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    Clinical Trial Results:
    A Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of BAY 41-6551 as Adjunctive Therapy in Intubated and Mechanically-Ventilated Patients with Gram-Negative Pneumonia

    Summary
    EudraCT number
    2013-001048-73
    Trial protocol
    CZ  
    Global end of trial date
    07 Apr 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Jul 2018
    First version publication date
    12 Apr 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    XML requested from Service Desk to support issue handling.

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY41-6551/13084
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    26 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that as adjunctive therapy to IV antibiotics, BAY 41-6551 400 mg (amikacin as free base) administered as an aerosol by the PDDS Clinical every 12 hours is safe and more effective than placebo (aerosolized normal saline) administered as an aerosol by the PDDS Clinical every 12 hours, in intubated and mechanically-ventilated patients with Gram-negative pneumonia.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    France: 64
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Hungary: 30
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Ukraine: 7
    Country: Number of subjects enrolled
    Brazil: 47
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    Philippines: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    China: 199
    Country: Number of subjects enrolled
    Japan: 63
    Country: Number of subjects enrolled
    United States: 90
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Czech Republic: 3
    Worldwide total number of subjects
    712
    EEA total number of subjects
    164
    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)
    326
    From 65 to 84 years
    335
    85 years and over
    51

    Subject disposition

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    Recruitment
    Recruitment details
    To shorten the time required to obtain data from the 2 clinical studies of Amikacin Inhale Phase 3 program, Bayer and the FDA decided that the results of studies NCT01799993 and NCT00805168 should be consolidated into a single report. The studies were conducted at 166 centers across 25 countries, between 22 APR 2013 (FPFV) and 07 APR 2017 (LPLV).

    Pre-assignment
    Screening details
    A total of 807 subjects were screened, of which 725 subjects were randomized for the 2 studies, 712 subjects were treated with study treatment per exposure data in EDC; 354 received aerosolized amikacin inhale and 358 received placebo.

    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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Amikacin inhale (BAY41-6551)
    Arm description
    Subjects received 400 mg (3.2 mL) aerosolized Amikacin (BAY41-6551) solution every 12 hours via Pulmonary Drug Delivery System (PDDS) Clinical from Day 1 to Day 10.
    Arm type
    Experimental

    Investigational medicinal product name
    Amikacin inhale
    Investigational medicinal product code
    BAY41-6551
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received 400 mg (3.2 mL) aerosolized Amikacin (BAY41-6551) solution every 12 hours via PDDS Clinical from Day 1 to Day 10.

    Arm title
    Placebo
    Arm description
    Subjects received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.
    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
    Subjects received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.

    Number of subjects in period 1
    Amikacin inhale (BAY41-6551) Placebo
    Started
    362
    363
    ITT population
    354
    358
    mITT population
    255
    253
    Completed
    229
    235
    Not completed
    133
    128
         Deterioration of general conditions
    2
    -
         Protocol driven decision point
    -
    3
         Didn't complete CRF page "End of Follow-up"
    30
    40
         Adverse event
    1
    -
         Screen failure
    -
    1
         Non-compliance with medical device
    1
    -
         Withdrawal by parent/guardian/LAR
    5
    3
         Withdrawal by parent/guardian
    -
    1
         Consent withdrawn by subject
    23
    24
         Recovery
    -
    1
         Logistical difficulties
    1
    -
         Protocol violation
    1
    1
         Death
    61
    45
         Unknown
    1
    -
         Subject didn't want to return for follow-up
    -
    1
         Lost to follow-up
    5
    8
         Lack of efficacy
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    712 712
    Age categorical
    Units: Subjects
        <18
    0 0
        18 to <45
    91 91
        18 to <65
    235 235
        65 to <75
    175 175
        >= 75
    211 211
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.9 ± 16.42 -
    Gender categorical
    Units: Subjects
        Female
    214 214
        Male
    498 498
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    512 512
        Hispanic or Latino
    104 104
        Not reported
    96 96
    APACHE II score
    Subjects who met all of the inclusion criteria and none of the exclusion criteria were stratified by geographic region (or country) and disease severity using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and randomized in a 1:1 ratio to one of the two treatment groups.
    Units: Subjects
        <20
    373 373
        >=20
    339 339
    CPIS
    The components of the Clinical Pulmonary Infection Score (CPIS) were collected, and the scores were calculated.
    Units: Point
        arithmetic mean (standard deviation)
    7.0 ± 1.34 -
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Included all subjects who were treated with at least one dose of study drug.

