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    Clinical Trial Results:
    A Randomized, Open Label, Multicenter Study of Liposomal Amikacin for Inhalation (LAI) in Adult Patients with Nontuberculous Mycobacterial (NTM) Lung Infections Caused by Mycobacterium avium complex (MAC) That are Refractory to Treatment

    Summary
    EudraCT number
    		 2014-005010-31
    Trial protocol
    		 DE   AT   IT   NL   ES   PL   SE  
    Global end of trial date
    03 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2020
    First version publication date
    17 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INS-212
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02344004
    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 Inc, +41 795432860, tom.vanthienen@insmed.com
    Scientific contact
    Tom Vanthienen, Insmed Inc, +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
    09 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of LAI (590 mg) administered once daily (QD), when added to a multi-drug regimen, for achieving culture conversion (3 consecutive monthly negative sputum cultures) by Month 6 compared to a multi-drug regimen alone
    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
    		 Throughout the duration of the study, subjects in both arms of the study continued the same multidrug (at least 2antibiotics) antimycobacterial regimen. The regimen was based on the 200 7ATS/IDSA (American Thoracic Society/Infectious Diseases Society of America) guidelines or respective local guidelines, and they were not to change during the treatment phase except for safety concerns or if rescue antimycobacterial therapy was required.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Feb 2015
    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
    Australia: 40
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Japan: 59
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 22
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    United States: 219
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 20
    Worldwide total number of subjects
    492
    EEA total number of subjects
    114
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    223
    From 65 to 84 years
    263
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 127 sites in 18 countries.

    Pre-assignment
    Screening details
    		 Disposition table reflects the disposition through end of the study (Month 28). The deaths under Reasons for Discontinuation reflect the primary reason (according to investigator's judgment) that the subject discontinued and does not represent all deaths in the trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAI + Multi-drug Regimen
    Arm description
    		 Subjects received Liposomal Amikacin for Inhalation (LAI) 590 mg once daily (QD) in addition to their already prescribed anti-mycobacterial regimen (based on the 2007 American Thoracic Society/Infectious Diseases Society of America [ATS/IDSA] Guidelines); LAI 590 mg QD, administered by inhaling drug product that had been aerosolized in an eFlow nebulizer over approximately 14 minutes
    Arm type
    		 Experimental

    Investigational medicinal product name
    LAI
    Investigational medicinal product code
    Other name
    Liposomal Amikacin for Inhalation
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    590 mg once daily (QD)

    Investigational medicinal product name
    MDR
    Investigational medicinal product code
    Other name
    Multi Drug Regimen
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    variable depending on the medication

    Arm title
    		 Multi-drug Regimen
    Arm description
    		 Subjects received their already prescribed anti-mycobacterial regimen (based on the 2007 ATS/IDSA Guidelines)
    Arm type
    		 Standard of Care

    Investigational medicinal product name
    MDR
    Investigational medicinal product code
    Other name
    Multi Drug Regimen
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    variable depending on the medication

    Number of subjects in period 1 [1]
    		LAI + Multi-drug Regimen Multi-drug Regimen
    Started
    224
    112
    Completed
    163
    98
    Not completed
    61
    14
         Adverse event, serious fatal
    9
    7
         Physician decision
    4
    1
         Consent withdrawn by subject
    22
    5
         Adverse event, non-fatal
    11
    1
         Rescue Medication
    2
    -
         Other not specified
    12
    -
         Protocol deviation
    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: The number 492 represents how many subjects were screened. Of these, 336 were randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LAI + Multi-drug Regimen
    Reporting group description
    		 Subjects received Liposomal Amikacin for Inhalation (LAI) 590 mg once daily (QD) in addition to their already prescribed anti-mycobacterial regimen (based on the 2007 American Thoracic Society/Infectious Diseases Society of America [ATS/IDSA] Guidelines); LAI 590 mg QD, administered by inhaling drug product that had been aerosolized in an eFlow nebulizer over approximately 14 minutes

