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    Clinical Trial Results:
    Dose Escalation Part: MULTIDOSE SAFETY AND TOLERABILITY STUDY OF DOSE ESCALATION OF LIPOSOMAL AMIKACIN FOR INHALATION (ARIKACE™) IN CYSTIC FIBROSIS PATIENTS WITH CHRONIC INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA Extension Part: MULTIDOSE SAFETY AND TOLERABILITY STUDY OF DOSE ESCALATION OF LIPOSOMAL AMIKACIN FOR INHALATION (ARIKACE™) IN CYSTIC FIBROSIS PATIENTS WITH CHRONIC INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA

    Summary
    EudraCT number
    		 2006-006980-22
    Trial protocol
    		 HU   SK   BE   PL  
    Global end of trial date
    02 Nov 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Aug 2020
    First version publication date
    04 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TR02-105
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00777296
    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
    Tom Vanthienen, Insmed Incorporated, +41 795432860, tom.vanthienen@insmed.com
    Scientific contact
    Tom Vanthienen, Insmed Incorporated, +41 795432860, tom.vanthienen@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?
    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
    11 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Dose Escalation Part: To evaluate the safety and tolerability of 28 days of daily dosing of two dose cohorts of nebulized Arikace™, liposomal amikacin for inhalation. Extension Part: To evaluate the longer-term safety, tolerability and efficacy of 560 mg once daily (QD) dose of Arikace™ administered for 6 cycles over 18 months. Each cycle comprised 28 days on treatment followed by 56 days off treatment.
    Protection of trial subjects
    This study was performed in compliance with Good Clinical Practice (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
    22 Feb 2007
    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
    Poland: 18
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 25
    Country: Number of subjects enrolled
    Serbia: 18
    Country: Number of subjects enrolled
    Ukraine: 24
    Worldwide total number of subjects
    124
    EEA total number of subjects
    57
    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)
    27
    Adolescents (12-17 years)
    46
    Adults (18-64 years)
    51
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited at 15 study centres for the Dose Escalation Part of the study, and at 11 study centres for the Extension Part.

    Pre-assignment
    Screening details
    		 The 2 cohorts involved in the Dose Escalation Part of the study were randomised to receive Arikace™ or a placebo at a 2:1 ratio. All subjects who progressed into the Extension Part of the study received Arikace™.

    Period 1
    Period 1 title
    TR02-105 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™
    Arm description
    		 Subjects in this cohort received 280 mg of Arikace™.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arikace™
    Investigational medicinal product code
    Other name
    Liposomal amikacin for inhalation
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received a once daily dose of Arikace™ 280 mg for 28 days in Cohort 1. Subjects received a once daily dose of Arikace™ 560 mg for 28 days in Cohort 2. Arikace™ was administered via a PARI eFlow nebulizer over approximately 20 minutes.

    Arm title
    		 Dose Escalation Part - Cohort 1 - Placebo
    Arm description
    		 Subjects in this arm of Cohort 1 received matching placebo.
    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 a once daily dose of the placebo for 28 days in Cohort 1. Subjects received a once daily dose of the placbo for 28 days in Cohort 2. The placebo was administered via a PARI eFlow nebulizer over approximately 20 minutes.

    Arm title
    		 Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Arm description
    		 Subjects in this cohort received 560 mg of Arikace™.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arikace™
    Investigational medicinal product code
    Other name
    Liposomal amikacin for inhalation
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects received a once daily dose of Arikace™ 280 mg for 28 days in Cohort 1. Subjects received a once daily dose of Arikace™ 560 mg for 28 days in Cohort 2. Arikace™ was administered via a PARI eFlow nebulizer over approximately 20 minutes.

    Arm title
    		 Dose Escalation Part - Cohort 2 - Placebo
    Arm description
    		 Subjects in this arm of Cohort 2 received matching placebo.
    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 a once daily dose of the placebo for 28 days in Cohort 1. Subjects received a once daily dose of the placebo for 28 days in Cohort 2. The placebo was administered via a PARI eFlow nebulizer over approximately 20 minutes.

    Arm title
    		 Extension Part
    Arm description
    		 Subjects in the Extension Part received 560 mg of Arikace™.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arikace™
    Investigational medicinal product code
    Other name
    Liposomal amikacin inhalation
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    All subjects received a dose of 560 mg of Arikace™ once daily for 28 days. Arikace™ was administered via a PARI eFlow nebulizer over approximately 10 minutes.

