Clinical trial NCT03460704
Conditions: Non Cystic Fibrosis Bronchiectasis
Keywords: NCFB NCFB pulmonary exacerbation Bronchiectasis
Sponsor: Zambon SpA
Start date: 2018-01-29; Completion date: 2022-03-15
Enrollment: 287 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the trial was to investigate the effect of the use of inhaled colistimethate sodium (CMS), administered twice a day (b.i.d.) via a specific nebulizer for 12 months, compared to placebo in subjects with non-cystic fibrosis bronchiectasis (NCFB) chronically infected with P. aeruginosa on the annualised frequency of pulmonary exacerbations.

Detailed description:
This was a randomised, multi-centre, double-blind, placebo-controlled, parallel-group interventional trial in subjects with NCFB chronic P. aeruginosa infection. Subjects were randomised to CMS or placebo in a 1:1 ratio. The study consisted of 7 clinic visits with a follow-up phone call 12.5 month after randomisation or 2 weeks after discontinuation of treatment. Additional clinic visits, where feasible, and weekly phone calls were conducted during or after pulmonary exacerbations (or any episodes of pneumonia) until resolution.

Every effort was made to have all planned and unscheduled visits at the study site. Mandatory on-site visits were Screening Visit (Visit 1) and Randomisation (Visit 2). However, if one of the visits after Visit 2 could not be performed at site due to COVID-19, remote visits (e.g., by telephone) were permitted. If the final visit (Visit 7) had to be conducted remotely, the subjects were asked to return to the clinic for on-site assessments at the earliest opportunity.

After consulting with the US Food and Drug Administration, the study was brought to an early close primarily due to the difficulty of recruiting subjects in the context of the COVID pandemic, but also due to the potential for loss of scientific equipoise and the ethical implications of continuing to expose subjects to placebo given the positive results from PROMIS I. Recruitment to PROMIS II was stopped as of 27 October 2021, with the study terminated as of 15 March 2022. The study was not stopped prematurely due to any safety or futility concerns and the accrued data were fully analysed and are presented.

Arms: arm 1: Inhaled colistimethate sodium twice daily. The active pharmaceutical ingredient consisting of pure CMS one million international units (MIU) / 80 mg of CMS / 33 mg colistin base activity (CBA) was provided as a powder for nebuliser solution in 10R Internation Organization for Standardization (ISO) glass vials. arm 2: Saline solution inhaled twice daily, provided and administered at the same way of the IMP.
Interventions: intervention 1: CMS intervention 2: Placebo
Intervention descriptions: intervention 1: 1 MIU equivalent to 80 mg colistimethate sodium diluted in 1 mL saline solution 0.45%. Investigational Medicinal Product (IMP) glass vials were shrink wrapped in opaque white plastic and provided in boxes of 30 vials (two weeks of b.i.d. dosing).

The 1 MIU/ml CMS/0.45% saline solution was transferred from the glass vial into a specific nebuliser system fitted with a 0.3 mL medication chamber, for administration by inhalation. This delivered a nominal dose of 0.3 MIU/24 mg CMS (11 mg CBA) from the device.

The first dose of the IMP was administered at the site under the supervision of the site staff and subjects were instructed how to prepare and self-administer the IMP at home via a specific nebuliser system, b.i.d. (morning and evening) over aperiod of 12 month.

At least 10 minutes (min) before each administration, an inhaled short-acting bronchodilator (e.g. salbutamol/albuterol), supplied by the Sponsor, could be taken to improve tolerability. intervention 2: 1 mL saline solution 0.45%. The placebo was made up of identical empty glass vials to which the same saline solution diluent was added in exactly the same way as the reconstitution of the active treatment by injecting the diluent through the rubber stopper. The glass vials were shrink wrapped with opaque white plastic to mantain the blind.

Protocol documents:
Prot_000.pdf: 
Z7224L02 
 
Final v.5.0, Date 22 July 2021 
Page 1 of 65 
 
SOP C.03.02.06 – App. 1 
 
 
 
 
 
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 
Z7224L02 
 
Protocol Name 
Promis II 
 
EudraCT Number  2016-004558-13 
IND Number 134361 
 
Final Date 
22-July-2021 
 
Version Final 5.0 
 
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.  
 