    Reporting group title
    Multi-drug Regimen
    Reporting group description
    		 Subjects received their already prescribed anti-mycobacterial regimen (based on the 2007 ATS/IDSA Guidelines)

    Reporting group values
    		 LAI + Multi-drug Regimen Multi-drug Regimen Total
    Number of subjects
    		 224 112 336
    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)
    		 64.6 ( 9.59 ) 64.9 ( 10.16 ) -
    Gender categorical
    Units: Subjects
        Female
    		 165 68 233
        Male
    		 59 44 103
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 10 5 15
        Not Hispanic or Latino
    		 211 102 313
        Unknown or Not Reported
    		 3 5 8
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 58 25 83
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 3 3 6
        White
    		 158 77 235
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 3 6 9
    If female, is subject of childbearing potential?
    Units: Subjects
        Yes
    		 13 6 19
        No
    		 152 62 214
        Not female
    		 59 44 103
    If not childbearing potential, specify
    Units: Subjects
        Postmenopausal
    		 114 50 164
        Surgically sterile
    		 38 12 50
        Naturally sterile
    		 0 0 0
        Female of childbearing potential
    		 13 6 19
        Not female
    		 59 44 103
    Region
    Units: Subjects
        North America
    		 104 55 159
        Asia (excluding Japan)
    		 14 6 20
        Japan
    		 34 14 48
        Rest of World
    		 72 37 109
    Multidrug regimen prior to enrollment
    Units: Subjects
        On treatment
    		 201 101 302
        Off treatment for at least 3 months
    		 23 11 34
    Smoking status (includes ecigarettes)
    Units: Subjects
        Current smoker
    		 26 10 36
        Not a current smoker
    		 198 102 300
    Prior nebulized IV amikacin
    Units: Subjects
        Prior nebulized IV amikacin
    		 24 15 39
        No prior nebulized IV amikacin
    		 200 97 297

    End points

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    End points reporting groups
    Reporting group title
    LAI + Multi-drug Regimen
    Reporting group description
    		 Subjects received Liposomal Amikacin for Inhalation (LAI) 590 mg once daily (QD) in addition to their already prescribed anti-mycobacterial regimen (based on the 2007 American Thoracic Society/Infectious Diseases Society of America [ATS/IDSA] Guidelines); LAI 590 mg QD, administered by inhaling drug product that had been aerosolized in an eFlow nebulizer over approximately 14 minutes

    Reporting group title
    Multi-drug Regimen
    Reporting group description
    		 Subjects received their already prescribed anti-mycobacterial regimen (based on the 2007 ATS/IDSA Guidelines)

    Primary: Number of Subjects Achieving Culture Conversion by Month 6 in the Liposomal Amikacin for Inhalation (LAI) + Multidrug Regimen (MDR) Arm Compared to the MDR Alone Arm

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    End point title
    		 Number of Subjects Achieving Culture Conversion by Month 6 in the Liposomal Amikacin for Inhalation (LAI) + Multidrug Regimen (MDR) Arm Compared to the MDR Alone Arm
    End point description
    Sputum specimens were collected at Screening (Visit 1), Baseline (Visit 2), and at Visits 3 (Month 1) through 8 (Month 6). A negative culture result reflected a negative culture result for all sputum samples collected at each visit. Subjects met the primary endpoint of culture conversion by Month 6 if they had 3 consecutive monthly MAC-negative sputum cultures during the first 6 months of the study. A subject needed to achieve the first of 3 consecutive negative sputum cultures (that defined culture conversion) by Month 4 in order to meet the primary endpoint by Month 6. Each subject in the intent to treat (ITT) population (ie, all randomized subjects) was classified as either a converter or non-converter by Month 6.
    End point type
    Primary
    End point timeframe
    by Month 6
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    224
    112
    Units: subjects
        Converter
    65
    10
        Non-converter
    159
    102
    Statistical analysis title
    		 Summary of Month 6 Conversion Rates
    Statistical analysis description
    The proportion of subjects achieving culture conversion by Month 6 was analyzed using the Cochran-Mantel-Haenszel test, stratified by smoking status and prior multi-drug regimen. The treatment comparison was tested at two-sided significance level of 0.05. The null hypothesis assumed that culture conversion by Month 6 is independent of treatment, and the alternative hypothesis assumed that culture conversion by Month 6 is associated with treatment.
    Comparison groups
    LAI + Multi-drug Regimen v Multi-drug Regimen
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - The final analysis of the primary endpoint, the number of subjects achieving culture conversion at by Month 6, was performed after the last subjects completed Month 6 and his/her Month 6 sputum culture result was available.

