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    Clinical Trial Results:
    Long Term Safety and Tolerability Study of Open-Label Liposomal Amikacin for Inhalation (Arikace™) in Cystic Fibrosis Patients with Chronic Infection due to Pseudomonas aeruginosa

    Summary
    EudraCT number
    		 2011-000443-24
    Trial protocol
    		 HU   GB   BE   IE   DE   FR   SE   GR   AT   NL   DK   BG   PL   ES   IT   SK  
    Global end of trial date
    16 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2020
    First version publication date
    26 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TR02-110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01316276
    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
    04 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the longer term safety, tolerability and efficacy of Arikace™ 560 mg administered once daily for up to twelve cycles with each cycle consisting of 28 days on-treatment followed by 28 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
    01 Aug 2012
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 22
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Serbia: 15
    Worldwide total number of subjects
    206
    EEA total number of subjects
    185
    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)
    32
    Adolescents (12-17 years)
    64
    Adults (18-64 years)
    110
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 206 subjects were randomized.

    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
    		 Liposomal Amikacin for Inhalation (LAI)
    Arm description
    		 590 mg LAI once daily (QD) via a PARI Investigational eFlow® Nebulizer System (eFlow®) for 28 days followed by a 28-day off-treatment period. This cycle (28 days on treatment, 28 days off treatment) was to be repeated for up to 12 cycles, divided into 2 periods of 6 cycles each (approximately 12 months each).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liposomal amikacin for inhalation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. • 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. • Administration time is approximately 13 minutes. • Liposomal amikacin for inhalation will be administered in two consecutive extension periods, each consisting of 6 cycles for a total of 12 cycles. Each cycle consists of 28 days on-treatment followed by 28 days off-treatment.

    Number of subjects in period 1
    		Liposomal Amikacin for Inhalation (LAI)
    Started
    206
    Completed
    139
    Not completed
    67
         Consent withdrawn by subject
    24
         Adverse event, non-fatal
    19
         Death
    1
         Other
    22
         Lost to follow-up
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 206 206
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 32 32
        Adolescents (12-17 years)
    		 64 64
        Adults (18-64 years)
    		 110 110
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 21.0 ± 9.73 -
    Gender categorical
    Units: Subjects
        Female
    		 103 103
        Male
    		 103 103
    Race/Ethnicity
    Units: Subjects
        Caucasian (not of Hispanic origin)
    		 200 200
        Hispanic
    		 5 5
        African
    		 1 1
    Geographic region
    Units: Subjects
        Western Europe / North America
    		 99 99
        Central Europe / Eastern Europe
    		 107 107

    End points

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    End points reporting groups
    Reporting group title
    Liposomal Amikacin for Inhalation (LAI)
    Reporting group description
    		 590 mg LAI once daily (QD) via a PARI Investigational eFlow® Nebulizer System (eFlow®) for 28 days followed by a 28-day off-treatment period. This cycle (28 days on treatment, 28 days off treatment) was to be repeated for up to 12 cycles, divided into 2 periods of 6 cycles each (approximately 12 months each).

    Primary: Treatment Emergent Adverse Events (TEAEs) up to Day 672

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    End point title
    		 Treatment Emergent Adverse Events (TEAEs) up to Day 672 [1]
    End point description
    Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        Subjects with ≥1 treatment-emergent AE
    183
        Subjects with ≥ 1 serious AE
    92
        Subjects with ≥1 AE leading to discontinuation
    21
    No statistical analyses for this end point

    Primary: Laboratory Abnormalities up to Day 672

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    End point title
    		 Laboratory Abnormalities up to Day 672 [2]
    End point description
    • Number of Subjects with Grade 3 or Higher Abnormalities in Clinical Laboratory Values • Number of Subjects with Grade 3 or Higher Hematology Laboratory Value Abnormalities • Number of Subjects with Grade 3 or Higher Chemistry Laboratory Value Abnormalities
    End point type
    Primary
    End point timeframe
    Baseline, Day 377 and Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        Baseline
    13
        Day 337/End of Study Year 1
    8
        Day 672/End of Study Year 2
    8
        Leukocytes (<2.0 × 109 /L)
    7
        Lymphocytes (<0.5 × 109 /L)
    12
        Neutrophils (<2.0 × 109 /L)
    23
        Platelets (<192 × 109 /L)
    1
        Alanine aminotransferase (>5.0 × ULN)
    2
        Aspartate aminotransferase (>5.0 × ULN)
    1
        Gamma-glutamyltransferase (>5.0 × ULN)
    2
        Indirect bilirubin (>3.0 × ULN)
    1
        Calcium (<2.1 mmol/L)
    1
        Serum glucose: >13.9 mmol/L
    14
        Serum glucose: < 2.2 mmol/L
    6
        Phosphate (<0.6 mmol/L)
    3
        Potassium: >6.0 mmol/L
    8
        Potassium: <3.6 mmol/L
    1
        Sodium: >155 mmol/L
    1
        Sodium: <130 mmol/L
    4
        Urate (> ULN with physiologic consequences)
    8
    No statistical analyses for this end point