 
 












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SOP C.03.02.06 – App. 1 
Protocol Version Final v.5.0; 22 July 2021 
Country-specific amendments of Protocol Version 
4.0 have been incorporated into this clinical trial 
protocol. 
Changes to the conduct and duration of the study 
required due to the Covid-19 pandemic have been 
made. 
Provisions have been included for the original 
sample size to be recalculated at a later date to take 
into consideration: a) treatment exposure for 
withdrawn subjects and b) a planned blinded review 
of the exacerbation rate. 
Clarification has been added to specify that subjects 
not using the recommended bronchodilator prior to 
IMP administration need to be clinically assessed to 
determine whether this is appropriate. 
The screening period (between Visits 1 and 2) has 
been extended from 30 days to 45 days to allow for 
sufficient time for the processing of sputum samples 
for the analysis of Pseudomonas aeruginosa. 
Clarification has been added that re-screening for 
subjects who screen fail for reasons other than a 
negative result for Pseudomonas aeruginosa is 
permitted at any time. For subjects with a negative 
result for Pseudomonas aeruginosa, re-screening is 
also permitted after approximately three months 
from the last screening test. 
The units for Pseudomonas aeruginosa have been 
corrected to cfu/mL. 
Provisions have been included for the use of paper 
Quality of Life questionnaires when the electronic 
tablet supplied to sites malfunctions or there are 
other technical issues. 
The reporting of episodes of pneumonia as 
pulmonary exacerbations has been clarified. 
A 
 
 
 
has 
been 
established for the assessment of the impact of 
Covid-19 on the study and blinded review of 
pulmonary exacerbation data and details have been 
included. 
For additional information, please refer to the 
Summary of Key Changes document associated 
with this protocol version. 
  
 
 
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Page 8 of 65 
 
SOP C.03.02.06 – App. 1 
 
1. TABLE OF CONTENTS 
 
ZAMBON CONTACT DETAILS ......................................................................................... 3 
CONTRACT RESEARCH ORGANISATION CONTACT DETAILS ..................................... 3 
OTHER INSTITUTIONS ..................................................................................................... 4 
LIST OF COMMITTEES ..................................................................................................... 5 
SUMMARY OF CHANGES HISTORY ............................................................................... 5 
1. 
Table of Contents .................................................................................................... 8 
2. 
Abbreviations ......................................................................................................... 11 
3. 
Summary ............................................................................................................... 13 
4. 
Introduction and Rationale ..................................................................................... 17 
4.1. 
Evaluation of the Anticipated Risks and Benefits ............................................ 20 
5. 
Objectives .............................................................................................................. 20 
6. 
Ethics Requirements .............................................................................................. 21 
7. 
Design and Duration of the Clinical Trial ................................................................ 21 
7.1. 
Clinical Trial Design ........................................................................................ 21 
7.2. 
Duration of Clinical Trial .................................................................................. 22 
8. 
Clinical Trial Population ......................................................................................... 23 
8.1. 
Number of Subjects ......................................................................................... 23 
8.2. 
Selection of Subjects ....................................................................................... 23 
8.2.1. Inclusion Criteria .......................................................................................... 23 
8.2.2. Exclusion Criteria ......................................................................................... 23 
9. 
Overall Clinical Trial Schedule ............................................................................... 25 
9.1. 
Visit 1 - Screening Visit (Within 45 Days of Visit 2) ......................................... 25 
9.2. 
Visit 2 - Randomisation Visit (Day 0) ............................................................... 26 
9.3. 
Visit 3 (Day 28 ± 1 Week) ................................................................................ 27 
9.4. 
Visit 4 (3 Months ± 1 Week) to Visit 6 (9 Months ± 1 Week), inclusive ............ 27 
9.5. 
Visit 7 (12 Months ± 1 Week); End of treatment .............................................. 28 
9.6. 
Follow-up Phone Call (2 Weeks ± 3 Days after End of Treatment) ................. 29 
9.7. 
Exacerbation Visit/Contact .............................................................................. 29 
10. 
Methodology .......................................................................................................... 31 
10.1. 
Methods of Assessment .................................................................................. 31 
10.1.1. 
Demography and Medical History ............................................................. 31 
10.1.2. 
Physical Examination................................................................................ 31 
10.1.3. 
Vital Signs ................................................................................................. 31 