    Primary: Number of Subjects Achieving Durable Culture Conversion Through 3 Months Off Treatment in the LAI + MDR Arm Compared to the MDR Arm Alone

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    End point title
    		 Number of Subjects Achieving Durable Culture Conversion Through 3 Months Off Treatment in the LAI + MDR Arm Compared to the MDR Arm Alone
    End point description
    Sputum specimens were collected at screening, baseline (Day 1), during treatment, and at Months 1, 3, 6, and 12 months off treatment. Culture conversion with durability was defined as achieving culture conversion by Month 6 and then having no more than 2 consecutive broth positive cultures and no Agar positive culture up to 3 months off treatment. Converters with missing broth or Agar sputum culture result after Month 6 up to 3 months off treatment were considered as not achieving culture conversion with durability except those subjects who are unable to produce sputum despite reasonable efforts, as reported by source documentation. Subjects who had relapse/recurrence, had "rescue" medication and/or died before reaching 3 months off treatment were considered as not achieving culture conversion with durability.
    End point type
    Primary
    End point timeframe
    Up to Month 19
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    224
    112
    Units: subjects
        Durable Conversion
    36
    0
        Non-durable Conversion
    188
    112
    Statistical analysis title
    		 Summary of Durable Culture Conversion
    Comparison groups
    LAI + Multi-drug Regimen v Multi-drug Regimen
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change From Baseline (Day 1) to Month 6 in the Six-Minute Walk Test (6MWT) Distance in the LAI + MDR Arm Compared to the MDR Alone Arm

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    End point title
    		 Change From Baseline (Day 1) to Month 6 in the Six-Minute Walk Test (6MWT) Distance in the LAI + MDR Arm Compared to the MDR Alone Arm
    End point description
    A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and at Month 6. The standardized protocol based on the ATS guidelines was used. The 6MWT was conducted by a site member who was blinded to the subject's open-label treatment assignment. The analysis of the change from Baseline (Day 1) to Month 6 in the 6MWT distance was performed after the last subject completed Month 6 and his/her 6MWT distance data were available.
    End point type
    Secondary
    End point timeframe
    at Month 6
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    223
    112
    Units: meters
    arithmetic mean (standard deviation)
        Baseline
    424.2 ( 1.12 )
    420.9 ( 0.48 )
        Month 6
    420.6 ( 4.73 )
    420.3 ( 2.57 )
        Change from Baseline to Month 6
    -3.6 ( 3.25 )
    -0.5 ( 4.20 )
    Statistical analysis title
    		 Summary of 6MWT
    Statistical analysis description
    This was analyzed using a mixed model repeated measures (MMRM) analysis of change from Baseline at Months 4&6. MMRM included treatment, month, treatment-by-month interaction, combination of smoking status & prior MDR (4 levels: Yes/Yes, Yes/No, No/Yes, and No/No) as fixed factors, baseline 6MWD as a covariate & baseline 6MWD-by-month interaction. An unstructured covariance matrix was used for the MMRM. Baseline is defined as the last non-missing value prior to first dose of study drug.
    Comparison groups
    Multi-drug Regimen v LAI + Multi-drug Regimen
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.7804 [3]
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Confidence interval
    Notes
    [2] - Statistics were obtained from an mixed-effects model repeated measures (MMRM) model with pattern-mixture modeling of missing values due to dropout, which included treatment, month, the treatment-by-month interaction, and the combination of smoking status and prior multidrug regimen as fixed factors, the baseline 6MWT distance as a covariate and baseline 6MWT distance-by-month interaction. MMRM included post postbaseline data through Month 6.
    [3] - For baseline, n is the number of subjects with a baseline score and at least 1 postbaseline score. For Month 6, n is the number of subjects with a baseline score and a postbaseline score at the summarized visit.