    Subject analysis set title
    mITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Included all subjects who had a culture-confirmed Gram-negative bacteria that had been treated with at least one dose of study treatment, and had an APACHE II score ≥ 10 at the time of diagnosis of pneumonia.

    Subject analysis set title
    ITT for Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all subjects in ITT anlaysis set who were analyzed as treated for safety analyses.

    Subject analysis set title
    ITT for Safety population - Amikacin inhale
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all subject in ITT analysis set who were analyzed as treated with Amikacin for safety analyses.

    Subject analysis set title
    ITT for Safety population - Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all subject in ITT analysis set who were analyzed as treated with placebo for safety analyses.

    Subject analysis set title
    ITT - Amikacin inhale
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Included all subject in ITT analysis set who were treated with Amikacin

    Subject analysis set title
    ITT - Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Included all subject in ITT analysis set who were treated with placebo

    Subject analysis sets values
    ITT mITT ITT for Safety population ITT for Safety population - Amikacin inhale ITT for Safety population - Placebo ITT - Amikacin inhale ITT - Placebo
    Number of subjects
    712
    508
    712
    353
    359
    354
    358
    Age categorical
    Units: Subjects
        <18
    0
    0
        18 to <45
    38
    53
        18 to <65
    130
    105
        65 to <75
    92
    83
        >= 75
    94
    117
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    63.8 ± 15.78
    64.1 ± 17.04
    Gender categorical
    Units: Subjects
        Female
    107
    107
        Male
    247
    251
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    262
    250
        Hispanic or Latino
    49
    55
        Not reported
    43
    53
    APACHE II score
    Subjects who met all of the inclusion criteria and none of the exclusion criteria were stratified by geographic region (or country) and disease severity using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and randomized in a 1:1 ratio to one of the two treatment groups.
    Units: Subjects
        <20
    187
    186
        >=20
    167
    172
    CPIS
    The components of the Clinical Pulmonary Infection Score (CPIS) were collected, and the scores were calculated.
    Units: Point
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    7.1 ± 1.38
    6.9 ± 1.29

    End points

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    End points reporting groups
    Reporting group title
    Amikacin inhale (BAY41-6551)
    Reporting group description
    Subjects received 400 mg (3.2 mL) aerosolized Amikacin (BAY41-6551) solution every 12 hours via Pulmonary Drug Delivery System (PDDS) Clinical from Day 1 to Day 10.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 3.2 mL aerosolized placebo solution every 12 hours via PDDS Clinical from Day 1 to Day 10.

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Included all subjects who were treated with at least one dose of study drug.

    Subject analysis set title
    mITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Included all subjects who had a culture-confirmed Gram-negative bacteria that had been treated with at least one dose of study treatment, and had an APACHE II score ≥ 10 at the time of diagnosis of pneumonia.

    Subject analysis set title
    ITT for Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all subjects in ITT anlaysis set who were analyzed as treated for safety analyses.

    Subject analysis set title
    ITT for Safety population - Amikacin inhale
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all subject in ITT analysis set who were analyzed as treated with Amikacin for safety analyses.

    Subject analysis set title
    ITT for Safety population - Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Included all subject in ITT analysis set who were analyzed as treated with placebo for safety analyses.

    Subject analysis set title
    ITT - Amikacin inhale
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Included all subject in ITT analysis set who were treated with Amikacin

    Subject analysis set title
    ITT - Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Included all subject in ITT analysis set who were treated with placebo

    Primary: Survival through LFU visit

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    End point title
    Survival through LFU visit
    End point description
    The primary efficacy variable is Survival through the late follow-up (LFU) visit. Survival is achieved when the subject is alive through the LFU visit. No other factors are considered in the evaluation of survival.
    End point type
    Primary
    End point timeframe
    Up to 28-32 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [1]
    253 [2]
    Units: Subjects
        Clinical Success (Survive)
    191
    196
        Clinical Failure (Did not survive)
    64
    57
    Notes
    [1] - mITT population
    [2] - mITT population
    Statistical analysis title
    Survival rates through LFU visit
    Statistical analysis description
    The primary analysis compared the Survival rates through LFU visit of patients in the amikacin inhale group versus the patients in the placebo group, using the combined data from studies 13084 and 13085. A Cochran-Mantel-Haenzel (CMH) test of general association, adjusting for randomized stratum (based on APACHE II score as a measure of disease severity) and geographic region was performed as the primary efficacy analysis.
    Comparison groups
    Amikacin inhale (BAY41-6551) v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4263
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.841
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.554
         upper limit
    1.277