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SOP C.03.02.06 – App. 1 
10.1.4. 
Laboratory Evaluations ............................................................................. 31 
10.1.5. 
Efficacy Evaluations.................................................................................. 32 
10.1.6. 
Safety Evaluations .................................................................................... 36 
10.2. 
Adherence with IMP Dosing Regimen ............................................................. 37 
10.3. 
Pharmacodynamics ......................................................................................... 37 
10.4. 
Pharmacokinetics ............................................................................................ 37 
11. 
Prior and Concomitant Treatments ........................................................................ 38 
11.1. 
Concomitant Medication .................................................................................. 39 
12. 
Investigational Medicinal Product .......................................................................... 39 
12.1. 
Investigational Medicinal Product Supplies and Packaging............................. 39 
12.2. 
Investigational Medicinal Product Dispensing and Administration ................... 40 
12.3. 
Randomisation ................................................................................................ 40 
12.4. 
Investigational Medicinal Product Accountability ............................................. 41 
13. 
Clinical Trial Amendments ..................................................................................... 42 
14. 
Deviations from the Clinical Trial Protocol ............................................................. 42 
14.1. 
Code Breaking ................................................................................................ 42 
15. 
Clinical Trial Withdrawals/Drop-outs ...................................................................... 42 
16. 
Stopping and Discontinuation Criteria for the Trial ................................................. 43 
17. 
Reporting Safety Information ................................................................................. 44 
17.1. 
Definition of Adverse Event ............................................................................. 44 
17.2. 
Definition of Adverse Event of Special Interest ............................................... 44 
17.3. 
Definition of Adverse Drug Reaction ............................................................... 44 
17.3.1. 
Definition of Unexpected Adverse Drug Reactions ................................... 44 
17.3.2. 
Definition of Medical Device Malfunction and Incident .............................. 45 
17.4. 
Definition of Serious Adverse Events or Serious Adverse Drug Reactions ..... 45 
17.4.1. 
Definition of Serious Adverse Event OR Serious Adverse Reaction ......... 45 
17.4.2. 
Definition of Suspected Unexpected Serious Adverse Reactions ............. 46 
17.5. 
Definition of Severity of Adverse Events ......................................................... 46 
17.6. 
Definition of Adverse Event Causality ............................................................. 46 
17.7. 
Adverse Event Recording ................................................................................ 46 
17.8. 
Adverse Event Reporting ................................................................................ 47 
17.8.1. 
Reporting Serious Adverse Events ........................................................... 47 
17.8.2. 
Reporting Adverse Events of Special Interest .......................................... 47 
17.9. 
Follow-up for Adverse Events ......................................................................... 47 
17.10. Pregnancy ....................................................................................................... 48 
18. 
Records ................................................................................................................. 48 
18.1. 
Case Report Forms, Source Data and Query Resolution ............................... 48 
18.2. 
Records Maintained by the Investigator .......................................................... 49 


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SOP C.03.02.06 – App. 1 
18.3. 
Trial Master File .............................................................................................. 49 
18.4. 
Trial Monitoring ............................................................................................... 49 
18.5. 
Confidentiality of Subject’s Information ........................................................... 50 
19. 
Biometrics .............................................................................................................. 50 
19.1. 
Data Management ........................................................................................... 50 
19.2. 
Study Variables ............................................................................................... 51 
19.3. 
Sample Size .................................................................................................... 51 
19.4. 
Statistical Analyses ......................................................................................... 52 
19.4.1. 
Trial Populations ....................................................................................... 52 
19.4.2. 
Efficacy Data ............................................................................................ 53 
19.4.3. 
Safety Data ............................................................................................... 56 
19.4.4. 
Handling of Missing Data .......................................................................... 57 
20. 
Informed Consent .................................................................................................. 57 
21. 
Ethics Committee/Investigational Review Board Approval .................................... 58 
22. 
Regulatory Requirements ...................................................................................... 58 
23. 
Quality Assurance .................................................................................................. 59 
24. 
Insurance ............................................................................................................... 59 
25. 
Clinical Trial Report ............................................................................................... 59 
26. 
Use of Information and Publication ........................................................................ 59 
27. 
References ............................................................................................................ 61 
28. 
Appendices ............................................................................................................ 63 
 
 
 
 