    Secondary: Time to Culture Conversion by Month 6 in the LAI + MDR Arm Compared to the MDR Alone Arm

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    End point title
    		 Time to Culture Conversion by Month 6 in the LAI + MDR Arm Compared to the MDR Alone Arm
    End point description
    The time to culture conversion was defined by the date of the first of at least 3 consecutive monthly culture specimens that were Mycobacterium avium complex (MAC)-negative. The 25th percentile time to conversion is the estimated time taken for 25% of subjects to convert. The 50th percentile time to conversion is the estimated time taken for 50% of subjects to convert. The 25th percentile time to conversion could not be estimated for the Multi-drug Regimen arm due to an insufficient proportion of subjects achieving culture conversion by Month 6. The 50th percentile time to conversion could not be estimated for either arm due to an insufficient proportion of patients achieving culture conversion by Month 6.
    End point type
    Secondary
    End point timeframe
    By Month 6
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    224
    112
    Units: months
    number (confidence interval 95%)
        25th Percentile
    2.13 (1.83 to 3.87)
    99999 (99999 to 99999)
        50th Percentile
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Summary of Time to Culture Conversion
    Statistical analysis description
    Kaplan Meier estimates for the distribution of time to culture conversion were constructed for treatment arms. The treatment comparison was made using the stratified log rank test for the ITT population. The estimated median time to culture conversion for each treatment arm was not estimable. The time to culture conversion was analyzed using Cox regression model to estimate hazards ratio.
    Comparison groups
    Multi-drug Regimen v LAI + Multi-drug Regimen
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.01
         upper limit
    		 7.63

    Secondary: Number of Subjects Achieving Sustained Culture Conversion at the End of Treatment (EOT) in the LAI + MDR Arm Compared to the MDR Arm Alone

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    End point title
    		 Number of Subjects Achieving Sustained Culture Conversion at the End of Treatment (EOT) in the LAI + MDR Arm Compared to the MDR Arm Alone
    End point description
    Sustained conversion was evaluated in subjects who completed at least 12 months of treatment from the start of culture conversion. Sustained conversion was defined as conversion (3 consecutive negative monthly sputum samples) by Month 6 with no positive agar media culture or no more than 2 broth media cultures up to and including the time point. Subjects who did not convert were considered non-sustained conversions.
    End point type
    Secondary
    End point timeframe
    up to Month 16
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    224
    112
    Units: subjects
        Sustained Conversion
    41
    3
        Non-Sustained Conversion
    183
    109
    No statistical analyses for this end point

    Secondary: Change in 6-Minute Walk Test (6MWT) Distance at EOT in the LAI Arm Compared to a Multi-drug Regimen Alone

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    End point title
    		 Change in 6-Minute Walk Test (6MWT) Distance at EOT in the LAI Arm Compared to a Multi-drug Regimen Alone
    End point description
    A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and up to EOT or Month 16. The standardized protocol based on the ATS guidelines was used. The 6MWT was conducted by a site member who was blinded to the subject's open-label treatment assignment. Due to the widely varying timepoints that makeup the EOT visit, this was not considered an appropriate analysis and was not performed.
    End point type
    Secondary
    End point timeframe
    up to Month 16
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: subjects
    Notes
    [4] - Refer to endpoint description
    [5] - Refer to endpoint description
    No statistical analyses for this end point