    Number of subjects in period 1 [1]
    		Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo Extension Part
    Started
    21
    11
    23
    11
    49
    Completed
    20
    10
    21
    10
    41
    Not completed
    1
    1
    2
    1
    8
         Consent withdrawn by subject
    1
    -
    -
    -
    3
         Adverse event, non-fatal
    -
    1
    -
    1
    1
         Pregnancy
    -
    -
    -
    -
    1
         Completed study but not 24 of 28 days
    -
    -
    -
    -
    2
         Case Report Form (CRF) not completed
    -
    -
    2
    -
    -
         Lack of efficacy
    -
    -
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Eligible subjects in the Dose Escalation Part of the study moved onto the Extension Part of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose Escalation Part - Cohort 1 - 280 mg Arikace™
    Reporting group description
    		 Subjects in this cohort received 280 mg of Arikace™.

    Reporting group title
    Dose Escalation Part - Cohort 1 - Placebo
    Reporting group description
    		 Subjects in this arm of Cohort 1 received matching placebo.

    Reporting group title
    Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Reporting group description
    		 Subjects in this cohort received 560 mg of Arikace™.

    Reporting group title
    Dose Escalation Part - Cohort 2 - Placebo
    Reporting group description
    		 Subjects in this arm of Cohort 2 received matching placebo.

    Reporting group title
    Extension Part
    Reporting group description
    		 Subjects in the Extension Part received 560 mg of Arikace™.

    Reporting group values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo Extension Part Total
    Number of subjects
    		 21 11 23 11 49 115
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.0 ( 5.3 ) 16.9 ( 7.9 ) 16.6 ( 6.1 ) 17.2 ( 5.8 ) 17.4 ( 6.22 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 8 11 4 29 68
        Male
    		 5 3 12 7 20 47

    End points

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    End points reporting groups
    Reporting group title
    Dose Escalation Part - Cohort 1 - 280 mg Arikace™
    Reporting group description
    		 Subjects in this cohort received 280 mg of Arikace™.

    Reporting group title
    Dose Escalation Part - Cohort 1 - Placebo
    Reporting group description
    		 Subjects in this arm of Cohort 1 received matching placebo.

    Reporting group title
    Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Reporting group description
    		 Subjects in this cohort received 560 mg of Arikace™.

    Reporting group title
    Dose Escalation Part - Cohort 2 - Placebo
    Reporting group description
    		 Subjects in this arm of Cohort 2 received matching placebo.

    Reporting group title
    Extension Part
    Reporting group description
    		 Subjects in the Extension Part received 560 mg of Arikace™.

    Subject analysis set title
    Pooled Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Placebo is a pooled value from cohort 280 mg and cohort 560 mg.

    Subject analysis set title
    Arikace™
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects who received either the 280 mg or the 560 mg doses of the Arikace™.

    Primary: Dose Escalation Part: Clinically Significant Laboratory Abnormalities

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    End point title
    		 Dose Escalation Part: Clinically Significant Laboratory Abnormalities [1] [2]
    End point description
    Changes in chemistry and hematology lab tests (clinically significant value of Common Terminology Criteria for Adverse Events [CTCAE] grade ≥ 3). The analysis population is the modified intent-to-treat (mITT) population, defined as all randomised subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    28 Days
    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: Statistical analysis was not planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo
    Number of subjects analysed
    21
    11
    21
    11
    Units: Subjects
        Neutrophils absolute
    1
    0
    8
    7
        Leucocytes
    1
    0
    3
    3
        Glucose
    0
    0
    2
    0
        Lymphocytes absolute
    1
    0
    2
    0
        Calcium
    0
    0
    1
    0
        Creatinine clearance
    0
    0
    1
    0
        Potassium
    3
    1
    1
    0
    No statistical analyses for this end point

    Primary: Extension Part: Adverse Event Profile of 560 mg Once Daily Dose of Arikace™ Administered for Six Cycles Over Eighteen Months

