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    Clinical Trial Results:
    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).

    Summary
    EudraCT number
    		 2015-002743-33
    Trial protocol
    		 GB   ES   DE   PT   NL   GR   IT  
    Global end of trial date
    09 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2023
    First version publication date
    02 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Z7224L01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03093974
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zambon SPA
    Sponsor organisation address
    Via Lillo Del Duca, 10, Bresso (MI), Italy, 20091
    Public contact
    Clinical Trial Manager, Zambon S.p.A., +39 02 665241, clinicaltrials@zambongroup.com
    Scientific contact
    Clinical Trial Manager, Zambon S.p.A., +39 02 665241, clinicaltrials@zambongroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to investigate the effect of the use of inhaled colistimethate sodium, administered twice daily via a specific nebuliser for 12 months, compared to placebo in subjects with NCFB chronically infected with P. aeruginosa on the frequency of pulmonary exacerbations.
    Protection of trial subjects
    This trial was conducted in compliance with the latest version of the Declaration of Helsinki, with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), in particular E6(R2), with the applicable regulatory requirements and with Zambon and contract research organisation (CRO) standard operating procedures (SOPs).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 63
    Country: Number of subjects enrolled
    New Zealand: 19
    Country: Number of subjects enrolled
    Israel: 41
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Portugal: 48
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Italy: 53
    Worldwide total number of subjects
    377
    EEA total number of subjects
    220
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    158
    From 65 to 84 years
    211
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 538 subjects were screened, of whom 377 (~70%) were randomised and 161 (~30%) were screen failures.

    Pre-assignment
    Screening details
    		 In total, 377 subjects were randomised 1:1 to CMS or placebo, with slightly more assigned to the placebo group (53.1% compared to 46.9% CMS).Of the 377 subjects randomized there were 177 randomized to CMS and 200 randomised to placebo. Four subjects (one randomised to CMS and three to placebo) did not receive any study medication.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Investigational site staff including the Investigator and all personnel involved in study procedures were blinded to treatment allocation. All CRO and Zambon study staff involved in monitoring, data management, or other aspects of the study were also blinded. The allocation to treatment was stored within the IWRS database until unblinding of the trial was requested.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CMS (Colistimethate Sodium)
    Arm description
    		 Inhaled CMS 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 International Organization for Standardization (ISO) glass vials. CMS: 1 MIU equivalent to 80 mg CMS 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 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 b.i.d. for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Colistimethate sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Inhaled colistimethate sodium twice daily. CMS: 1 MIU equivalent to 80 mg CMS 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 fitted with a 0.3 mL medication chamber, for administration by inhalation. This delivered a nominal dose of 0.3 MIU/24 mg CMS (~10 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 a period of 12 months. At least 10 min before each administration, an inhaled short-acting bronchodilator (e.g. salbutamol/albuterol), supplied by the sponsor could be taken to improve tolerability.

    Arm title
    		 Placebo
    Arm description
    		 Saline solution inhaled twice daily, provided and adminitered at the same way of the IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Saline solution inhaled twice daily, provided and adminitered at the same way of the IMP. Placebo: 1 ml saline solution 0.45%. the placebo was made up of identical empty glass vials to which the same saline 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 maintain the blind.

    Number of subjects in period 1
    		CMS (Colistimethate Sodium) Placebo
    Started
    177
    200
    Completed
    123
    129
    Not completed
    54
    71
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    32
    27
         Adverse event, non-fatal
    17
    24
         Protocol-specified withdrawal criterion met
    3
    16
         Unknown
    1
    2
         Non-compliance with study drug
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CMS (Colistimethate Sodium)
    Reporting group description
    		 Inhaled CMS 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 International Organization for Standardization (ISO) glass vials. CMS: 1 MIU equivalent to 80 mg CMS 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 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 b.i.d. for 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline solution inhaled twice daily, provided and adminitered at the same way of the IMP.

    Reporting group values
    		 CMS (Colistimethate Sodium) Placebo Total
    Number of subjects
    		 177 200 377
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 70 88 158
        From 65-84 years
    		 103 108 211
        85 years and over
    		 4 4 8
    Age continuous
    Units: years
        median (standard deviation)
    		 64.2 ( 14.78 ) 64.3 ( 13.03 ) -
    Gender categorical
    Units: Subjects
        Female
    		 124 129 253
        Male
    		 53 71 124
    Subject analysis sets

    Subject analysis set title
    CMS mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intention-To-Treat (mITT) Population is the Full Analysis Set and comprised all subjects who provided informed consent, were randomised and received at least one dose or partial dose of the IMP.

    Subject analysis set title
    Placebo mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intention-To-Treat (mITT) Population is the Full Analysis Set and comprised all subjects who provided informed consent, were randomised and received at least one dose or partial dose of the IMP.