    Secondary: Adjudicated pneumonia-related mortality through LFU visit

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    End point title
    Adjudicated pneumonia-related mortality through LFU visit
    End point description
    Death through LFU visit was adjudicated as pneumonia-related or pneumonia-unrelated for subjects in the amikacin inhale group and subjects in the placebo group.
    End point type
    Secondary
    End point timeframe
    Up to 28-32 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    64 [3]
    57 [4]
    Units: Subjects
        Pneumonia-related mortality
    43
    36
        Pneumonia-unrelated mortality
    21
    21
    Notes
    [3] - Participants who died through LFU visit in mITT population set
    [4] - Participants who died through LFU visit in mITT population set
    Statistical analysis title
    Pneumonia-related mortality through LFU visit
    Statistical analysis description
    Pneumonia-related mortality through LFU visit was formally tested to determine if the difference between the amikacin inhale group versus the placebo group was statistically significant. The null hypothesis of no difference between amikacin inhale and placebo was tested using an unadjusted chi-square test in the mITT population.
    Comparison groups
    Amikacin inhale (BAY41-6551) v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6421
    Method
    Chi-squared
    Confidence interval

    Secondary: Early Clinical Response

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    End point title
    Early Clinical Response
    End point description
    Early Clinical Response was determined by the following: 1. CPIS scoring at Days 3, 5, and 10 compared to baseline (a. On Day 3, CPIS increase from baseline by at least 2 points was considered a failure. b. On Day 5, CPIS decrease from baseline of at least 1 point was not a failure. CPIS of no change from baseline was considered a failure. Any CPIS increase from baseline was a failure. c. On Day 10, CPIS decrease from baseline of at least 2 points was not a failure. CPIS decrease of only 1 point is a failure. CPIS of no change was considered a failure. Any CPIS increase from baseline was a failure.). 2. All-cause mortality through EOT visit was a failure. 3. The development of empyema or lung abscess through the EOT visit was a failure.
    End point type
    Secondary
    End point timeframe
    Up to 10 days after start of study treatment.
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [5]
    253 [6]
    Units: Subjects
        Early Clinical Response - Success
    149
    145
        Early Clinical Response - Failure
    106
    108
    Notes
    [5] - mITT population
    [6] - mITT population
    Statistical analysis title
    Early Clinical Response
    Statistical analysis description
    Early Clinical Response was formally tested to determine if the difference between the amikacin inhale group versus the placebo group was statistically significant. The null hypothesis of no difference between amikacin inhale and placebo was tested using an unadjusted chi-square test in the mITT population.
    Comparison groups
    Amikacin inhale (BAY41-6551) v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7984
    Method
    Chi-squared
    Confidence interval

    Secondary: Number of days on mechanical ventilation through the LFU visit

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    End point title
    Number of days on mechanical ventilation through the LFU visit
    End point description
    Number of days on mechanical ventilator was summarized by descriptive statistics. Duration was defined as the number of days from the date of first study drug through the LFU visit. For subjects who lived through the LFU visit, the ventilation days were actual days on ventilation with a maximum value of 28 days. For subjects who died after Day 28 but on or before their LFU visit, the days on ventilator was censored at 28 days. For subjects who died or discontinued off ventilation, the number of days on ventilation was actual days on ventilation with a maximum value of 28 days. For subjects who died or discontinued on ventilation, the number of days on ventilation was 28 days. Further analysis of the number of days on mechanical ventilator was to be performed with censoring at Day 28 for subset of subjects on ventilation without censoring.
    End point type
    Secondary
    End point timeframe
    Up to 28-32 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [7]
    253 [8]
    Units: Days
        arithmetic mean (standard deviation)
    20.6 ± 10.09
    20.2 ± 10.24
    Notes
    [7] - mITT population
    [8] - mITT population
    Statistical analysis title
    Number of days on mechanical ventilation
    Statistical analysis description
    Analysis of variance was used to test the null hypothesis of no difference between amikacin inhale and placebo for the number of days on mechanical ventilation.
    Comparison groups
    Amikacin inhale (BAY41-6551) v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7144
    Method
    ANOVA
    Confidence interval