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    End point title
    		 Extension Part: Adverse Event Profile of 560 mg Once Daily Dose of Arikace™ Administered for Six Cycles Over Eighteen Months [3] [4]
    End point description
    Number of subjects with indicated adverse events in subject receiving 560 mg once daily dose of Arikace™ administered for 6 cycles over 18 months.
    End point type
    Primary
    End point timeframe
    18 Months
    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 analysis was planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Extension Part
    Number of subjects analysed
    49
    Units: Subjects
        Any Adverse Event
    48
        Treatment-related adverse events
    15
        Grade 1: Mild
    28
        Grade 2: Moderate
    15
        Grade 3: Severe
    4
        Grade 4: Life-threatening or disabling
    1
        Grade 5: Death
    0
        Serious Adverse Events
    15
        Treatment-related serious adverse events
    0
        Deaths
    0
        Permanent discontinuations due to adverse events
    1
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Pharmacokinetics (PK) of Arikace™ in Serum

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    End point title
    		 Dose Escalation Part: Pharmacokinetics (PK) of Arikace™ in Serum [5]
    End point description
    Measure PK parameters (AUC0-infinity) of Arikace™ in serum. The PK population consisted of subjects who received amikacin, had at least one serum PK assessment and were not replaced.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 14 and Day 28
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Number of subjects analysed
    21
    21
    Units: mg.hr/L
    arithmetic mean (standard deviation)
        Day 1
    5.73 ( 3.40 )
    7.92 ( 3.55 )
        Day 14
    7.61 ( 4.04 )
    12.5 ( 10.9 )
        Day 28
    8.03 ( 6.12 )
    14.6 ( 11.7 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Pharmacokinetic (PK) of Arikace™ in Serum (Cmax)

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    End point title
    		 Dose Escalation Part: Pharmacokinetic (PK) of Arikace™ in Serum (Cmax) [6]
    End point description
    Measure PK parameter (Cmax) of Arikace™ in serum. The PK population consisted of subjects who received Arikace™, had at least one serum PK assessment and were not replaced.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 14 and Day 28
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Number of subjects analysed
    21
    21
    Units: mg/L
    arithmetic mean (standard deviation)
        Day 1
    0.95 ( 0.58 )
    1.08 ( 0.51 )
        Day 14
    1.28 ( 1.02 )
    1.84 ( 1.35 )
        Day 28
    1.42 ( 1.45 )
    2.27 ( 1.58 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Pharmacokinetics (PK) of Arikace™ in Sputum (AUC)

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    End point title
    		 Dose Escalation Part: Pharmacokinetics (PK) of Arikace™ in Sputum (AUC) [7]
    End point description
    Measure PK parameter (AUC0-24) of Arikace™ in sputum.
    End point type
    Secondary
    End point timeframe
    28 days
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Number of subjects analysed
    21
    21
    Units: mcg*hr/g
        arithmetic mean (standard deviation)
    13120 ( 21386 )
    22445 ( 18652 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Pharmacokinetics (PK) of Arikace™ in Urine

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    End point title
    		 Dose Escalation Part: Pharmacokinetics (PK) of Arikace™ in Urine [8]
    End point description
    Measure PK parameter (Ae0-24 ((mg)) of Arikace™. The PK population consisted of subjects who received amikacin, had at least one serum PK assessment and were not replaced.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 14 and Day 28
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Number of subjects analysed
    21
    21
    Units: mg
    arithmetic mean (standard deviation)
        Day 1
    17.7 ( 12.3 )
    27.0 ( 25.2 )
        Day 14
    27.3 ( 16.5 )
    39.8 ( 42.7 )
        Day 28
    25.2 ( 19.5 )
    43.7 ( 48.9 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Sputum Amikacin Levels of Arikace™

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    End point title
    		 Dose Escalation Part: Sputum Amikacin Levels of Arikace™ [9]
    End point description
    Measure PK parameter (sputum amicakin concentration) of Arikace™ in sputum.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 14 and Day 28
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Number of subjects analysed
    21
    21
    Units: mcg/g
    arithmetic mean (standard deviation)
        Day 1
    1197 ( 1.56 )
    2395 ( 0.866 )
        Day 14
    1174 ( 1.01 )
    3496 ( 0.973 )
        Day 28
    1911 ( 1.28 )
    2635 ( 1.23 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Pulmonary Function: FEV1 %-Predicted