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SOP C.03.02.06 – App. 1 
2. 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  
IRB                    Investigational Review Board 
ITT 
Intention-to-treat 
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SOP C.03.02.06 – App. 1 
IU 
International Unit 
IWRS 
Interactive web response system 
MedDRA  
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
mITT 
Modified Intention-to-treat 
MIU 
Million International Unit 
mL 
Millilitre 
NCFB                Non-CF-Bronchiectasis 
NTM                  Non-Tuberculous Mycobacterial 
P. aeruginosa Pseudomonas aeruginosa 
PP 
Per-protocol population 
Q1 
Quarter one 
 
 
 
 
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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SOP C.03.02.06 – App. 1 
Duration of Patient 
Participation: 
Screening period of up to 45 days, followed by 12 months treatment 
duration and a follow-up ‘phone call two weeks after discontinuation of 
treatment. 
Participating Countries: 
Number of countries: 12. 
Number of Sites: 
Approximately 120. 
Sample Size: 
A total of 420 randomised patients (210 per group) is foreseen assuming 
a withdrawal rate of approximately 20%, to achieve approximately 170 
completed patients 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%. 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%. It is anticipated that a blinded review of the exacerbation rate 
across treatment groups will be conducted prior to the end of enrolment 
to determine whether the FOE is in line with these assumptions, given the 
potential impact of Covid-19. The sample size will then be recalculated 
and, in addition, take into consideration treatment exposure for withdrawn 
subjects at that stage. 
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); 






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SOP C.03.02.06 – App. 1 
4. 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 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 
[7]. However, there is no conclusive data in the literature on whether the presence of P. 
aeruginosa is correlated with accelerated decline of lung function [e.g.  8] or not [e.g. 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 
effective in NCFB as it is in CF and seems to be associated with an increase in NCFB 
pulmonary exacerbation and hospitalisation rates and antibiotic use [10, 11]. Other 


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SOP C.03.02.06 – App. 1 
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 (tobramycin, gentamicin, aztreonam) for the prevention of 
pulmonary exacerbations have yielded mixed results and none of these antibiotics is 
currently approved for this indication. [12, 13, 14]. 
 
Trial Rationale  
To date, no therapies have been shown to cure or to reverse the progression of the disease. 
There are no official US guidelines for the treatment of NCFB patients. 
In 2010, the British Thoracic Society published guidelines for the management of patients 
with NCFB [10]. 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 [15]. 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. 
Colistimethate sodium is an antibacterial cationic cyclic polypeptide belonging to the 
polymyxin group; it is currently approved in the US for intravenous administration and in 
Europe for both intravenous and inhaled administration. 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. 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.  
Colistimethate sodium (1 million International Units [MIU], equivalent to 33 mg colistin base 
activity [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 use in treating patients with CF who have Pseudomonas lung 
infections. 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). 
Promixin®/Tadim® (colistimethate sodium) has been authorised for nebulised treatment of 
colonisation and infections of the lung by susceptible P. aeruginosa in patients with CF 
since 2003. Authorisation was granted based on a bibliographic submission.  
To date, two clinical studies with Promixin® (colistimethate sodium) have been completed 
and reported. One was a pharmacokinetic study in healthy subjects (
), 
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SOP C.03.02.06 – App. 1 
8. CLINICAL TRIAL POPULATION 
8.1. NUMBER OF SUBJECTS 
A target 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 the sample size calculation, please refer to Section 19.3. 
8.2. SELECTION OF SUBJECTS 
8.2.1. 
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 CT (or high-resolution CT) 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.  
8.2.2. 
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; 
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 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; 