    Secondary: Number of days in the ICU through LFU visit

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    End point title
    Number of days in the ICU through LFU visit
    End point description
    Number of days in ICU was summarized by descriptive statistics. Duration was defined as the number of days from the date of first study drug through the LFU visit. For subjects who lived in ICU through the LFU visit, the ICU days were actual days in ICU with a maximum value of 28 days. For subjects who died after Day 28 but on or before their LFU visit, the days in ICU was censored at 28 days. For subjects who died or discontinued in ICU, the number of days in ICU was 28 days. Further analysis of the number of days in ICU was to be performed with censoring at Day 28 for subset of subjects on ventilation and without censoring.
    End point type
    Secondary
    End point timeframe
    Up to 28-32 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [9]
    253 [10]
    Units: Days
        arithmetic mean (standard deviation)
    21.3 ± 8.17
    21.9 ± 7.99
    Notes
    [9] - mITT population
    [10] - mITT population
    Statistical analysis title
    Number of days in the ICU through the LFU visit
    Statistical analysis description
    Analysis of variance was used to test the null hypothesis of no difference between amikacin inhale and placebo for the number of days in the ICU.
    Comparison groups
    Placebo v Amikacin inhale (BAY41-6551)
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4278
    Method
    ANOVA
    Confidence interval

    Other pre-specified: Per pathogen microbiological response rates at TOC visit

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    End point title
    Per pathogen microbiological response rates at TOC visit
    End point description
    The percentage of subjects with microbiological response for each pathogen among the total number of subjects with baseline pathogen isolates for each pathogen was determined. If a subject had 3 pathogens, all 3 were tabulated. Eradication ( defined as the absence of the original pathogen(s) at the post-treatment test-of-cure [TOC] visit culture of specimens from the original site of infection) and presumed eradication (defined as absence of appropriate culture material in a patient judged to be a clinical cure; he or she was unable to produce sputum and invasive procedures were not warranted) rates were reported to reveal the microbiological responses. The data were displayed for each bacterial genus/species. Baseline pathogen was defined as pathogens tested at Screening and Day 1 visit by central laboratory. "99999" denotes that data were not calculated as no subject with baseline pathogen isolates for the specified species in the specified arm.
    End point type
    Other pre-specified
    End point timeframe
    Up to 17-19 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [11]
    253 [12]
    Units: percentage of subjects
    number (not applicable)
        Achromobacter xylosoxidans
    0
    100.0
        Acinetobacter
    50.0
    99999
        Acinetobacter anitratus
    59.7
    62.3
        Acinetobacter junii
    100.0
    99999
        Burkholderia cepacia complex
    50.0
    50.0
        Chryseobacterium indologenes
    99999
    100.0
        Citrobacter farmeri
    100.0
    99999
        Citrobacter freundii complex
    75.0
    66.7
        Citrobacter koseri
    42.9
    100.0
        Corynebacterium argentoratense
    100.0
    99999
        Corynebacterium propinquum
    99999
    0
        Corynebacterium striatum
    100.0
    0
        Elizabethkingia meningoceptica
    100.0
    100.0
        Enterobacter aerogenes
    100.0
    40.0
        Enterobacter cloacae
    60.0
    62.5
        Enterococcus faecalis
    100.0
    100.0
        Enterococcus faecium
    100.0
    100.0
        Escherichia coli
    75.0
    65.5
        Ewingella americana
    99999
    100.0
        Haemophilus influenzae
    80.0
    100.0
        Haemophilus parahaemolyticus
    100.0
    99999
        Haemophilus parainfluenzae
    100.0
    99999
        Hafnia alvei
    50.0
    100.0
        Kerstersia gyiorum
    100.0
    0
        Klebsiella oxytoca
    66.7
    71.4
        Klebsiella pneumoniae
    71.7
    63.6
        Kluyvera intermedia
    100.0
    99999
        Moraxella catarrhalis
    100.0
    100.0
        Morganella morganii
    0
    99999
        Neisseria
    100.0
    0
        Pantoea agglomerans
    100.0
    99999
        Pasteurella multocida
    100.0
    99999
        Proteus mirabilis
    66.7
    60.0
        Proteus vulgaris
    0
    99999
        Providencia stuartii
    99999
    100.0
        Pseudomonas aeruginosa
    73.3
    50.0
        Pseudomonas putida
    0
    100.0
        Raoultella ornithinolytica
    0
    99999
        Raoultella planticola
    75
    66.7
        Serratia liquefaciens
    100
    99999
        Serratia marcescens
    75
    76.5
        Staphylococcus aureus
    75
    66.7
        Staphylococcus haemolyticus
    100
    99999
        Stenotrophomonas maltophilia
    75
    62.5
        Streptococcus agalactiae
    100
    100
        Streptococcus anginosus group
    99999
    100
        Streptococcus mitis group
    50
    0
        Streptococcus pneumoniae
    100
    99999
    Notes
    [11] - mITT population
    [12] - mITT population
    No statistical analyses for this end point