    Primary: Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose

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    End point title
    		 Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose [3]
    End point description
    Number of Subjects with a >15% in Decline in Forced Expiratory Volume in 1 Second (FEV1) From Predose to Postdose.
    End point type
    Primary
    End point timeframe
    Day 1, Day 84, Day 196, Day 281, Day 337, Day 449, Day 532 and Day 644
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        Day 1
    6
        Day 84
    6
        Day 196
    1
        Day 281
    5
        Day 337
    5
        Day 449
    6
        Day 532
    2
        Day 644
    3
    No statistical analyses for this end point

    Primary: Respiratory Rate: Change From Baseline to Day 672

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    End point title
    		 Respiratory Rate: Change From Baseline to Day 672 [4]
    End point description
    Respiratory rate was recorded at every visit as per standard practice at each investigational site. Safety Population Subjects with missing data were excluded.
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    133
    Units: breaths per minute
        arithmetic mean (standard deviation)
    -0.8 ± 3.02
    No statistical analyses for this end point

    Primary: Heart Rate: Change From Baseline From Day 672

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    End point title
    		 Heart Rate: Change From Baseline From Day 672 [5]
    End point description
    Pulse rate (after at least 5-minute rest) was recorded at every visit as per standard practice at each investigational site.
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: beats/min
        arithmetic mean (standard deviation)
    -0.9 ± 12.46
    No statistical analyses for this end point

    Primary: Systolic BP: Change From Baseline at Day 672

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    End point title
    		 Systolic BP: Change From Baseline at Day 672 [6]
    End point description
    Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: mmHg
        arithmetic mean (standard deviation)
    2.3 ± 11.39
    No statistical analyses for this end point

    Primary: Diastolic BP: Change From Baseline at Day 672

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    End point title
    		 Diastolic BP: Change From Baseline at Day 672 [7]
    End point description
    Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: mmHg
        arithmetic mean (standard deviation)
    1.5 ± 9.16
    No statistical analyses for this end point

    Primary: Body Temperature: Change From Baseline at Day 672

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    End point title
    		 Body Temperature: Change From Baseline at Day 672 [8]
    End point description
    Body temperature was recorded at every visit as per standard practice at each investigational site.
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Degrees Celcius
        arithmetic mean (standard deviation)
    0.03 ± 0.316
    No statistical analyses for this end point

    Primary: Oxygen Saturation: Change From Baseline at Day 672

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    End point title
    		 Oxygen Saturation: Change From Baseline at Day 672 [9]
    End point description
    Change in oxygen saturation as measured with pulse oximetry was performed via finger probes placed on the extremity opposite arterial lines and noninvasive blood pressure monitoring devices so that pulsatile flow was not interrupted.
    End point type
    Primary
    End point timeframe
    From Study Initiation up to Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Percent of Hemoglobin
        arithmetic mean (standard deviation)
    -0.1 ± 1.47
    No statistical analyses for this end point

    Primary: Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672

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    End point title
    		 Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 [10]
    End point description
    Sputum was cultured for quantitative microbiological evaluation of Pa and Burkholderia species in designated regional central microbiology laboratories. A standard microbiology protocol was used for Pa culture and identification for each morphologically distinct Pa phenotype. Although planned in the Statistical Analysis Plan (SAP), MICs of amikacin Burkholderia species were not determined due to the small number of isolates with Burkholderia. In addition, susceptibility testing of isolates of Pa and Burkholderia species against a panel of commonly used antipseudomonal antibiotics was planned but was not performed. The results of the following analyses for Pa isolates are presented. • Frequency of MIC of Amikacin • Frequency of MIC of Tobramycin MIC50: lowest concentration of the antibiotic at which 50 % of the isolates were inhibited. Subjects with missing data were excluded.
    End point type
    Primary
    End point timeframe
    Day 1, Day 169, Day 337, Day 505 and Day 672
    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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206 [11]
    Units: µg/mL
    median (full range (min-max))
        Amikacin MIC50: Day 1
    16.000 (2.00 to 2048.00)
        Amikacin MIC50: Day 169
    16.000 (1.00 to 2048.00)
        Amikacin MIC50: Day 337
    16.000 (2.00 to 2048.00)
        Amikacin MIC50: Day 505
    16.000 (0.25 to 2048.00)
        Amikacin MIC50: Day 672
    16.000 (1.00 to 2048.00)
        Tobramycin MIC50: Day 1
    2.000 (0.25 to 1024.00)
        Tobramycin MIC50: Day 169
    2.000 (0.12 to 1024.00)
        Tobramycin MIC50: Day 337
    2.000 (0.25 to 1024.00)
        Tobramycin MIC50: Day 505
    2.000 (0.12 to 1024.00)
        Tobramycin MIC50: Day 672
    1.000 (0.12 to 1024.00)
    Notes
    [11] - Day 1: 180 subjects Day 169: 159 Day 337: 143 Day 505: 119 Day 672: 109
    No statistical analyses for this end point