    Secondary: Change From Baseline (Day 1) at Month 6 in the St. George's Respiratory Questionnaire (SGRQ) Total Score

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    End point title
    		 Change From Baseline (Day 1) at Month 6 in the St. George's Respiratory Questionnaire (SGRQ) Total Score
    End point description
    The SGRQ was completed before administration of study drug at Baseline (Day 1) and Months 3, 6, 8, and 12, and at the EOT visit and the 3 months off treatment visit. The SGRQ is a self-administered questionnaire that has been validated in subjects with airways disease, specifically in subjects with bronchiectasis. The SGRQ assesses health-related quality of life in subjects with chronic pulmonary disease by evaluating 3 health domains: symptoms (distress caused by respiratory symptoms); activity (effects of disturbances on mobility and physical activity); and impacts (the effect of disease on factors such as employment, personal control of one’s health, and need for medication). A composite total score is derived as the sum of domain scores for symptoms, activity, and impact (0=the best possible score and 100=the worst possible score). A within patient reduction from baseline in score of 4 units is generally recognized as a clinically meaningful improvement in quality of life.
    End point type
    Secondary
    End point timeframe
    At Month 6
    End point values
    		 LAI + Multi-drug Regimen Multi-drug Regimen
    Number of subjects analysed
    224 [6]
    112 [7]
    Units: score on a scale
    arithmetic mean (standard deviation)
        SGRQ Total Score at Baseline
    36.555 ( 21.3777 )
    38.409 ( 21.5753 )
        SGRQ Total Score at Month 6
    38.715 ( 22.3559 )
    37.368 ( 23.6868 )
        Change from Baseline to Month 6
    2.009 ( 13.4128 )
    -1.312 ( 11.6216 )
    Notes
    [6] - Actual number analyzed: Baseline: 168 Month 6: 169 Change: 168
    [7] - Actual number analyzed: Baseline: 104 Month 6: 106 Change: 104
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (AEs) were assessed at Baseline (Day 1) and all subsequent study visits through Month 28 (end of study).
    Adverse event reporting additional description
    The analysis population consisted of the safety population, defined as all subjects who received at least 1 dose of either LAI+ MDR (multi-drug regimen) or MDR alone. Subjects counted in all-cause mortality constitutes all deaths, regardless of whether or not there was an adverse event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    LAI + Multi-drug Regimen
    Reporting group description
    		 Subjects received LAI 590 mg QD in addition to their already prescribed anti-mycobacterial regimen (based on the 2007 ATS/IDSA Guidelines); LAI 590 mg QD, administered by inhaling drug product that had been aerosolized in an eFlow nebulizer over approximately 14 minutes

    Reporting group title
    Multi-Drug Regimen
    Reporting group description
    		 Subjects received their already prescribed anti-mycobacterial regimen (based on the 2007 ATS/IDSA Guidelines)