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    End point title
    		 Dose Escalation Part: Pulmonary Function: FEV1 %-Predicted [10]
    End point description
    Relative change (%) from baseline to end of treatment (Day 28) and Day 56 in pulmonary function.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 and Day 56
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Pooled Placebo
    Number of subjects analysed
    21
    21
    22
    Units: Relative Percent (%) change in FEV1
    arithmetic mean (standard deviation)
        Baseline
    66.4 ( 20.0 )
    62.9 ( 18.2 )
    68.0 ( 22.4 )
        Day 28
    9.6 ( 13.7 )
    11.0 ( 16.4 )
    0.5 ( 10.5 )
        Day 56
    1.8 ( 8.8 )
    13.8 ( 26.2 )
    -3.8 ( 13.5 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Pulmonary Function: FEV1

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    End point title
    		 Dose Escalation Part: Pulmonary Function: FEV1 [11]
    End point description
    Mean percent change (%) from baseline to end of treatment (Day 28) and Day 56 in pulmonary function. The analysis population is the modified intent-to-treat (mITT) population, defined as all randomised subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 and Day 56
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Pooled Placebo
    Number of subjects analysed
    21
    21
    22
    Units: Mean Percent (%) Change in FEV1
    arithmetic mean (standard deviation)
        Baseline
    2.022 ( 0.788 )
    1.937 ( 0.936 )
    1.968 ( 0.654 )
        Day 28
    10.1 ( 12.8 )
    13.2 ( 16.2 )
    2.2 ( 11.9 )
        Day 56
    2.0 ( 8.6 )
    13.2 ( 24.3 )
    -4.4 ( 13.0 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Change From Baseline in Log10CFU Per Gram (Density) of Pseudomonas Aeruginosa in Sputum

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    End point title
    		 Dose Escalation Part: Change From Baseline in Log10CFU Per Gram (Density) of Pseudomonas Aeruginosa in Sputum [12]
    End point description
    End of treatment (Day 28) from baseline in density of P. aeruginosa (log10 CFU/g) in sputum. The analysis population is the modified intent-to-treat (mITT) population, defined as all randomised subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 7, Day 14, Day 21, Day 28 and Day 35
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Pooled Placebo
    Number of subjects analysed
    21
    21
    22
    Units: log10CFU per gram
    arithmetic mean (standard deviation)
        Day 7
    0.080 ( 1.882 )
    -1.101 ( 2.170 )
    0.052 ( 1.303 )
        Day 14
    -1.366 ( 2.013 )
    -1.570 ( 2.161 )
    -0.574 ( 1.006 )
        Day 21
    -1.044 ( 2.155 )
    -2.283 ( 2.775 )
    -0.440 ( 1.280 )
        Day 28
    -0.622 ( 1.881 )
    -1.515 ( 1.699 )
    -0.677 ( 1.043 )
        Day 35
    -0.380 ( 1.425 )
    -1.313 ( 2.852 )
    -0.445 ( 1.201 )
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Duration of Systemic Antipseudomonal Rescue Therapy

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    End point title
    		 Dose Escalation Part: Duration of Systemic Antipseudomonal Rescue Therapy [13]
    End point description
    Duration of systemic antipseudomonal rescue therapy during the study in both the Arikace™ and placebo groups. The analysis population is the modified intent-to-treat (mITT) population, defined as all randomised subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Through study duration, approximately 56 days
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo
    Number of subjects analysed
    21
    11 [14]
    21 [15]
    11
    Units: Days
        arithmetic mean (standard deviation)
    14.00 ( 0.00 )
    27.00 ( 99999 )
    19.00 ( 99999 )
    21.00 ( 11.31 )
    Notes
    [14] - 99999 is used where standard deviation doesn't apply as only 1 subject required rescue therapy.
    [15] - 99999 is used where standard deviation doesn't apply as only 1 subject required rescue therapy.
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: Number of Subjects Requiring Antipseudomonal Rescue Therapy

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    End point title
    		 Dose Escalation Part: Number of Subjects Requiring Antipseudomonal Rescue Therapy
    End point description
    Number of subjects requiring systemic antipseudomonal rescue therapy during the study in both the Arikace™ and placebo groups. The analysis population is the modified intent-to-treat (mITT) population, defined as all randomised subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Through study duration, approximately 56 days
    End point values
    		 Pooled Placebo Arikace™
    Number of subjects analysed
    22
    42
    Units: Subjects
    3
    4
    No statistical analyses for this end point