    Other pre-specified: Per subject microbiological response rate at TOC visit

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    End point title
    Per subject microbiological response rate at TOC visit
    End point description
    The responses of eradication (defined as the absence of the original pathogen(s) at the post-treatment TOC culture of specimens from the original site of infection) and presumed eradication (defined as absence of appropriate culture material in a subject judged to be a clinical cure; he or she was unable to produce sputum and invasive procedures were not warranted) were tabulated for each subject to reveal the microbiological responses. All pathogen isolates from a subjects must be eradicated (or presumed eradicated) to tabulate an eradicated (or presumed eradicated) response. Baseline pathogen was defined as pathogens tested at Screening and Day 1 visit by central laboratory.
    End point type
    Other pre-specified
    End point timeframe
    Up to 17-19 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [13]
    253 [14]
    Units: Percentage of subjects
        number (not applicable)
    58.8
    46.6
    Notes
    [13] - mITT population
    [14] - mITT population
    No statistical analyses for this end point

    Other pre-specified: Microbiological recurrence rates at LFU visit

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    End point title
    Microbiological recurrence rates at LFU visit
    End point description
    The responses of recurrence were tabulated for each subject. Recurrence was defined as the reappearance of the original pathogen(s) from a specimen taken after the TOC visit. If one or more pathogen reappeared, all isolates from a subject were tabulated as “recurrence”. Baseline pathogen was defined as pathogens tested at Screening and Day 1 visit by central laboratory.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28-32 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [15]
    253 [16]
    Units: Percentage of subjects
        number (not applicable)
    4.7
    4.7
    Notes
    [15] - mITT population
    [16] - mITT population
    No statistical analyses for this end point

    Other pre-specified: Emergence of new respiratory pathogens during the aerosol treatment period

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    End point title
    Emergence of new respiratory pathogens during the aerosol treatment period
    End point description
    New pathogens also denoted as superinfection was defined as the isolation of a new pathogen (not the original baseline pathogen) from a specimen taken while the subject was on antibiotic therapy (Day 1 to EOT) and having a need for alternative antimicrobial therapy. Rates of emergence of any new pathogen by-subject after start of study drug were summarized for each treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Up to 10 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [17]
    253 [18]
    Units: Percentage of subjects
        number (not applicable)
    8.2
    13.4
    Notes
    [17] - mITT population
    [18] - mITT population
    No statistical analyses for this end point

    Other pre-specified: Emergence of resistance among pathogens by subject

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    End point title
    Emergence of resistance among pathogens by subject
    End point description
    Resistance to amikacin was determined for the bacterial isolates by using a standardized microbiology laboratory test that generates a minimum inhibitory concentration (MIC) for amikacin and bacterial isolate. The same microbiology resistance standard was used for all bacteria tested against amikacin. Resistant bacteria have a MIC value of 64 μg/mL or greater. Percentages of resistance were calculated based on the percentage of subjects infected with any treatment-emergent pathogens resistant to amikacin. If a subject had a more than one occurrence of a specific pathogen during pre-treatment period, the worst case of testing was used.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28-32 days after start of study treatment
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    186 [19]
    194 [20]
    Units: Percentage of subjects
        number (not applicable)
    7.0
    8.8
    Notes
    [19] - mITT population subjects with pathogen susceptible to amikacin in pre-treatment period
    [20] - mITT population subjects with pathogen susceptible to amikacin in pre-treatment period
    No statistical analyses for this end point

    Other pre-specified: Number of subjects who received at least one dose of study drug and reported an adverse event

