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    Clinical Trial Results:
    Safety and Tolerability Study of SLIT™ Amikacin 500mg Once Daily for 14 Days by Inhalation in Cystic Fibrosis Study Subjects Chronically Infected with Pseudomonas Aeruginosa

    Summary
    EudraCT number
    		 2005-004389-17
    Trial protocol
    		 HU  
    Global end of trial date
    18 Sep 2006

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Jun 2023
    First version publication date
    29 Jul 2020
    Other versions
    		 v1
    Version creation reason
    Summary report(s)
    		 CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    TR02-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Insmed Incorporated
    Sponsor organisation address
    700 US Highway 202/206, Bridgewater, United States, 08807-1704
    Public contact
    Insmed Medical Information, Insmed Incorporated, medicalinformation@Insmed.com
    Scientific contact
    Insmed Medical Information, Insmed Incorporated, medicalinformation@Insmed.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?
    Yes
    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
    18 Sep 2006
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2006
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and tolerability of nebulized amikacin in a sustained release lipid inhalation targeting (SLIT)™ formulation administered 500 milligrams (mg) once daily (QD) for 14 days.
    Protection of trial subjects
    This trial was performed in compliance with Good Clinical Practices (GCP), including the archiving of essential documents, the International Council for Harmonisation (ICH) Guidelines, and is consistent with the ethical principles of the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Apr 2006
    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
    Hungary: 11
    Country: Number of subjects enrolled
    Serbia: 2
    Worldwide total number of subjects
    13
    EEA total number of subjects
    11
    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)
    5
    Adults (18-64 years)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in this trial at investigative sites in Serbia and Hungary from 14 April 2006 to 18 September 2006.

    Pre-assignment
    Screening details
    		 13 subjects with cystic fibrosis (CF), chronically infected with Pseudomonas aeruginosa were enrolled and received Amikacin in a SLIT™ formulation (Arikace™) by inhalation.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Amikacin 500 mg
    Arm description
    		 Subjects received amikacin 500 mg QD by inhalation for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SLIT™ Amikacin
    Investigational medicinal product code
    Other name
    Arikace™
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Nasal use
    Dosage and administration details
    Inhalation dispersion administered via nasal route by means of a nebuliser and compressor.

    Number of subjects in period 1
    		Amikacin 500 mg
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Amikacin 500 mg
    Reporting group description
    		 Subjects received amikacin 500 mg QD by inhalation for 14 days.

    Reporting group values
    		 Amikacin 500 mg Total
    Number of subjects
    		 13 13
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 8 8
    Gender Categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 6 6
    Race
    Units: Subjects
        Caucasian
    		 13 13
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 13 13
    Forced Expiratory Volume in 1 Second (FEV1)
    FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
    Units: Litres
        arithmetic mean (standard deviation)
    		 2.30 ± 0.82 -
    Forced Vital Capacity (FVC)
    FVC is measured during a spirometry test, also known as a pulmonary function test, which involves forcefully breathing out into a mouthpiece connected to a spirometer machine. FVC is the volume of air that can be forcibly and completely blown out after full inspiration.
    Units: Litres
        arithmetic mean (standard deviation)
    		 3.28 ± 0.88 -
    FEV1 Percent (%) Predicted
    FEV1 (measured by handheld spirometer) is the volume of air that can be forcibly exhaled from the lungs in the first second. The percent predicted FEV1 equals the subject's observed FEV1 divided by the subject's predicted FEV1 (determined by height and race) and converted to a percentage by multiplying by 100%.
    Units: percent
        arithmetic mean (standard deviation)
    		 63.80 ± 16.71 -
    Forced Expiratory Flow (FEF) 25-75%
    The FEF 25%-75% (measured by handheld spirometer) is the forced expiratory flow from 25% to 75% of FVC (volume of air that can be forcibly and completely blown out after full inspiration).
    Units: Litres per second (L/sec)
        arithmetic mean (standard deviation)
    		 1.62 ± 1.04 -
    Vital Capacity (VC)
    The vital capacity is called the sum total volume of air that can be expired after maximum inhalation or maximum air that a subject can breathe in after forced expiration and is an important indicator of a subject’s respiratory health.
    Units: Litres
        arithmetic mean (standard deviation)
    		 3.23 ± 0.82 -

    End points

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    End points reporting groups
    Reporting group title
    Amikacin 500 mg
    Reporting group description
    		 Subjects received amikacin 500 mg QD by inhalation for 14 days.

    Primary: Number of Subjects With Adverse Events (AEs)

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    End point title
    		 Number of Subjects With Adverse Events (AEs) [1]
    End point description
    An adverse event is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Intent-to-Treat (ITT) Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to last follow-up visit (Day 42)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: subjects
    9
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Changes in Vital Signs

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    End point title
    		 Number of Subjects With Clinically Significant Changes in Vital Signs [2]
    End point description
    Vital sign measurements included heart rate, respiratory rate, blood pressure, temperature, and oxygen saturation. ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to last follow-up visit (Day 42)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: subjects
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in Quality of Life Questionnaire Total Score

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    End point title
    		 Change From Baseline in Quality of Life Questionnaire Total Score [3]
    End point description
    The cystic fibrosis quality of life questionnaire revised (CFQ-R), a validated disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with CF. It is self-administered and consists of 44 items, divided into 12 generic and disease-specific scales. The scale includes physical functioning, role, vitality, emotional functioning, social functioning, body image, eating disturbances, treatment burden, health perceptions, weight, respiratory symptoms, and digestive symptoms. Scale range: 0 to 100 (maximum). Higher values indicate better quality of life. ITT Population included all subjects who received any amount of study drug. 9999 indicates that the data is not available as descriptive analysis to generate summarised data was not performed.
    End point type
    Primary
    End point timeframe
    Days 1 and 15
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this endpoint.
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: score on a scale
    least squares mean (standard error)
        Day 1
    9999 ± 9999
        Day 15
    9999 ± 9999
    No statistical analyses for this end point

