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    Clinical Trial Results:
    Prospective phase IIA multicenter double-blinded randomized placebo-controlled clinical trial evaluating the efficacy and safety of inhaled, aerosolized Tobramycin (TOBI®) b.i.d. in patients with ventilator-associated pneumonia (VAP)

    Summary
    EudraCT number
    		 2012-003621-21
    Trial protocol
    		 DE  
    Global end of trial date
    30 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2022
    First version publication date
    03 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTBM100DDE04T
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité University Hospital Berlin
    Sponsor organisation address
    Charité University Hospital Berlin, Berlin, Germany, 10177
    Public contact
    Dr. Stefan Angermair, Charité -Campus Benjamin Franklin, Department of Anesthesiology and surgical intensive care medicin, 49 30450551585, stefan.angermair@charite.de
    Scientific contact
    Dr. Carsten Schwarz, Charité - Campus Mitte, Department of Internal Medicine with a focus on infectiology and pneumology, 49 30450556552, carsten.schwarz@charite.de
    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
    30 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is the reduction and eradication of the endobronchial gram-negative bacteria in the pulmonal system, assessed as eradication of the pathogen at day 6 measured by the decrease in gram-negative pathogen-load in pulmonary infiltrate (either by gram-staining of the pathogen, by measurement of copies of DNA per ml in end-point PCR analysis or by kinetic laser measurement of turbidity increase of particles).
    Protection of trial subjects
    The safety of the therapy with TOBI or aerosolized sodium chlorid solution was assessed each day of the sty by physical examination, vital signs, laboratory test and evaluation of adverse events. Furthermore, the patients were monitored for spontaneous complaints after treatments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2013
    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
    Germany: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    9
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 5 study centers at 3 Campi of Charité in Berlin, between 10 February 2014 and 14 May 2019. Each patient fulfilling inclusion criteria (with VAP, between 18-85 ages, treated < 48 h with standard therapy before diagnosis VAP, gram-negativity diagnose within 24 h...) after given written consent by him/legal representative.

    Pre-assignment
    Screening details
    		 The originally planned sample size was 90 subjects (45 per treatment group; estimated drop-out rate 10%). After the approved amendment a total of 28 patients suffering from VAP were enrolled. 27 subjects were randomized. Consent withdraw by subject: 1 in the control group.

    Period 1
    Period 1 title
    overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard therapy +TOBI
    Arm description
    		 Subjects received a systemic antibiotic standard care therapy (i.e. intravenous penicillin, cephalosporine, carbapenem, chinolone or aminoglycosides) and 300 mg (5ml) inhalative of tobramycin twice daily for 5 days on day 0,1,2,3 and 4 (visit 1-5). The inhalation did not take longer 15 minutes. There were 3 follow-up dates (visit 6-8) . The final investigation was at day of discharge of the patient from ICU (visit 9, at maximum 90 day from enrollment)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tobramycin
    Investigational medicinal product code
    32986-56-4
    Other name
    TOBI
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received 300 mg (5ml) tobramycin twice daily for 5 days at Visit (1-5). The inhalation did not take longer than 15 minutes.

    Arm title
    		 Standard therapy + Placebo
    Arm description
    		 Subjects received a systemic antibiotic standard care therapy (i.e. intravenous penicillin, cephalosporine, carbapenem, chinolone or aminoglycosides) and 5ml of aerosolized 0,9 % sodium chlorid solution twice daily for 5 days on day 0,1,2,3 and 4 (visit 1-5). The inhalation did not take longer 15 minutes.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received placebo matched to tobramycin, twice daily for 5 days (Visit 1-5). The inhalation did not take longer than 15 minutes.

    Number of subjects in period 1
    		Standard therapy +TOBI Standard therapy + Placebo
    Started
    14
    13
    Completed
    14
    12
    Not completed
    0
    1
         Adverse event, serious fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard therapy +TOBI
    Reporting group description
    		 Subjects received a systemic antibiotic standard care therapy (i.e. intravenous penicillin, cephalosporine, carbapenem, chinolone or aminoglycosides) and 300 mg (5ml) inhalative of tobramycin twice daily for 5 days on day 0,1,2,3 and 4 (visit 1-5). The inhalation did not take longer 15 minutes. There were 3 follow-up dates (visit 6-8) . The final investigation was at day of discharge of the patient from ICU (visit 9, at maximum 90 day from enrollment)

    Reporting group title
    Standard therapy + Placebo
    Reporting group description
    		 Subjects received a systemic antibiotic standard care therapy (i.e. intravenous penicillin, cephalosporine, carbapenem, chinolone or aminoglycosides) and 5ml of aerosolized 0,9 % sodium chlorid solution twice daily for 5 days on day 0,1,2,3 and 4 (visit 1-5). The inhalation did not take longer 15 minutes.