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    End point title
    Number of subjects who received at least one dose of study drug and reported an adverse event
    End point description
    AE was untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. AEs, occurred any time after the first dose of therapy and through 7 days after the EOT were recorded as treat-emergent AEs (TEAEs).
    End point type
    Other pre-specified
    End point timeframe
    Up to 7 days after the end of study treatment
    End point values
    ITT for Safety population - Amikacin inhale ITT for Safety population - Placebo
    Number of subjects analysed
    353 [21]
    359 [22]
    Units: Subjects
    295
    303
    Notes
    [21] - ITT for Safety population
    [22] - ITT for Safety population
    No statistical analyses for this end point

    Other pre-specified: Number of subjects who received at least one dose of study drug and reported a serious adverse event

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    End point title
    Number of subjects who received at least one dose of study drug and reported a serious adverse event
    End point description
    AE was untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. Serious AE: AE resulting in following outcomes or deemed significant for any reason: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent; significant disability/incapacity; congenital anomaly/birth defect; medical important serious event judged by investigator. SAEs, occurred any time after the first dose of therapy and through 7 days after the EOT were recorded as treat-emergent SAEs (TESAEs).
    End point type
    Other pre-specified
    End point timeframe
    Up to 7 days after the end of study treatment
    End point values
    ITT for Safety population - Amikacin inhale ITT for Safety population - Placebo
    Number of subjects analysed
    353 [23]
    359 [24]
    Units: Subjects
    101
    97
    Notes
    [23] - ITT for Safety population
    [24] - ITT for Safety population
    No statistical analyses for this end point

    Other pre-specified: Progression and incidence rates of organ failure

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    End point title
    Progression and incidence rates of organ failure
    End point description
    The overall percentage of subjects with any organ failure was summarized for each treatment group. Organ failure was defined by a specific organ type and by a collection of MedDRA version 20.0 preferred terms that were determined by the sponsor’s clinical team. A subject with multiple AEs within a system organ class or preferred term is counted a single time for that system organ class (SOC) or preferred term.
    End point type
    Other pre-specified
    End point timeframe
    Up to 7 days after the end of study treatment
    End point values
    ITT for Safety population - Amikacin inhale ITT for Safety population - Placebo
    Number of subjects analysed
    353 [25]
    359 [26]
    Units: Percentage of subjects
        number (not applicable)
    19.5
    18.7
    Notes
    [25] - ITT for Safety population
    [26] - ITT for Safety population
    No statistical analyses for this end point

    Other pre-specified: All-cause mortality rate through Day 10 and Day 15

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    End point title
    All-cause mortality rate through Day 10 and Day 15
    End point description
    Number of deaths due to any reason through Day 10 and Day 15 were summarized for each treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Up to 10 days and 15 days after start of study treatment, respectively
    End point values
    Amikacin inhale (BAY41-6551) Placebo
    Number of subjects analysed
    255 [27]
    253 [28]
    Units: Subjects
        Number of death through Day 10
    23
    32
        Number of death through Day 15
    32
    39
    Notes
    [27] - mITT population
    [28] - mITT population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first dose of study drug and no later than 7 days after end of treatment
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Amikacin Inhale 400mg q12h
    Reporting group description
    Patients received 400 mg (3.2 mL) aerosolized Amikacin (BAY41-6551) solution every 12 hours via PDDS Clinical from Day 1 to Day 10.

    Reporting group title
    Placebo
    Reporting group description
    Patients received 3.2 mL placebo solution aerosolized every 12 hours via PDDS Clinical from Day 1 to Day 10.