    Secondary: Dose Escalation Part: CFQ-R Respiratory Scale (Absolute Change From Baseline)

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    End point title
    		 Dose Escalation Part: CFQ-R Respiratory Scale (Absolute Change From Baseline) [16]
    End point description
    Quality of Life was measured by the absolute change from baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory scale. Disease specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms in subjects with a diagnosis of cystic fibrosis. Scores range from 0 to 100, with higher scores indicating better health. Scores for each Health Related Quality of Life (HRQoL) domain; after recoding, each item is summed to generate a domain score and standardized. The analysis population is the modified intent-to-treat (mITT) population, defined as all randomised subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline/Day 1, Day 15, Day 28 and Day 42
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo
    Number of subjects analysed
    21
    11
    21
    11
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 1/Baseline
    72.619 ( 11.630 )
    71.212 ( 14.921 )
    67.989 ( 12.748 )
    61.364 ( 21.425 )
        Day 15
    2.632 ( 10.078 )
    -0.505 ( 12.349 )
    3.704 ( 16.133 )
    -2.778 ( 16.054 )
        Day 28
    4.306 ( 12.760 )
    -3.283 ( 14.154 )
    5.688 ( 11.669 )
    1.667 ( 13.302 )
        Day 42
    1.080 ( 12.169 )
    -4.012 ( 19.598 )
    3.042 ( 18.213 )
    0.556 ( 12.200 )
    No statistical analyses for this end point

    Secondary: Extension Part: FEV1 % Predicted

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    End point title
    		 Extension Part: FEV1 % Predicted [17]
    End point description
    A summary of relative change from the Extension Part of the study baseline time points in FEV1 % predicted is presented for the overall safety population and by treatment received. Safety population.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 14, 28, 56, 70, 85, 98, 112, 140, 154, 169, 182,196, 224, 238, 253, 266, 280, 308, 322, 337, 350, 364, 392, 406, 421, 434, 448, 476, 490 and 504
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Extension Part
    Number of subjects analysed
    49 [18]
    Units: Percent (%) predicted
    arithmetic mean (standard deviation)
        Baseline
    59.73 ( 20.047 )
        Day 1
    3.13 ( 8.553 )
        Day 14
    7.62 ( 15.246 )
        Day 28
    6.83 ( 14.593 )
        Day 56
    3.02 ( 11.174 )
        Day 70
    2.96 ( 13.580 )
        Day 85
    4.04 ( 15.450 )
        Day 98
    9.97 ( 16.594 )
        Day 112
    8.19 ( 20.116 )
        Day 140
    4.86 ( 19.337 )
        Day 154
    6.76 ( 20.633 )
        Day 169
    3.90 ( 19.141 )
        Day 182
    10.22 ( 18.349 )
        Day 196
    7.56 ( 20.607 )
        Day 224
    2.57 ( 19.165 )
        Day 238
    5.46 ( 17.872 )
        Day 253
    3.37 ( 17.755 )
        Day 266
    9.07 ( 19.747 )
        Day 280
    8.54 ( 19.179 )
        Day 308
    5.77 ( 19.633 )
        Day 322
    5.25 ( 20.946 )
        Day 337
    5.18 ( 21.740 )
        Day 350
    10.49 ( 21.615 )
        Day 364
    3.82 ( 18.895 )
        Day 392
    3.07 ( 18.380 )
        Day 406
    2.74 ( 18.301 )
        Day 421
    1.63 ( 19.094 )
        Day 434
    7.11 ( 20.022 )
        Day 448
    5.66 ( 20.422 )
        Day 476
    0.83 ( 21.741 )
        Day 490
    1.61 ( 19.922 )
        Day 504
    0.06 ( 22.196 )
    Notes
    [18] - Number of subjects analysed ranged from 49 to 42.
    No statistical analyses for this end point