    Reporting group values
    		 Standard therapy +TOBI Standard therapy + Placebo Total
    Number of subjects
    		 14 13 27
    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)
    		 0 0 0
        From 65-84 years
    		 6 5 11
        85 years and over
    		 8 8 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.6 ( 14 ) 62.9 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5 10
        Male
    		 9 8 17
    BMI
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 26.0 ( 4.3 ) 26.0 ( 6.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Standard therapy +TOBI
    Reporting group description
    		 Subjects received a systemic antibiotic standard care therapy (i.e. intravenous penicillin, cephalosporine, carbapenem, chinolone or aminoglycosides) and 300 mg (5ml) inhalative of tobramycin twice daily for 5 days on day 0,1,2,3 and 4 (visit 1-5). The inhalation did not take longer 15 minutes. There were 3 follow-up dates (visit 6-8) . The final investigation was at day of discharge of the patient from ICU (visit 9, at maximum 90 day from enrollment)

    Reporting group title
    Standard therapy + Placebo
    Reporting group description
    		 Subjects received a systemic antibiotic standard care therapy (i.e. intravenous penicillin, cephalosporine, carbapenem, chinolone or aminoglycosides) and 5ml of aerosolized 0,9 % sodium chlorid solution twice daily for 5 days on day 0,1,2,3 and 4 (visit 1-5). The inhalation did not take longer 15 minutes.

    Primary: change eradication of gram-negative pathogens

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    End point title
    		 change eradication of gram-negative pathogens
    End point description
    End point type
    Primary
    End point timeframe
    from visit 1 up to visit 9
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    14
    12
    Units: patients
        number (not applicable)
    14
    3
    Statistical analysis title
    		 Sensitivity Analysis
    Statistical analysis description
    Per protocol analysis p value was derived via Boschloo-test. Due to almost perfect separation Firth logistic regression was used for calculation of the Odds ratio and the 95% confidence interval.
    Comparison groups
    Standard therapy +TOBI v Standard therapy + Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00003
    Method
    		 Boschloo' Exact Test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.97
         upper limit
    		 9.32

    Secondary: Length of stay in ICU

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    End point title
    		 Length of stay in ICU
    End point description
    End point type
    Secondary
    End point timeframe
    from visit 1 up to visit 9 (max .90 days)
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    7
    6
    Units: days
        arithmetic mean (standard deviation)
    15.7 ( 12.1 )
    15.8 ( 10.8 )
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    at final visit
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    14
    13
    Units: patients have died
    number (not applicable)
        PP
    1
    1
        FAS
    1
    2
    No statistical analyses for this end point

    Secondary: Clinical cure of pneumonia

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    End point title
    		 Clinical cure of pneumonia
    End point description
    End point type
    Secondary
    End point timeframe
    From Visit 1 up to Visit 9
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    14 [1]
    13 [2]
    Units: number of YES
        V1
    0
    1
        V2
    0
    1
        V3
    5
    2
        V4
    10
    6
        V5
    10
    6
        V6
    10
    7
        V7
    8
    8
        V8
    3
    4
        V9
    11
    8
    Notes
    [1] - for FAS
    [2] - for FAS
    No statistical analyses for this end point

    Secondary: Duration of systematic antibiotic treatment for pneumonia

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    End point title
    		 Duration of systematic antibiotic treatment for pneumonia
    End point description
    FAS: total n= 13; 7.3 +/- 2.3 days
    End point type
    Secondary
    End point timeframe
    at final visit
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    7
    6
    Units: days
        arithmetic mean (standard deviation)
    8.1 ( 2.0 )
    6.3 ( 2.3 )
    No statistical analyses for this end point

    Secondary: Systemic antibiotic-free days

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    End point title
    		 Systemic antibiotic-free days
    End point description
    After the inclusion of the patient into the study
    End point type
    Secondary
    End point timeframe
    at final visit
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    5
    5
    Units: days
        arithmetic mean (standard deviation)
    6.2 ( 6.1 )
    5.2 ( 5.0 )
    No statistical analyses for this end point

    Secondary: Duration of ventilation of pneumonia

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    End point title
    		 Duration of ventilation of pneumonia
    End point description
    End point type
    Secondary
    End point timeframe
    at final visit
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    14
    13
    Units: days
        arithmetic mean (standard error)
    9.1 ( 5.5 )
    7.6 ( 3.4 )
    No statistical analyses for this end point

    Secondary: Ventilator-free days

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    End point title
    		 Ventilator-free days
    End point description
    End point type
    Secondary
    End point timeframe
    at day of discharge from ICU
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    7
    6
    Units: days
        arithmetic mean (standard error)
    6.7 ( 6.9 )
    7.0 ( 7.3 )
    No statistical analyses for this end point

    Secondary: Reinfection of pneumonia caused by the same pathogen

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    End point title
    		 Reinfection of pneumonia caused by the same pathogen
    End point description
    End point type
    Secondary
    End point timeframe
    at discharge from ICU
    End point values
    		 Standard therapy +TOBI Standard therapy + Placebo
    Number of subjects analysed
    5
    8
    Units: number of patients
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from visit 1 up to visit 9 or discharge from the ICU
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 own
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 -

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 13 (15.38%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    tension pneumothorax left side
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 14 (71.43%)
    5 / 13 (38.46%)
    Respiratory, thoracic and mediastinal disorders
    residual pneumothorax left side
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    swelling left arm
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Fever > 38.5 Celsius
         subjects affected / exposed
    7 / 14 (50.00%)
    5 / 13 (38.46%)
         occurrences all number
    18
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2014
    Reduction of planned subjects ends based on new findings of the effectiveness of tobramycin, new study protocol V1.2
    22 Nov 2016
    Extension of study duration to 3 years an d 9 months
    24 Apr 2019
    Extension of study duration to 6 years an 4 months

    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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    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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