    Subject analysis sets values
    		 CMS mITT Placebo mITT
    Number of subjects
    176
    197
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (standard deviation)
    64.2 ( 14.86 )
    64.2 ( 13.06 )
    Gender categorical
    Units: Subjects
        Female
    123
    126
        Male
    53
    71

    End points

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    End points reporting groups
    Reporting group title
    CMS (Colistimethate Sodium)
    Reporting group description
    		 Inhaled CMS 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 International Organization for Standardization (ISO) glass vials. CMS: 1 MIU equivalent to 80 mg CMS 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 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 b.i.d. for 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Saline solution inhaled twice daily, provided and adminitered at the same way of the IMP.

    Subject analysis set title
    CMS mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intention-To-Treat (mITT) Population is the Full Analysis Set and comprised all subjects who provided informed consent, were randomised and received at least one dose or partial dose of the IMP.

    Subject analysis set title
    Placebo mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified Intention-To-Treat (mITT) Population is the Full Analysis Set and comprised all subjects who provided informed consent, were randomised and received at least one dose or partial dose of the IMP.

    Primary: Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate

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    End point title
    		 Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate
    End point description
    The primary efficacy assessment for an individual subject was the frequency of pulmonary exacerbations (exacerbation rate). A pulmonary exacerbation was defined as the presence concurrently of at least three of the following eight symptoms/signs for at least 24 hours: • increased cough; • increased sputum volume and/or consistency; • increased sputum purulence; • new or increased haemoptysis; • increased wheezing; • increased dyspnoea; • increased fatigue/malaise; • episodes of fever (temperature ≥38°C). AND It was clinically determined that the subject required and was prescribed systemic antibiotic therapy. AND The episode of exacerbation lasted for at least 24 hours. The overall episode of exacerbation needs to last at least 24 hours, but individual symptoms/signs can last less than 24 hours (e.g, a temperature). AND in the opinion of the Investigator, the subject required and started treatment with systemic antibiotics.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 CMS mITT Placebo mITT
    Number of subjects analysed
    176
    194
    Units: Number of pulmonary exacerbations
        least squares mean (confidence interval 95%)
    0.580 (0.001 to 9999.999)
    0.948 (0.001 to 9999.999)
    Statistical analysis title
    		 CMS (Colistimethate Sodium) vs Placebo
    Statistical analysis description
    The number of NCFB pulmonary exacerbations was compared between treatment groups using a negative binomial model including treatment, pooled site (country) and baseline use of stable concomitant therapy with oral macrolides as fixed effects and log-time on treatment as an offset.
    Comparison groups
    CMS mITT v Placebo mITT
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.00101
    Method
    		 Two sided Wald chi-square test
    Parameter type
    		 LS Mean rate ratio
    Point estimate
    0.612
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.457
         upper limit
    		 0.82
    Notes
    [1] - The number of NCFB pulmonary exacerbations was compared between treatment groups using a negative binomial model including treatment, pooled site (country) and baseline use of stable concomitant therapy with oral macrolides as fixed effects and log-time on treatment as an offset.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring from the day of the first IMP administration, i.e. Visit 2 (day 0), up to the follow-up (54 weeks after the beginning of the trial), when follow-up phone call took place.
    Adverse event reporting additional description
    AEs will be recorded by the Investigator in the appropriate eCRF Section starting with the date of informed consent until the follow-up phone call. At each contact (i.e. clinical visit or phone call), subjects will be asked in a non-leading manner if they experienced any AE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    CMS (Colistimethate Sodium) (SAF)
    Reporting group description
    		 -

    Reporting group title
    Placebo (SAF)
    Reporting group description
    		 The Safety Population comprised all subjects who provided informed consent, were randomised and received at least one dose or partial dose of IMP. Subjects were analysed according to the treatment they actually received.

    Serious adverse events
    		 CMS (Colistimethate Sodium) (SAF) Placebo (SAF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 176 (17.61%)
    46 / 197 (23.35%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 176 (0.57%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 176 (0.57%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder polyp
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Empyema
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    15 / 176 (8.52%)
    29 / 197 (14.72%)
         occurrences causally related to treatment / all
    0 / 17
    1 / 36
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 176 (0.57%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 176 (2.27%)
    5 / 197 (2.54%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CMS (Colistimethate Sodium) (SAF) Placebo (SAF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    142 / 176 (80.68%)
    159 / 197 (80.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 176 (2.27%)
    11 / 197 (5.58%)
         occurrences all number
    4
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 176 (6.82%)
    5 / 197 (2.54%)
         occurrences all number
    12
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 176 (11.93%)
    19 / 197 (9.64%)
         occurrences all number
    24
    19
    Dyspnoea
         subjects affected / exposed
    22 / 176 (12.50%)
    16 / 197 (8.12%)
         occurrences all number
    34
    19
    Haemoptysis
         subjects affected / exposed
    9 / 176 (5.11%)
    19 / 197 (9.64%)
         occurrences all number
    19
    33
    Sputum increased
         subjects affected / exposed
    13 / 176 (7.39%)
    7 / 197 (3.55%)
         occurrences all number
    13
    9
    Infections and infestations
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    67 / 176 (38.07%)
    110 / 197 (55.84%)
         occurrences all number
    110
    196

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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