    Secondary: Extension Part: Absolute Change in Sputum Density

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    End point title
    		 Extension Part: Absolute Change in Sputum Density [19]
    End point description
    A summary of change from the Extension Part baseline to all post-baseline time points during the treatment periods and at the end of the off treatment periods in P aeruginosa sputum density (log10 CFU/mL) is presented for the overall safety population and by treatment received. Per Protocol population defined as all subjects who completed at least 24 of the 28 days of dosing for each of the 6 cycles
    End point type
    Secondary
    End point timeframe
    Baseline, Days 14, 28, 85, 98, 112, 140, 169, 182,196, 253, 266, 280, 337, 350, 364, 421, 434 and 448
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Extension Part
    Number of subjects analysed
    49 [20]
    Units: Log 10 CFU/mL
    arithmetic mean (standard deviation)
        Baseline
    6.289 ( 2.8587 )
        Day 14
    -1.196 ( 2.0736 )
        Day 28
    -0.416 ( 1.8584 )
        Day 85
    0.154 ( 2.4433 )
        Day 98
    -0.623 ( 1.9127 )
        Day 112
    -0.781 ( 1.1625 )
        Day 140
    -0.266 ( 0.2871 )
        Day 169
    -0.144 ( 1.2470 )
        Day 182
    -1.087 ( 1.9582 )
        Day 196
    -0.599 ( 1.3450 )
        Day 253
    0.213 ( 1.4059 )
        Day 266
    -0.991 ( 2.5040 )
        Day 280
    -0.702 ( 1.7419 )
        Day 337
    0.375 ( 1.9924 )
        Day 350
    -0.311 ( 1.6342 )
        Day 364
    -0.107 ( 1.8027 )
        Day 421
    0.494 ( 2.0058 )
        Day 434
    0.111 ( 1.9098 )
        Day 448
    0.034 ( 2.0020 )
    Notes
    [20] - Subjects analysed ranged from 49 to 30.
    No statistical analyses for this end point

    Secondary: Extension Part: Antipseudomonal Rescue Therapy - Duration of Therapy

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    End point title
    		 Extension Part: Antipseudomonal Rescue Therapy - Duration of Therapy [21]
    End point description
    The duration of IV and all systemic or inhaled antipseudomonal rescue therapy is presented for the overall safety population and by treatment received.
    End point type
    Secondary
    End point timeframe
    18 Months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Extension Part
    Number of subjects analysed
    49
    Units: Days
        arithmetic mean (standard deviation)
    39.7 ( 44.57 )
    No statistical analyses for this end point

    Secondary: Extension Part: Antipseudomonal Rescue Therapy - Time to Therapy

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    End point title
    		 Extension Part: Antipseudomonal Rescue Therapy - Time to Therapy [22]
    End point description
    The time to IV and all systemic or inhaled antipseudomonal rescue therapy is presented for the overall safety population and by treatment received.
    End point type
    Secondary
    End point timeframe
    18 Months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Extension Part
    Number of subjects analysed
    49
    Units: Percentage (%) subjects
    number (not applicable)
        By Day 85
    2.0
        By Day 253
    17.2
        By Day 504
    32.9
    No statistical analyses for this end point

    Secondary: Extension Part: Analysis of Cystic Fibrosis Questionnaire - Revised (CFQ-R) for Absolute Change in Score

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    End point title
    		 Extension Part: Analysis of Cystic Fibrosis Questionnaire - Revised (CFQ-R) for Absolute Change in Score [23]
    End point description
    A summary of absolute change from baseline in the CFQ-R scales at each on treatment assessment between Day 14 and Day 448 is presented for all subjects and by main study treatment group for the safety population. CFQ-R is a disease specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms on a scale from 0 to 100 points. Higher values represent a more favorable outcome.
    End point type
    Secondary
    End point timeframe
    Days 14, 28, 85, 98, 112, 169, 182,196, 253, 266, 280, 337, 350, 364, 421, 434 and 448
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the study design, arms for the baseline period have been split between the Dose Escalation Part and Extension Part of the study. Results will be presented for the applicable arms.
    End point values
    		 Extension Part
    Number of subjects analysed
    49 [24]
    Units: Percentage (%)
    arithmetic mean (standard deviation)
        Day 14
    7.616 ( 14.1662 )
        Day 28
    11.486 ( 14.9347 )
        Day 85
    9.697 ( 12.9834 )
        Day 98
    11.235 ( 14.5552 )
        Day 112
    11.768 ( 13.9321 )
        Day 169
    5.159 ( 13.6851 )
        Day 182
    9.233 ( 16.3635 )
        Day 196
    9.404 ( 12.4334 )
        Day 253
    7.097 ( 13.7509 )
        Day 266
    10.041 ( 14.5240 )
        Day 280
    6.111 ( 11.3611 )
        Day 337
    9.017 ( 13.8786 )
        Day 350
    12.108 ( 13.8668 )
        Day 364
    11.875 ( 12.9679 )
        Day 421
    11.895 ( 14.1632 )
        Day 434
    13.718 ( 13.1377 )
        Day 448
    13.120 ( 14.0144 )
    Notes
    [24] - Subjects analysed ranged from 48 to 39.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Dose Escalation Part: AEs were assessed from the first dose (Visit 2) until the completion of the study follow-up (14 days after 28 days of dosing in cohort 2). The total duration is approximately 84 days. Extension Part: 18 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Dose Escalation Part - Cohort 1 - 280 mg Arikace™
    Reporting group description
    		 Subjects in this cohort received 280 mg of Arikace™.