    Serious adverse events
    Amikacin Inhale 400mg q12h Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 353 (28.61%)
    97 / 359 (27.02%)
         number of deaths (all causes)
    86
    85
         number of deaths resulting from adverse events
    52
    59
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric cancer
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lung
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    3 / 353 (0.85%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Shock haemorrhagic
         subjects affected / exposed
    0 / 353 (0.00%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Deep vein thrombosis
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    5 / 353 (1.42%)
    5 / 359 (1.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 5
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Asphyxia
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 353 (0.00%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemothorax
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    4 / 353 (1.13%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    5 / 353 (1.42%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory acidosis
         subjects affected / exposed
    0 / 353 (0.00%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    9 / 353 (2.55%)
    4 / 359 (1.11%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    Sputum retention
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reexpansion pulmonary oedema
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute interstitial pneumonitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Respiratory rate decreased
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (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
    Brain herniation
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multiple injuries
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis chemical
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weaning failure
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 353 (0.85%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrioventricular block complete
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    5 / 353 (1.42%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure acute
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         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
    3 / 353 (0.85%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain hypoxia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stroke in evolution
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coagulopathy
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 353 (0.57%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Intestinal perforation
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal perforation
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    5 / 353 (1.42%)
    4 / 359 (1.11%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    3 / 353 (0.85%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mediastinitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pathogen resistance
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 353 (1.42%)
    5 / 359 (1.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 353 (1.42%)
    4 / 359 (1.11%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Septic shock
         subjects affected / exposed
    7 / 353 (1.98%)
    15 / 359 (4.18%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 15
         deaths causally related to treatment / all
    0 / 6
    0 / 14
    Urosepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Device related sepsis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacillus bacteraemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Amikacin Inhale 400mg q12h Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    207 / 353 (58.64%)
    214 / 359 (59.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 353 (3.68%)
    7 / 359 (1.95%)
         occurrences all number
    13
    8
    Hypotension
         subjects affected / exposed
    23 / 353 (6.52%)
    12 / 359 (3.34%)
         occurrences all number
    24
    12
    Deep vein thrombosis
         subjects affected / exposed
    9 / 353 (2.55%)
    3 / 359 (0.84%)
         occurrences all number
    9
    3
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    5 / 353 (1.42%)
    9 / 359 (2.51%)
         occurrences all number
    5
    9
    Oedema peripheral
         subjects affected / exposed
    9 / 353 (2.55%)
    13 / 359 (3.62%)
         occurrences all number
    12
    14
    Pyrexia
         subjects affected / exposed
    18 / 353 (5.10%)
    21 / 359 (5.85%)
         occurrences all number
    21
    24
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    10 / 353 (2.83%)
    2 / 359 (0.56%)
         occurrences all number
    15
    2
    Dyspnoea
         subjects affected / exposed
    7 / 353 (1.98%)
    9 / 359 (2.51%)
         occurrences all number
    9
    9
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    8 / 353 (2.27%)
    12 / 359 (3.34%)
         occurrences all number
    8
    12
    Delirium
         subjects affected / exposed
    14 / 353 (3.97%)
    9 / 359 (2.51%)
         occurrences all number
    15
    9
    Insomnia
         subjects affected / exposed
    6 / 353 (1.70%)
    11 / 359 (3.06%)
         occurrences all number
    6
    11
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    5 / 353 (1.42%)
    8 / 359 (2.23%)
         occurrences all number
    5
    10
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    9 / 353 (2.55%)
    10 / 359 (2.79%)
         occurrences all number
    9
    10
    Tachycardia
         subjects affected / exposed
    6 / 353 (1.70%)
    11 / 359 (3.06%)
         occurrences all number
    6
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    36 / 353 (10.20%)
    44 / 359 (12.26%)
         occurrences all number
    38
    49
    Coagulopathy
         subjects affected / exposed
    5 / 353 (1.42%)
    10 / 359 (2.79%)
         occurrences all number
    5
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    30 / 353 (8.50%)
    32 / 359 (8.91%)
         occurrences all number
    30
    32
    Diarrhoea
         subjects affected / exposed
    27 / 353 (7.65%)
    33 / 359 (9.19%)
         occurrences all number
    30
    34
    Vomiting
         subjects affected / exposed
    6 / 353 (1.70%)
    17 / 359 (4.74%)
         occurrences all number
    7
    18
    Gastrointestinal haemorrhage
         subjects affected / exposed
    13 / 353 (3.68%)
    6 / 359 (1.67%)
         occurrences all number
    13
    6
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    12 / 353 (3.40%)
    13 / 359 (3.62%)
         occurrences all number
    12
    13
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    11 / 353 (3.12%)
    14 / 359 (3.90%)
         occurrences all number
    11
    14
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    3 / 353 (0.85%)
    8 / 359 (2.23%)
         occurrences all number
    3
    8
    Renal impairment
         subjects affected / exposed
    4 / 353 (1.13%)
    9 / 359 (2.51%)
         occurrences all number
    4
    9
    Acute kidney injury
         subjects affected / exposed
    9 / 353 (2.55%)
    7 / 359 (1.95%)
         occurrences all number
    9
    9
    Infections and infestations
    Septic shock
         subjects affected / exposed
    8 / 353 (2.27%)
    5 / 359 (1.39%)
         occurrences all number
    11
    5
    Urinary tract infection
         subjects affected / exposed
    10 / 353 (2.83%)
    10 / 359 (2.79%)
         occurrences all number
    11
    10
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    8 / 353 (2.27%)
    10 / 359 (2.79%)
         occurrences all number
    8
    11
    Hyperkalaemia
         subjects affected / exposed
    14 / 353 (3.97%)
    10 / 359 (2.79%)
         occurrences all number
    14
    10
    Hypernatraemia
         subjects affected / exposed
    9 / 353 (2.55%)
    12 / 359 (3.34%)
         occurrences all number
    9
    12
    Hypoglycaemia
         subjects affected / exposed
    5 / 353 (1.42%)
    9 / 359 (2.51%)
         occurrences all number
    5
    12
    Hypokalaemia
         subjects affected / exposed
    32 / 353 (9.07%)
    37 / 359 (10.31%)
         occurrences all number
    36
    40
    Hypomagnesaemia
         subjects affected / exposed
    8 / 353 (2.27%)
    7 / 359 (1.95%)
         occurrences all number
    9
    7
    Hyponatraemia
         subjects affected / exposed
    17 / 353 (4.82%)
    12 / 359 (3.34%)
         occurrences all number
    17
    12
    Hypophosphataemia
         subjects affected / exposed
    6 / 353 (1.70%)
    11 / 359 (3.06%)
         occurrences all number
    6
    11
    Hypoproteinaemia
         subjects affected / exposed
    8 / 353 (2.27%)
    4 / 359 (1.11%)
         occurrences all number
    9
    4
    Metabolic alkalosis
         subjects affected / exposed
    8 / 353 (2.27%)
    10 / 359 (2.79%)
         occurrences all number
    10
    10