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SOP C.03.02.06 – App. 1 
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 evidence of bronchial hyper-
reactivity following inhaled colistimethate sodium; 
14) treatment with long term (≥ 30 days) prednisone at a dose of 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) or started between Visit 1 and Visit 2; 
16) use of any intravenous or intramuscular or oral or inhaled anti-pseudomonal 
antibiotic (except chronic macrolides 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. 
Female subjects can be enrolled if they are either post-menopausal for at least 2 years, or 
surgically sterilized or have undergone hysterectomy. 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 10.1.5), and should use a highly effective method 
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 (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
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• intrauterine device  
• intrauterine hormone-releasing system  
• surgical sterilization (e.g. bilateral tubal ligation or occlusion)  
• male sterilization (vasectomised partner)  
• sexual abstinence.  
9. 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 
on-site clinic visits. Due to the Covid-19 pandemic, on-site visits are not always feasible 
and several “visits” are being conducted remotely by ‘phone to collect as much information 
as possible. This does, however, mean that aspects such as physical examinations, blood 
sampling and spirometry cannot be performed. Missed study procedures are recorded as 
protocol deviations (pre-fixed with “Covid-19”) to determine the impact of Covid-19 on the 
performance of the study and are reviewed on a regular basis for their relative importance. 
Direct-to-patient supply of IMP has also been established where necessary to minimize 
subject’s potential exposure to Covid-19 after Investigators have confirmed that subjects 
are safe to continue in the study. (See also the Zambon PROMIS I/II Coronavirus [2019-
nCoV] Contingency Plan.) 
9.1. VISIT 1 - SCREENING VISIT (WITHIN 45 DAYS OF VISIT 2) 
At Visit 1 (Screening), the following procedures will be performed: 
• obtain written Informed Consent (including separate written Informed Consent for 
subjects participating in the pharmacokinetic sub-study at selected sites); 
• 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, 
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 10.1.3); 
• 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 10.1.6); 
• blood samples for clinical laboratory assessments (haematology, clinical chemistry 
and renal function tests) (Section 10.1.4); 
• dip-stick pregnancy test for women of child-bearing potential. 
• spirometry (if not done in the 30 days beforehand); pre-bronchodilator FEV1 must be 
≥25% of predicted for the patient normal value (determined using Global Lung 
Function Initiative [GLI] reference equations); 
• collection of sputum samples for P. aeruginosa 
 
(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 
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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 45 days. 
9.2. VISIT 2 - RANDOMISATION VISIT (DAY 0) 
At Visit 2 (Randomisation), the following procedures will be performed: 
• check if subject is still eligible according to the 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 the 
electronic clinical outcome assessment (eCOA) device, or on paper, before other 
study procedures (Note: paper questionnaires can be used in exceptional 
circumstances such as when the eCOA malfunctions or because of other technical 
issues); 
• 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 200/180 mcg of short-acting bronchodilator; if the patient prefers not to use a 
bronchodilator, and the Investigator confirms that the subject can tolerate IMP 
without it, 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 in FEV1 – not due to 
poor technique - from pre-bronchodilator baseline after first IMP intake, or clinically 
determined bronchospasm, the subject will be immediately withdrawn from the trial); 
• blood samples for pharmacokinetic analysis (selected sites only); 
• 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 ± 1 week).  
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 which 
should be addressed as appropriate. 
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10. METHODOLOGY 
10.1. 
METHODS OF ASSESSMENT 
10.1.1. 
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, number of lobes impacted and, if known, the underlying cause of the 
bronchiectasis. Body weight will also be measured at Visit 7.  
Additionally, 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/HCRT results, to confirm the 
diagnosis of NCFB as per inclusion criterion 3 (see Section 8.2.1).  
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 18). 
10.1.2. 
PHYSICAL EXAMINATION 
At Visit 1 and Visit 7, a physical examination of general body systems will be performed 
according to current medical standards 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 18). 
10.1.3. 
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. 
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 18). 
10.1.4. 
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 
analysed 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 
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it is clinically determined that the subject requires and is prescribed systemic antibiotic 
therapy. Any occurrence of these symptoms with the prescription of systemic antibiotic 
therapy, irrespective of cause, should be reported as a pulmonary exacerbation.  
For clarification purposes (and the generation of relevant data queries to sites), a further 
clarification to the protocol definition for pulmonary exacerbations has been provided as 
follows: 
• the presence of 3 or more pre-defined symptoms / signs1 within any 24-hour 
period2 
and 
• the episode of exacerbation lasted for at least 24 hours3 
and 
• in the opinion of the Investigator, the subject required and started treatment with 
systemic antibiotics 
 
Explanatory notes: 
1The pre-defined symptoms / signs are: increased cough; increased sputum volume and / or consistency; 
increase sputum purulence; new or increased haemoptysis; increased wheezing; increased dyspnoea; 
increased fatigue / malaise; episodes of fever (38C or 100.4F). 
 
