject out has been revised. 
The date for last subject out has 
been amended to Q4 2020 to 
reflect the increased recruitment 
period required to achieve the 
required sample size. 
Section 7.2.1: Inclusion Criteria 
Inclusion criteria #3 has been 
amended from “diagnosed with 
NCFB by computerised 
tomography (CT) or high-
resolution CT (HRCT) as 
recorded in the subject’s notes” 
to “are diagnosed with NCFB by 
computerised tomography (CT) 
or high-resolution CT (HRCT) as 
recorded in the subject’s notes 
and this is their predominant 
condition being treated”. 
Amended to emphasize and 
clarify that NCFB should be the 
predominant condition 
experienced by the study patient 
requiring treatment (as opposed 
to, for example, chronic 
obstructive pulmonary disease. 
Inclusion criteria #4 amended to 
allow patients experiencing 2 
NCFB pulmonary exacerbations 
requiring inhaled antibiotics to 
be enrolled. 
Discussions with sites have 
indicated that inhaled antibiotics 
are routinely being used at 
several sites and not just oral 
antibiotics as routine 
management for patients with 
NCFB pulmonary exacerbations. 
Inclusion criteria #7 has been 
amended to allow patients with 
a pre-bronchodilator FEV1 ≥25% 
(as opposed to ≥30%). 
The FEV1 level has been 
adjusted downwards after 
consultation with experts in the 
field who agree this cut off level 
would not negatively impact the 
study in terms of safety but 
would help with recruitment. 
Inclusion criteria #8 has been 
amended to reflect the fact that 
any positive result for one of the 
three potential sputum samples 
collected during the periods 
between Visit 1 and Visit 2 
Amended to reflect the sputum 
sample collection details 
documented in relevant sections 
of the study protocol. 
 

Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 7 of 9 
allows for patient inclusion. 
Section 7.2.2: Exclusion Criteria 
Exclusion criteria #3 has been 
amended to remove the 
reference to myeloproliferative 
disease. 
This was an exclusion criterion 
in the Zambon phase 2 trial but 
has not been an exclusion 
criteria in similar phase 3 trials. 
Removal of this exclusion 
criteria will have no negative 
impact on the safety of the trial 
or efficacy assessments. There 
are no known confounding 
factors with NCFB and 
myeloproliferative disease. 
Other exclusion criteria will 
ensure patient safety; in 
particular exclusion criteria #20 
(as renumbered). 
Exclusion criteria #8 has been 
deleted in its entirety. 
The amendment to inclusion 
criteria #3 detailed above makes 
this exclusion criterion 
redundant. 
Exclusion criteria #8 (as re-
numbered) has been amended 
from “respiratory failure requiring 
long-term domiciliary oxygen 
therapy or non-invasive 
ventilation” to “respiratory failure 
that would compromise patient 
safety or confound the 
evaluation of safety or efficacy 
of the study in the opinion of the 
Investigator.” 
The intention of the criteria was 
to exclude patients with 
respiratory failure who may not 
be fit enough to take part in a 
one-year trial. The use of 
oxygen or ventilation was a way 
of defining respiratory failure. 
Experience has shown that this 
is, in fact, confusing and 
patients using oxygen or night-
time ventilation without 
respiratory failure were 
unnecessarily being excluded. 
Exclusion criteria #9 (as re-
numbered) has been amended 
to include squamous cell 
carcinoma. 
Localised squamous cell skin 
cancer (like basal cell 
carcinoma) does not pose a risk 
to the safety or efficacy 
assessments of the study. 
Exclusion criteria #10 (as re-
numbered) has been amended 
to remove methotrexate. 
Methotrexate does not have 
significant immunosuppressive 
properties. 
Exclusion criteria #12 (as re-
numbered) has been amended 
from “current diagnosis or 
current treatment for non-
tuberculous mycobacterial 
(NTM) pulmonary infection or 
tuberculosis” to “current 
treatment for non-tuberculous 
mycobacterial (NTM) lung 
disease or tuberculosis”. 
Clarification of the intent of the 
exclusion criterion: amended for 
alignment with the ATS 
guidelines and the clinical study 
protocol for Promis I. 
Exclusion criteria #14 (“known to 
be intolerant to inhaled beta-2 
agonists (bronchodilators”) has 
been deleted. 
This has been removed as 
Zambon have removed the 
absolute requirement to use a 
bronchodilator before each IMP 
administration. Zambon have 
removed this requirement due to 
feedback that, as many patients 
 

Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 8 of 9 
can tolerate the IMP without it, 
then the mandated use is an 
unnecessary burden on patients 
who would prefer not to use it. 
The use of the bronchodilator is 
to aid tolerability not to improve 
efficacy. 
Exclusion criteria #13 (as re-
numbered) has been amended 
from “known or suspected to be 
allergic or unable to tolerate 
colistimethate sodium or other 
polymixins (intravenous or 
inhaled) including evidence of 
bronchial hyperreactivity” to 
“known or suspected to be 
allergic or unable to tolerate 
colistimethate sodium 
(intravenous or inhaled) or other 
polymixins, including evidence 
of bronchial hyper-reactivity 
following inhaled colistimethate 
sodium”. 
Clarification of exclusion 
criterion. 
Section 8.2: Visit 2 - 
Randomisation Visit (Day 0) 
Wording has been added to 
allow patients to continue in the 
study without pre-bronchodilator 
use prior to IMP administration. 
As stated above, this 
requirement has been removed 
due to feedback that, as many 
patients can tolerate the IMP 
without it, then the mandated 
use or a short-acting inhaled 
bronchodilator prior to IMP 
administration is an 
unnecessary burden on patients 
who would prefer not to use it. 
The use of the bronchodilator is 
to aid tolerability not to improve 
efficacy. 
The timing for the administration 
of any pre-bronchodilator (at 
least 10 minutes prior to IMP 
administration) and post-IMP 
administration spirometry 
assessment (30 ± 10 minutes) 
have been amended. 
The timings have been 
amended to reflect a more 
practical timeline and to indicate 
acceptable assessment ranges. 
Section 8.5: Visit 7 (12 Months ± 
1 Week); End of Treatment 
The timing for the administration 
of any pre-bronchodilator (at 
least 10 minutes prior to IMP 
administration) and post-IMP 
administration spirometry 
assessment (30 ± 10 minutes) 
have been amended. 
The timings have been 
amended to reflect a more 
practical timeline and to indicate 
acceptable assessment ranges. 
The reference to 
 
devices being returned via 
 has been deleted. 
This study procedure/logistic is 
not working effective and a new 
work instruction for the return of 
the 
 device is 
currently being created. 
Section 9.1.6: Safety 
Evaluations 
The timing for the spirometry 
assessments prior to the 
administration of any pre-
The timings have been 
amended to reflect a more 
practical timeline and to indicate 
 
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Protocol Code: Z7224L01 Amendment 6 (Version 7.0) 
SOP C.03.02.06 – App. 3 Page 9 of 9 
bronchodilator (at least 10 
minutes prior to IMP 
administration) and post-IMP 
administration (30 ± 10 minutes) 
have been amended. 
acceptable assessment ranges. 
Section 11.2: Investigational 
Medicinal Product Dispensing 
and Administration 
A statement has been added to 
allow patients to continue in the 
study without pre-bronchodilator 
use prior to IMP administration. 
As stated above, this 
requirement has been removed 
due to feedback that, as many 
patients can tolerate the IMP 
without it, then the mandated 
use or a short-acting inhaled 
bronchodilator prior to IMP 
administration is an 
unnecessary burden on patients 
who would prefer not to use it. 
The use of the bronchodilator is 
to aid tolerability not to improve 
efficacy. 
The timing for the administration 
of any pre-bronchodilator (at 
least 10 minutes prior to IMP 
administration) and post-IMP 
administration spirometry 
assessment (30 ± 10 minutes) 
have been amended. 
The timings have been 
amended to reflect a more 
practical timeline and to indicate 
acceptable assessment ranges. 
Section 17.8.1: Reporting 
Serious Adverse Events 
The contact details for SAE 
reporting have been amended. 
Contact details have been 
amended to those relating to the 
new CRO managing the study. 
Section 18.2: Study Variables 
Testing for 
 
 has been extended to 
all clinic visits at which 
 
samples are collected. 
As some subjects may be 
considered eligible for the study 
based on local laboratory results 
for the presence of 
 
, additional central 
analyses at Visit 2 may capture 
some additional pre-existing 
resistance data. 
At Visit 3 we will also look at the 
 
. This is to 
identify if a pre-existing resistant 
strain present before 
commencement of IMP is 
growing preferentially if the IMP 
is suppressing the growth of 
susceptible strains.  This will 
help differentiate from emergent 
resistance that may develop 
throughout the course of the 
study. 
Section 26: References 
The date for the reference UK 
SmPC for Promixin has been 
amended from 2018 to 2019. 
Annual update to the SmPC. 
The date the relevant web-site 
for the 
 reference was 
last known/accessed has been 
included. 
The web-site no longer appears 
to be operational. 
 
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