    Primary: Change From Baseline in FEV1 at Day 42

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    End point title
    		 Change From Baseline in FEV1 at Day 42 [4]
    End point description
    FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Day 42
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: Litres
        arithmetic mean (standard deviation)
    0.31 ± 0.42
    No statistical analyses for this end point

    Primary: Percentage of Oxygen Saturation (SaO2)

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    End point title
    		 Percentage of Oxygen Saturation (SaO2) [5]
    End point description
    ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    At last follow-up visit (Day 42)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: percentage on room air
        arithmetic mean (standard deviation)
    97.69 ± 0.75
    No statistical analyses for this end point

    Primary: Pulmonary Function Test : Change From Baseline in FVC at Day 42

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    End point title
    		 Pulmonary Function Test : Change From Baseline in FVC at Day 42 [6]
    End point description
    FVC is measured during a spirometry test, also known as a pulmonary function test, which involves forcefully breathing out into a mouthpiece connected to a spirometer machine. FVC is the volume of air that can be forcibly and completely blown out after full inspiration. ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Day 42
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: Litres
        arithmetic mean (standard deviation)
    0.23 ± 0.38
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Laboratory Abnormalities

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities [7]
    End point description
    Laboratory assessments included analysis of hematology (hemoglobin, hematocrit, white blood cells [WBC], neutrophils, platelets) and serum chemistry (blood urea nitrogen [BUN], creatinine, sodium, carbon dioxide, phosphate, gamma-glutamyl transferase [GGT], aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, bilirubin, total cholesterol, low-density lipoprotein [LDL] and high-density lipoprotein [HDL], glucose, total protein, albumin, uric acid). Any abnormal value observed was to be flagged to the attention of the investigator who was to judge whether the finding was clinically significant. ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to last follow-up visit (Day 42)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: subjects
        Hematology
    2
        Serum Chemistry
    5
    No statistical analyses for this end point

    Primary: Pulmonary Function Test: Change From Baseline in Percentage of Predicted FEV1 at Day 42

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    End point title
    		 Pulmonary Function Test: Change From Baseline in Percentage of Predicted FEV1 at Day 42 [8]
    End point description
    FEV1 (measured by handheld spirometer) is the volume of air that can be forcibly exhaled from the lungs in the first second. The percent predicted FEV1 equals the subject's observed FEV1 divided by the subject's predicted FEV1 (determined by height and race) and converted to a percentage by multiplying by 100%. ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Day 42
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: percentage
        arithmetic mean (standard deviation)
    8.31 ± 9.40
    No statistical analyses for this end point

    Primary: Pulmonary Function Test: Change From Baseline in FEF During mid Expiration 25-75% at Day 42

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    End point title
    		 Pulmonary Function Test: Change From Baseline in FEF During mid Expiration 25-75% at Day 42 [9]
    End point description
    The FEF 25%-75% (measured by handheld spirometer) is the forced expiratory flow from 25% to 75% of FVC (volume of air that can be forcibly and completely blown out after full inspiration). ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Day 42
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: L/sec
        arithmetic mean (standard deviation)
    0.69 ± 1.08
    No statistical analyses for this end point

    Primary: Pulmonary Function Test: Change From Baseline in VC at Day 42

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    End point title
    		 Pulmonary Function Test: Change From Baseline in VC at Day 42 [10]
    End point description
    The vital capacity is called the sum total volume of air that can be expired after maximum inhalation or maximum air that a subject can breathe in after forced expiration and is an important indicator of a subject’s respiratory health. ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Day 42
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: Litres
        arithmetic mean (standard deviation)
    0.14 ± 0.30
    No statistical analyses for this end point

    Primary: Number of Subjects With Positive Sputum Culture for Pseudomonas Aeruginosa

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    End point title
    		 Number of Subjects With Positive Sputum Culture for Pseudomonas Aeruginosa [11]
    End point description
    ITT Population included all subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Day 42
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for this endpoint
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: subjects
    13
    No statistical analyses for this end point

    Secondary: Change From Baseline in Density of Pseudomonas Aeruginosa in Sputum at Day 14

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    End point title
    		 Change From Baseline in Density of Pseudomonas Aeruginosa in Sputum at Day 14
    End point description
    Density of Pseudomonas aeruginosa in sputum was measured in colony forming units per gram (CFU/g). ITT Population included all subjects who received any amount of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 14
    End point values
    		 Amikacin 500 mg
    Number of subjects analysed
    13
    Units: CFU/g
        arithmetic mean (confidence interval 95%)
    -1.09 (-2.09 to -0.09)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to last follow-up visit (Day 42)
    Adverse event reporting additional description
    ITT Population included all subjects who received any amount of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Amikacin 500 mg
    Reporting group description
    		 Subjects received amikacin 500 mg QD by inhalation for 14 days.

    Serious adverse events
    		 Amikacin 500 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Amikacin 500 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Productive cough
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Throat irritation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Diabetes mellitus (incl subtypes)
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2005
    The following changes were implemented with Amendment 1: -The word "randomisation" was revised to read "registration". -Specialist oral pharyngeal assessment was added to the pre-treatment complete physical exam. -Chest x-ray at Visit 42 was added to the off study evaluations. -Blood and sputum PK assessment at Visit 1 screening indicated was deleted. -Specialist oral pharyngeal assessment prior to Day 1 and Day 21 and other visits if clinically indicated was added. -Chest x-ray at follow-up was changed to Day 42 and if clinically indicated. -Devilbiss compressor was changed to EasyComp compressor.

    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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