    Serious adverse events
    		 LAI + Multi-drug Regimen Multi-Drug Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 223 (20.18%)
    23 / 112 (20.54%)
         number of deaths (all causes)
    11
    8
         number of deaths resulting from adverse events
    6
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alveolitis allergic
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial fistula
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 223 (3.14%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    4 / 12
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    6 / 223 (2.69%)
    5 / 112 (4.46%)
         occurrences causally related to treatment / all
    4 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maxillary sinus pseudocyst
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 223 (1.35%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 223 (0.90%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Computerised tomogram thorax abnormal
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Microvascular coronary artery disease
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypercapnic coma
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    5 / 223 (2.24%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 223 (0.90%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycetoma mycotic
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium avium complex infection
         subjects affected / exposed
    1 / 223 (0.45%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    8 / 223 (3.59%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scedosporium infection
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dehydration
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LAI + Multi-drug Regimen Multi-Drug Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    199 / 223 (89.24%)
    72 / 112 (64.29%)
    Investigations
    Weight decreased
         subjects affected / exposed
    18 / 223 (8.07%)
    3 / 112 (2.68%)
         occurrences all number
    19
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 223 (9.87%)
    5 / 112 (4.46%)
         occurrences all number
    25
    6
    Dizziness
         subjects affected / exposed
    15 / 223 (6.73%)
    3 / 112 (2.68%)
         occurrences all number
    16
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    36 / 223 (16.14%)
    8 / 112 (7.14%)
         occurrences all number
    36
    8
    Pyrexia
         subjects affected / exposed
    17 / 223 (7.62%)
    5 / 112 (4.46%)
         occurrences all number
    22
    6
    Chest discomfort
         subjects affected / exposed
    13 / 223 (5.83%)
    3 / 112 (2.68%)
         occurrences all number
    13
    4
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    18 / 223 (8.07%)
    1 / 112 (0.89%)
         occurrences all number
    22
    1
    Hypoacusis
         subjects affected / exposed
    7 / 223 (3.14%)
    6 / 112 (5.36%)
         occurrences all number
    7
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    29 / 223 (13.00%)
    5 / 112 (4.46%)
         occurrences all number
    31
    5
    Nausea
         subjects affected / exposed
    25 / 223 (11.21%)
    4 / 112 (3.57%)
         occurrences all number
    30
    4
    Vomiting
         subjects affected / exposed
    14 / 223 (6.28%)
    3 / 112 (2.68%)
         occurrences all number
    17
    4
    Constipation
         subjects affected / exposed
    6 / 223 (2.69%)
    6 / 112 (5.36%)
         occurrences all number
    6
    6
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    104 / 223 (46.64%)
    2 / 112 (1.79%)
         occurrences all number
    140
    2
    Cough
         subjects affected / exposed
    85 / 223 (38.12%)
    17 / 112 (15.18%)
         occurrences all number
    111
    20
    Dyspnoea
         subjects affected / exposed
    47 / 223 (21.08%)
    10 / 112 (8.93%)
         occurrences all number
    59
    10
    Haemoptysis
         subjects affected / exposed
    37 / 223 (16.59%)
    14 / 112 (12.50%)
         occurrences all number
    48
    17
    Oropharyngeal pain
         subjects affected / exposed
    24 / 223 (10.76%)
    2 / 112 (1.79%)
         occurrences all number
    30
    2
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    15 / 223 (6.73%)
    2 / 112 (1.79%)
         occurrences all number
    25
    3
    Wheezing
         subjects affected / exposed
    15 / 223 (6.73%)
    3 / 112 (2.68%)
         occurrences all number
    16
    4
    Sputum increased
         subjects affected / exposed
    13 / 223 (5.83%)
    1 / 112 (0.89%)
         occurrences all number
    15
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 223 (6.73%)
    3 / 112 (2.68%)
         occurrences all number
    16
    3
    Back pain
         subjects affected / exposed
    13 / 223 (5.83%)
    4 / 112 (3.57%)
         occurrences all number
    15
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 223 (5.38%)
    8 / 112 (7.14%)
         occurrences all number
    15
    10
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    15 / 223 (6.73%)
    5 / 112 (4.46%)
         occurrences all number
    16
    6
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 223 (3.59%)
    7 / 112 (6.25%)
         occurrences all number
    9
    10
    Pneumonia
         subjects affected / exposed
    2 / 223 (0.90%)
    6 / 112 (5.36%)
         occurrences all number
    2
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 223 (6.73%)
    8 / 112 (7.14%)
         occurrences all number
    17
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2015
    Updates were made to include pharmacokinetic sampling in Japanese subjects, additional assessments, clarifications, administrative changes, removal of some lab tests.
    11 Jun 2015
    Update was done to modify endpoints and objectives, include additional objectives, study procedures, diagnostic testing, inclusion/exclusion criteria, additional analyses, clarification of inclusion/exclusion criteria, clarifications, define terms
    22 Feb 2016
    Administrative changes, removed some evaluations, updated procedures, updates to study design, revised inclusion/exclusion criteria, clarifications.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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