2 The pre-defined symptoms / signs need to occur within the same 24-hour period (and this defines the start 
date of the Protocol-Defined Exacerbation) but do not need to be present at exactly the same time. 
 
3 The overall episode of exacerbation needs to last at least 24 hours, but individual symptoms / signs can last 
less than 24 hours (for example, a temperature). 
 
The start date of a 
 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 (and corresponding AE) is defined as the date of 
completion of the required course(s) of systemic antibiotic treatment and/or the 
Investigator’s judgement 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 
period or escalated to intravenous therapy in accordance with standard clinical practice.  
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 9.7 (Exacerbation Visit/Contact).  
 
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 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 at Visit 7 (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. 
 
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 8.2.2); abnormalities of clinical significance 
recorded at Visit 7 will be reported as AEs.  
Repeat measurements will be performed, if needed. 
10.2. 
ADHERENCE WITH IMP DOSING REGIMEN 
The Investigator will assess the subjects’ adherence with the IMP dosing regimen on an 
ongoing basis using 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 10.1.5. 
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. 
10.3. 
PHARMACODYNAMICS 
Not applicable.  
10.4. 
PHARMACOKINETICS 
Additional plasma samples will be collected from approximately 30 subjects recruited at 
selected investigational sites for the determination of plasma concentrations of polymyxin 
E1. Samples will be collected at Visit 2 (Randomisation), Visit 3 (Day 28), and Visit 7 (End 
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of Treatment) and sparse ambient pharmacokinetics will be analysed relative to the time of 
the last IMP administration. 
Blood samples will be stored in a water-ice bath until centrifugation. The samples will then 
be centrifuged at 1500g and 4C for 10 minutes within 1 hour of being drawn. A minimum 
of 1.2 mL of plasma will be placed in aliquot 1. If the volume of plasma is greater than 
2.4 mL, it will be divided equally between two cryovials. The plasma samples will be frozen 
at –80C within 2 hours of being drawn and will be stored until the end of the study for batch 
transfer to a central laboratory with validated methods for the determination of polymyxin 
E1.  
11. 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 Screening (Visit 
1) will be documented in the eCRF. In particular, any prior use of inhaled colistimethate 
sodium, 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. 
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]; 
• 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; 
• seasonal influenza and Covid-19 vaccinations. 
 
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 8.2.2). 


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11.1. 
CONCOMITANT MEDICATION 
Concomitant 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 concomitant medications they have taken to 
self-treat at home. Concomitant 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. 
12. INVESTIGATIONAL MEDICINAL PRODUCT 
12.1. 
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 bronchodilators (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.  
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12.2. 
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 ten 
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.  The IMP must be reconstituted by carefully removing 
the red plastic cap on top of the vial 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 aluminium collar seal can be removed and the stopper can be opened 
and all of the solution transferred into the 
 chamber (with a 0.3 mL dosing chamber to 
give a delivered dose of 0.333 MIU colistimethate sodium/10 mg CBA). Active treatment 
and placebo solutions are identical so that neither the Investigator nor the subject can 
recognise 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. Direct-to-patient supply of IMP has also been 
established where necessary to minimize subject’s potential exposure to Covid-19. 
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. Should the need arise, courier collections have 
also been established due to Covid-19 restrictions. 
12.3. 
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. 
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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/erythromycin/ 
clarithromycin) (Yes/No) will be considered for balancing randomisation. Thus, within each 
site, subjects with azithromycin/erythromycin/clarithromycin use will be randomised 
independently from subjects without use of azithromycin/erythromycin/ 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 oral azithromycin or erythromycin or clarithromycin will be 
administered to a subject or not will have been made at least 30 days prior to the Screening 
Visit (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 SAEs where knowledge of treatment assignment is essential 
for the future management of patient care (see Section 14.1).  
12.4. 
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/sub-
Investigators/study coordinators as detailed in the Site Signature/Delegation Log, and 
to subjects in this trial. 
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13. 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/IRB 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/IRB/CA for notification as applicable per local requirements, and may be 
implemented at the site before EC/IRB notification according to local rules.  
14. 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. Protocol deviations 
specifically relating to Covid-19 will be prefixed with “Covid-19” for separate consideration. 
All deviations will be reported to the EC/IRB 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.  
14.1. 
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 EC/IRBs. 
15. 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;  
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• 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 17.9); 
• 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/IRB(s), 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 17.8 and Section 17.9. 
If possible, the subject should return to the clinic for an early End of Study Visit. The subject 
must return the medications and 
, and details regarding AEs (including exacerbations) 
and concomitant medications will be collected.  
16. 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/IRB 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. 
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17. REPORTING SAFETY INFORMATION 
17.1. 
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. 
17.2. 
DEFINITION OF ADVERSE EVENT OF SPECIAL INTEREST  
No AEs of special interest are defined for this trial.  
17.3. 
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. that 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. 
17.3.1. 
DEFINITION OF UNEXPECTED ADVERSE DRUG REACTIONS 
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 