    Reporting group title
    Dose Escalation Part - Cohort 1 - Placebo
    Reporting group description
    		 Subjects in this arm of cohort 1 received matching placebo.

    Reporting group title
    Dose Escalation Part - Cohort 2 - 560 mg Arikace™
    Reporting group description
    		 Subjects in this cohort received 560 mg of Arikace™.

    Reporting group title
    Dose Escalation Part - Cohort 2 - Placebo
    Reporting group description
    		 Subjects in this arm of cohort 2 received matching placebo.

    Reporting group title
    Extension Part
    Reporting group description
    		 Subjects in the Extension Part received 560 mg of Arikace™.

    Serious adverse events
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo Extension Part
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    15 / 49 (30.61%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Endoscopy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    11 / 49 (22.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Drug therapy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular appendage torsion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug abuse
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose Escalation Part - Cohort 1 - 280 mg Arikace™ Dose Escalation Part - Cohort 1 - Placebo Dose Escalation Part - Cohort 2 - 560 mg Arikace™ Dose Escalation Part - Cohort 2 - Placebo Extension Part
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 21 (47.62%)
    6 / 11 (54.55%)
    5 / 21 (23.81%)
    2 / 11 (18.18%)
    29 / 49 (59.18%)
    Investigations
    Neutrophil count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    2
    1
    0
    0
    3
    Syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 11 (18.18%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    5 / 49 (10.20%)
         occurrences all number
    1
    2
    0
    0
    7
    Gastrointestinal disorders
    Aphthous stomatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    14 / 49 (28.57%)
         occurrences all number
    2
    0
    0
    0
    33
    Haemoptysis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    12 / 49 (24.49%)
         occurrences all number
    2
    1
    0
    0
    20
    Lung disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    1
    2
    2
    0
    1
    Productive cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    11 / 49 (22.45%)
         occurrences all number
    4
    1
    0
    1
    14
    Rhinitis allergic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    2
    0
    0
    0
    2
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    2 / 49 (4.08%)
         occurrences all number
    0
    0
    0
    1
    5
    Asthma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Urticaria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    1
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    14 / 49 (28.57%)
         occurrences all number
    1
    1
    1
    1
    26
    Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    5 / 49 (10.20%)
         occurrences all number
    2
    0
    0
    0
    5
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    4 / 49 (8.16%)
         occurrences all number
    2
    0
    0
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2007
    Summary of key changes: - Fax number was corrected - Updated the number of subjects planned for enrollment - Added clarification to the inclusion and exclusion criteria - Updated pharmacokinetic (PK) collection schedule - Updated vital sign and oxygen saturation measurement timing details - Updated blood, urine and sputum collection timings - Updated serious adverse event relatedness criteria
    08 May 2007
    Summary of key changes: - Updated the PK collection schedule - Updated the Schedule of In-Clinic Evaluations
    27 Sep 2007
    Summary of key changes: - Updated the exclusion criteria - Added clarification to the Post-Dose Pulmonary Function Testing schedule - Removed Post-Dose Sputum collection 4 hours post-dose - Added Data and Safety Monitoring Board (DSMB) meeting
    16 Jun 2008
    Summary of key changes: - Added information regarding the total number of treatment cycles - Added a Secondary Objective - Added treatment supplier details
    05 Aug 2008
    Summary of key changes: - The treatment follow-up period was extended - Study duration was increased
    27 Oct 2008
    Summary of key changes: - New text added regarding secondary endpoints - Added new text regarding the Extension Part - Main criteria for inclusion and exclusion was updated - Drug administration table added

    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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