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2016
    To shorten the time required to obtain the data from the two Phase 3 clinical studies of the Amikacin Inhale program (BAY 41 6551/13084 [Inhale I] and BAY 41-6551/13085 [Inhale II]) to sustain regulatory submission, the Sponsor, Bayer AG, decided that the results of both studies should be consolidated into a single integrated report. As there will be no second study to corroborate the findings in the consolidated report it was considered necessary to review the endpoints to ensure optimal clinical relevance. During a blinded review of the data from 106 patients entered into the Phase 3 program it was found that there was an artificially high failure rate occasioned by the original antibiotic use rules. These failures did not correspond with data that are used as medical management tools and were considered spurious. Certain other elements of the original endpoint were also considered not to accurately reflect clinical benefit. This required modifications a priori of the statistical analysis plan, but did not require any alterations to patient management, modifications to data collection tools, or changes to clinical/laboratory evaluations being performed at the ICU to assess Clinical Failure or Success. The aim was that the patient population recruited into the study and the management of the patients would be the same after the implementation of this amendment as it was before. Recruitment continued in the two studies until a total of approximately 724 patients had been enrolled. Enrollment was competitive and both studies were planned to stop once the number was reached. The primary efficacy endpoint had been modified to allow antibiotic rules to better reflect Clinical Success or Failure and the other variables to be more clearly aligned with clinical response. The secondary variables, Days in hospital and relapses rates were removed, pneumonia-related mortality added and speed of response based on CPIS success or failure added.
    30 Aug 2016
    A correction was made in the temperature criterion for the calculation of CPIS points. This correction accurately reflects the programming that has been used in the electronic case report form by the investigators to calculate the CPIS score throughout the study, i.e., it did not represent a change in the conduct of the study. Note: This was an error in the original protocol that was carried forward in other amendments.
    07 Apr 2017
    The amendment date was 29-Aug-2017. During a blinded review of the data from 454 mITT patients entered into the Phase III program it was found that there was an artificially high failure rate due to the antibiotic criteria. These failures did not correspond with data that are used as medical management tools and were considered spurious. Certain other elements of the endpoint related to the TOC date were also considered not to accurately reflect clinical benefit. These data necessitated a change in the primary endpoint. It was decided to narrow the primary endpoint to all-cause mortality alone through the LFU visit (Days 28-32). This primary endpoint is in alignment with current FDA draft guidance for ventilated pneumonia. All-cause mortality through the LFU visit was the sole criterion for evaluation. Survival was the new primary endpoint.

    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.
    To shorten the time required to obtain data from the 2 clinical studies of Amikacin Inhale Phase 3 program, Bayer and the FDA decided that the results of studies NCT01799993 and NCT00805168 should be consolidated into a single report.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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