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patient population, pulmonary exacerbations (including pneumonia) are also considered as 
expected adverse events. 
17.3.2. 
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. 
17.4. 
DEFINITION OF SERIOUS ADVERSE EVENTS OR SERIOUS 
ADVERSE DRUG REACTIONS 
17.4.1. 
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 
reported or defined as per clinical judgement); 
• 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 
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17.4.2. 
DEFINITION OF SUSPECTED UNEXPECTED SERIOUS ADVERSE 
REACTIONS 
A Suspected, Unexpected Serious Adverse Reaction (SUSAR) is a subset of SARs that, 
although foreseeable, are potentially related to the IMP and not identified in the reference 
safety information. SUSARs will be reported to the appropriate regulatory authorities and 
Investigators following local and global guidelines and requirements. 
17.5. 
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. 
17.6. 
DEFINITION OF ADVERSE EVENT CAUSALITY 
Causality shall be determined according to the definition of ADRs as given in Section 17.3. 
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 
AE;  
• alternative explanations. 
17.7. 
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 17.8.1).  
The Investigator performs an evaluation with respect to seriousness and causality of the AEs 
and records it on the appropriate section of the eCRF. 


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17.8. 
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. 
17.8.1. 
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 also be 
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. 
17.8.2. 
REPORTING ADVERSE EVENTS OF SPECIAL INTEREST  
No specific provisions relate to reporting of AEs of special interest.  
17.9. 
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 
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the eCRF for accuracy and can also generate queries to the investigational staff for 
resolution.  
Any correction to the eCRF 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. 
18.2. 
RECORDS MAINTAINED BY THE INVESTIGATOR 
A copy of all trial records (any documents sent or received from the Sponsor/CRO, 
correspondence with EC/IRB 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. Records will be retained in compliance with applicable 
FDA and ICH-GCP regulations and guidelines. 
18.3. 
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 relevant Sponsor and CRO 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. The Investigator files will be left on site after the end 
of the study. 
18.4. 
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, 
. During the Covid-
19 pandemic, provisions for remote monitoring and source data verification will be 
implemented, where possible, in compliance with national and local site procedures and 
data protection laws. 
In addition, to aid data cleaning, a 
 has been 
established. The committee is responsible for assessing the impact of Covid-19 on the 
study and to aid data cleaning by conducting a blinded review of the primary efficacy 
endpoint variable, to ensure the protocol-defined pulmonary exacerbations have been 
appropriately recorded and proposing data queries for Investigators to respond to, where 
appropriate. The 
 only ask questions of the Investigators and do not change any data 
entered by sites. 
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18.5. 
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 
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 Syneos Health, 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. 
19. BIOMETRICS 
19.1. 
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 Syneos Health. 
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 system – eCRFs 
• 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. 
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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. 
 
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. 
19.4.2. 
EFFICACY DATA 
The primary analysis will be performed on the mITT population. Analyses conducted using 
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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. 
 
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. 
19.4.4. 
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. 
20. 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. 
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Prior to the beginning of the trial, the Investigator must have received the EC/IRB 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 EC/IRB/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. The signature can also be from a legally acceptable representative (if 
applicable) in accordance with local law. 
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.  
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 to the subject. 
21. ETHICS COMMITTEE/INVESTIGATIONAL REVIEW BOARD 
APPROVAL 
This trial will be undertaken only after written and dated approval from an appropriate 
EC/IRB has been received by the Investigator and by the Sponsor for the CTP, all its 
appendices, ICF, and subjects’ recruitment procedures (i.e. advertisements), if applicable. 
In addition to the documents mentioned above, the EC/IRB will be provided with an updated 
SmPC and Investigator’s Brochure, the Investigator’s up-to-date Curriculum Vitae and/or 
other documentation evidencing qualifications, and any other documents that the EC/IRB 
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/IRB, if requested. 
22. REGULATORY REQUIREMENTS 
The trial is to be conducted in compliance with Federal regulations and the European 
legislations (Directive 2001/20/EC and Directive 2005/28/EC), the European Regulation 
536/2014 and any applicable local regulations. 
Selection of subjects will not start prior to the approval of the EC/IRB has been obtained 
and the trial notified to or authorised by CAs.  