    Primary: Evaluation of Audiology

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    End point title
    		 Evaluation of Audiology [12]
    End point description
    Hearing was evaluated using air conduction [AC]. Bone conduction was required if the AC testing demonstrated a decrease of >20 decibels [dB]. Hearing loss was categorized using Common Terminology Criteria for Adverse Events as follows: GRADE 1 (best): Adults [A] on a Monitoring Program [MP]: Threshold shift of 15-25 dB; Pediatric [P]: Threshold shift >20 dB at 8 kilohertz (kHz). GRADE 2: [A] on a MP: Threshold shift of >25 dB; [A] not enrolled in MP: hearing loss; hearing aid/intervention not indicated; [P]: Threshold shift >20 dB at 4 kHz and above. GRADE 3: [A] enrolled in MP: Threshold shift of >25 dB; therapeutic intervention indicated; [A]: Not enrolled in MP: hearing aid/intervention; [P]: therapeutic intervention, including hearing aids: Threshold shift >20 dB at 3 kHz and above; additional speech-language related services. GRADE 4 (worst): [A]: Profound bilateral hearing loss; non-serviceable hearing; [P]: cochlear implant & additional speech-language related services.
    End point type
    Primary
    End point timeframe
    Day 337 and Day 672
    Notes
    [12] - 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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        Day 337 - None or minimal change
    133
        Day 337 - Grade 1
    2
        Day 337 - Grade 2
    0
        Day 337 - Grade 3
    0
        Day 337 - Grade 4
    0
        Day 337 - Indeterminate
    26
        Day 337 - Missing
    45
        Day 672 - None or minimal change
    120
        Day 672 - Grade 1
    6
        Day 672 - Grade 2
    0
        Day 672 - Grade 3
    1
        Day 672 - Grade 4
    0
        Day 672 - Indeterminate
    7
        Day 672 - Missing
    72
    No statistical analyses for this end point

    Primary: Change in Serum Creatinine Throughout the Study

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    End point title
    		 Change in Serum Creatinine Throughout the Study [13]
    End point description
    • Common Terminology Criteria for Adverse Events (CTCAE) Grade 1: > ULN-1.5 × ULN • CTCAE Grade 2: > 1.5 × ULN to 3.0 x ULN
    End point type
    Primary
    End point timeframe
    Baseline, Day 337 and Day 672
    Notes
    [13] - 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: Summary statistics only were planned for this endpoint
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        CTCAE Grade 1: Baseline - Yes
    1
        CTCAE Grade 1: Baseline - No
    205
        CTCAE Grade 1: Day 337/End of Study Year 1 - Yes
    0
        CTCAE Grade 1: Day 337/End of Study Year 1 - No
    158
        CTCAE Grade 1: Day 672/End of Study Year 2 - Yes
    0
        CTCAE Grade 1: Day 672/End of Study Year 2 - No
    131
        CTCAE Grade 2: Baseline - Yes
    0
        CTCAE Grade 2: Baseline - No
    206
        CTCAE Grade 2: Day 337/End of Study Year 1 - Yes
    0
        CTCAE Grade 2: Day 337/End of Study Year 1 - No
    158
        CTCAE Grade 2: Day 672/End of Study Year 2 - Yes
    0
        CTCAE Grade 2: Day 672/End of Study Year 2 - No
    131
    No statistical analyses for this end point

    Secondary: Percent Change in FEV1 Throughout the Study

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    End point title
    		 Percent Change in FEV1 Throughout the Study
    End point description
    Percent Change From Baseline in Predose FEV1. Modified Intention to Treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 337 and Day 672
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206 [14]
    Units: Percent (%) change
    arithmetic mean (standard deviation)
        Baseline
    2.104 ± 0.8650
        Day 337
    2.36 ± 14.359
        Day 672
    3.62 ± 18.485
    Notes
    [14] - Day 337 = 158 subjects Day 672 = 131 subjects
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation

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    End point title
    		 Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation
    End point description
    For number of subjects to first protocol-defined pulmonary exacerbation, follow-up time began at the first dose of study drug (Day 1) and ended no later than Day 700 (28-day follow up).
    End point type
    Secondary
    End point timeframe
    From Study Initiation up to Day 700
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        Number of subjects with the event through Day 700
    151
        Number censored
    55
    No statistical analyses for this end point

    Secondary: Number of Subjects Initiating Treatment

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    End point title
    		 Number of Subjects Initiating Treatment
    End point description
    The number of subjects initiating antipseudomonal therapy for protocol-defined pulmonary exacerbation confirmed by the investigator, and for investigator-defined pulmonary exacerbation were summarized. The data presented below is the Frequency of Systemic or Inhaled Antipseudomonal Therapy for Protocol-defined Pulmonary Exacerbations Confirmed by Investigator. Time to First Use of Any New Antibiotic Treatment, Censoring at Date of Last Contact.
    End point type
    Secondary
    End point timeframe
    From Study Initiation up to Day 672
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        After Day 1 through Day 337
    81
        After Day 1 through Day 672
    108
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation

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    End point title
    		 Number of Subjects Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    From Study Initiation up to Day 700
    End point values
    		 Liposomal Amikacin for Inhalation (LAI)
    Number of subjects analysed
    206
    Units: Subjects
        Number of subjects with the event through Day 700
    148
        Number censored
    58
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment up to a maximum of 672 Days (end of study, year 2)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Liposomal Amikacin for Inhalation (LAI)
    Reporting group description
    		 590 mg LAI QD via a PARI Investigational eFlow® Nebulizer System (eFlow®) for 28 days followed by a 28-day off-treatment period. This cycle (28 days on treatment, 28 days off treatment) was to be repeated for up to 12 cycles, divided into 2 periods of 6 cycles each (approximately 12 months each).

    Serious adverse events
    		 Liposomal Amikacin for Inhalation (LAI)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 206 (44.66%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid rhinorrhoea
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    81 / 206 (39.32%)
         occurrences causally related to treatment / all
    27 / 139
         deaths causally related to treatment / all
    0 / 1
    Appendicitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Measles
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Liposomal Amikacin for Inhalation (LAI)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 206 (81.07%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 206 (9.22%)
         occurrences all number
    25
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    13 / 206 (6.31%)
         occurrences all number
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 206 (7.28%)
         occurrences all number
    23
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    30 / 206 (14.56%)
         occurrences all number
    69
    Cough
         subjects affected / exposed
    27 / 206 (13.11%)
         occurrences all number
    45
    Dysphonia
         subjects affected / exposed
    25 / 206 (12.14%)
         occurrences all number
    40
    Oropharyngeal pain
         subjects affected / exposed
    16 / 206 (7.77%)
         occurrences all number
    26
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    129 / 206 (62.62%)
         occurrences all number
    359
    Nasopharyngitis
         subjects affected / exposed
    52 / 206 (25.24%)
         occurrences all number
    88
    Upper respiratory tract infection
         subjects affected / exposed
    32 / 206 (15.53%)
         occurrences all number
    64
    Pharyngitis
         subjects affected / exposed
    18 / 206 (8.74%)
         occurrences all number
    20
    Rhinitis
         subjects affected / exposed
    16 / 206 (7.77%)
         occurrences all number
    19
    Sinusitis
         subjects affected / exposed
    15 / 206 (7.28%)
         occurrences all number
    18
    Viral infection
         subjects affected / exposed
    15 / 206 (7.28%)
         occurrences all number
    15
    Bronchitis
         subjects affected / exposed
    11 / 206 (5.34%)
         occurrences all number
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2011
    Summary of key changes: - Number of anticipated participants was updated - Exclusion criteria were updated - Schedule of assessments was updated - Details about the TR02-105 Extension were added - Summary of risks/benefits for ARIKACE™ treatment were added - Updates made to On-Treatment Study Site Procedures - Detail added to audiology testing section - Additional references added
    14 Nov 2011
    Summary of key changes: - Updated sponsor address - Updated introduction to include results from TR02-105 Extension study - Added clarification to exclusion criteria - Clarified that pregnancies need to be reported within the same timeframe as an SAE - Corrected visit window addition to Day 1 - Added clarification to prohibited medications section - Added clarifications to Study Evaluation section - Updated the date on the Investigator Drug Brochure in the references - Replaced the word “volume” with “liters” whenever FEV1 (volume) is used in the protocol
    30 Oct 2013
    Summary of key changes: - The delivered dose of 8mL per vial of 70mg/mL Arikace, which equates to a delivered dose of 560mg has been updated to 590mg throughout Amendment 3 - Removed reference to blinding for DMC and steering committee - Updated informed consent signing time frame - Added clarification text regarding early discontinuation visit - Added clarification text regarding study drug discontinuation criteria

    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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