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23. QUALITY ASSURANCE 
This CTP has been audited by the Sponsor’s Quality Assurance department. The Audit 
Plan for the study includes site audits and TMF audit. Audits will be planned and conducted 
according to the Sponsor’s SOPs, whenever possible, depending on any travel restrictions 
due to Covid-19 and the impact of Covid-19 on clinical site activities. 
24. 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; 
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. 
Additionally, 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. 
25. 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/IRB/Regulatory Authorities according to current regulations. 
26. 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 


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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 
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27. REFERENCES 
1. Cole PJ. Inflammation. A two-edged sword—the model of bronchiectasis. Eur J 
Respir Dis Suppl. 1986;147:6–15. 
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aeruginosa on pulmonary function in patients with bronchiectasis. Eur Respir J. 
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SOP C.03.02.06 – App. 1 
28. APPENDICES 
 
Appendix 1: Trial Flow Chart 
Appendix 2: Investigator Signature Page 
 
 


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SOP C.03.02.06 – App. 1 
Appendix 1: Trial Flow Chart 
VISITS  
Visit 1 
Screening 
Visit 2 
Randomisation 
Phone call  
 
Visit 3 
Visit 4-6 
Visit 7 
EoT 
Follow-Up 
‘Phone 
Call 
Exacer-
bation  
Visit 
ACTIVITIES (see Sections 9 & 10 for details) 
Within 45 Days  
of Visit 2* 
Day 0 
Day 7 
Day 28 
± 1 week 
 Every 3 
months 
± 1 week 
12 months 
± 1 week 
2 weeks ± 
3 days 
after EoT 
------ 
Informed consent  
X 
 
 
 
 
 
 
 
Medical history/demography 
X 
 
 
 
 
 
 
 
Pregnancy test  
X 
X 
 
X 
X 
X 
 
 
Vital signs 
X 
 
 
 
 
X 
 
X 
Physical examination 
X 
 
 
 
 
X 
 
X 
Previous/concomitant medications  
X 
X 
 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
 
Obtain blood samples: 
Haematology and clinical chemistry/Renal Function/PK 
X 
Xc 
 
Xa, c 
Xb 
X 
 
 
Collect 
 sample 
X 
X 
 
X 
Xd 
X 
 
X 
Verify eligibility for randomisation 
X 
X 
 
 
 
 
 
 
Spirometry: FEV1 and FVC 
X 
Xe 
 
X 
X 
Xe 
 
X 
 
 
X 
 
Xf 
X 
X 
 
 
 Training, Dispensing/Collection  
 
X 
 
 
 
X 
 
 
Review of IMP administration &
 use (adherence) 
 
X 
X 
X 
X 
X 
 
 
Study Medication: Dispense/Accountability 
 
X 
 
X 
X 
X 
 
 
Record of 
 and 
 
 
 
X 
X 
X 
X 
 
X 
AE monitoring including exacerbations not otherwise reported 
X 
X 
X 
X 
X 
X 
X 
X 
Weekly follow up phone calls to determine end of Pulmonary 
Exacerbations 
 
 
 
 
 
 
 
X 
* Informed consent must be obtained prior to any study procedure. Study procedures at Visit 1 can be performed any time prior to Visit 2.  
a; renal function test only. b; haematology, clinical chemistry and renal function test at Visit 5 (6 Months) only. c; PK sampling only (for relevant sites). d; Visit 5 only. e; FEV1 and FVC to be 
measured pre-bronchodilator and 30 ± 10 minutes post IMP dose. f; The 4 week version of the 
 is used at Visit 3 whilst all other visits use the 3 month version.  
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Page 65 of 65 
SOP C.03.02.06 – App. 1  
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 IRB/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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: