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    Clinical Trial Results:
    A phase III, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with stages AJCC/UICC v. 8 II -IIIA and IIIB (T>5cm N2) completely resected (R0) non-small cell lung cancer (NSCLC)

    Summary
    EudraCT number
    		 2017-004011-39
    Trial protocol
    		 DE   GR   GB   FR   IT   ES   NO   AT   PT   CZ   PL   BG   HU   SI   IS   IE   RO  
    Global end of trial date
    07 Feb 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Feb 2024
    First version publication date
    12 Jan 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CACZ885T2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03447769
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    07 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary purpose of the study was to compare the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with stages II -IIIA according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) version 8 criteria and the subset of IIIB (T>5cm N2 disease) completely resected (R0) non-small cell lung cancer (NSCLC).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Mar 2018
    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
    Argentina: 14
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 9
    Country: Number of subjects enrolled
    China: 100
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    France: 99
    Country: Number of subjects enrolled
    Georgia: 21
    Country: Number of subjects enrolled
    Germany: 131
    Country: Number of subjects enrolled
    Greece: 50
    Country: Number of subjects enrolled
    Hong Kong: 13
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Iceland: 5
    Country: Number of subjects enrolled
    India: 7
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 68
    Country: Number of subjects enrolled
    Japan: 167
    Country: Number of subjects enrolled
    Jordan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 58
    Country: Number of subjects enrolled
    Lebanon: 13
    Country: Number of subjects enrolled
    Malaysia: 19
    Country: Number of subjects enrolled
    Norway: 13
    Country: Number of subjects enrolled
    Panama: 4
    Country: Number of subjects enrolled
    Peru: 3
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 157
    Country: Number of subjects enrolled
    Slovenia: 4
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Taiwan: 63
    Country: Number of subjects enrolled
    Thailand: 39
    Country: Number of subjects enrolled
    Türkiye: 32
    Country: Number of subjects enrolled
    United Kingdom: 48
    Country: Number of subjects enrolled
    United States: 50
    Country: Number of subjects enrolled
    Viet Nam: 9
    Worldwide total number of subjects
    1382
    EEA total number of subjects
    514
    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)
    836
    From 65 to 84 years
    546
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted across 290 centers in 41 countries. A total of 1830 subjects were screened of which 1382 participants were randomized to treatment on a 1:1 basis.

    Pre-assignment
    Screening details
    		 1 participant randomized in the canakinumab arm was never treated due to subject decision. The numbers in the patient disposition table correspond to the treatment period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Canakinumab
    Arm description
    		 Participants receive 200mg of canakinumab subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    200 mg of canakinumab administered subcutaneously on day 1 of every 21-day cycle for 18 cycles. Canakinumab solution for injection was provided by Novartis as ready-to-use pre-filled syringes to be administered by study personnel.

    Arm title
    		 Placebo
    Arm description
    		 Participants receive canakinumab placebo subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered subcutaneously on day 1 of every 21-day cycle for 18 cycles. Placebo solution for injection was provided by Novartis as ready-to-use pre-filled syringes to be administered by study personnel

    Number of subjects in period 1
    		Canakinumab Placebo
    Started
    693
    689
    Treated
    692
    689
    Completed
    414
    420
    Not completed
    279
    269
         Adverse event, serious fatal
    2
    7
         Patient decision
    27
    27
         Physician decision
    13
    5
         Study terminated by Sponsor
    60
    44
         Adverse event, non-fatal
    34
    31
         Technical problems
    1
    -
         Protocol deviation
    4
    6
         Progressive disease
    138
    148
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Participants receive 200mg of canakinumab subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive canakinumab placebo subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)

    Reporting group values
    		 Canakinumab Placebo Total
    Number of subjects
    		 693 689 1382
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 414 422 836
        From 65-84 years
    		 279 267 546
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.5 ± 8.90 61.6 ± 9.00 -
    Sex: Female, Male
    Units: Participants
        Female
    		 263 257 520
        Male
    		 430 432 862
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 393 391 784
        Asian
    		 248 236 484
        Black or African American
    		 3 4 7
        American Indian or Alaska Native
    		 0 5 5
        Multiple
    		 0 1 1
        Missing
    		 49 52 101

    End points

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    End points reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Participants receive 200mg of canakinumab subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)

    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive canakinumab placebo subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)

    Primary: Disease free survival (DFS) by local investigator

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    End point title
    		 Disease free survival (DFS) by local investigator
    End point description
    DFS is the time from the date of randomization to the date of the first documented NSCLC disease recurrence as assessed by local investigator radiologically or death due to any cause. Disease recurrence included diagnoses of new primary lung malignancies. Clinical deterioration was not considered as a recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment was performed to confirm NSCLC recurrence. The median DFS was estimated using the Kaplan-Meier method. DFS was censored if no DFS event was observed prior to the analysis cut-off date or subjects who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date was the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy date. 9999 indicates the value was not estimable
    End point type
    Primary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
        median (confidence interval 95%)
    35.02 (28.55 to 9999)
    29.73 (23.72 to 9999)
    Statistical analysis title
    		 DFS: Canakinumab vs Placebo
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    1382
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.258 [1]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.14
    Notes
    [1] - 1-sided p-value

    Secondary: Overall Survival (OS) in CD8 subgroups

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    End point title
    		 Overall Survival (OS) in CD8 subgroups
    End point description
    Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. The OS was censored at the latest date the subject was known to be alive. The OS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier medians and 95% confidence intervals of the medians were presented for each treatment group. OS analysis was performed by CD8 subgroups with the median of baseline CD8 expression as cut-off. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    up to approximately 4.3 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    429
    449
    Units: Months
    median (confidence interval 95%)
        CD8 < median (n= 213 / 225)
    46.95 (32.23 to 9999)
    9999 (-9999 to 9999)
        CD8 ≥ median (n= 216 / 224)
    51.12 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. The OS was censored at the latest date the subject was known to be alive. The OS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier medians and 95% confidence intervals of the medians were presented for each treatment group. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 4.3 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
        median (confidence interval 95%)
    51.12 (46.95 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in PD-L1 subgroups

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    End point title
    		 Overall Survival (OS) in PD-L1 subgroups
    End point description
    Overall Survival (OS) is the time from the date of randomization to the date of death due to any cause. The OS was censored at the latest date the subject was known to be alive. The OS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians were presented for each treatment group. OS analysis was performed by programmed cell death-ligand 1 (PD-L1) expression status: PD-L1 <1%, PD-L1 ≥1% and <49%, and PD-L1 ≥50%. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 4.3 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    396
    418
    Units: Months
    median (confidence interval 95%)
        PD-L1 <1% (n= 211 / 203)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
        PD-L1 ≥1% and <49% (n=99 / 119)
    46.95 (22.11 to 9999)
    9999 (-9999 to 9999)
        PD-L1 ≥50% (n=86 / 96)
    51.12 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Disease free survival (DFS) by local investigator in PD-L1 subgroups

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    End point title
    		 Disease free survival (DFS) by local investigator in PD-L1 subgroups
    End point description
    DFS is the time from the date of randomization to the date of the first documented NSCLC disease recurrence as assessed by local investigator radiologically or death due to any cause. Disease recurrence included diagnoses of new primary lung malignancies. Clinical deterioration was not considered as a recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment was performed to confirm NSCLC recurrence. The median DFS was estimated using the Kaplan-Meier method. DFS was censored if no DFS event was observed prior to the analysis cut-off date or subjects who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date was the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy date. DFS analysis was performed by baseline programmed cell death-ligand 1 (PD-L1) expression status: PD-L1 <1%, PD-L1 ≥1% and <49%, and PD-L1 ≥50%. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    396
    418
    Units: Months
    median (confidence interval 95%)
        PD-L1 <1% (n= 211 / 203)
    30.72 (23.52 to 9999)
    9999 (23.03 to 9999)
        PD-L1 ≥1% and <49% (n= 99 / 119)
    30.42 (21.42 to 9999)
    9999 (17.05 to 9999)
        PD-L1 ≥50% (n = 86 / 96)
    46.95 (19.45 to 9999)
    9999 (22.31 to 9999)
    Statistical analysis title
    		 DFS in PD-L1 subgroups: Canakinumab vs Placebo
    Statistical analysis description
    PD-L1 <1%
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    814
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.676 [2]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.58
    Notes
    [2] - 1-sided p-value
    Statistical analysis title
    		 DFS in PD-L1 subgroups: Canakinumab vs Placebo
    Statistical analysis description
    PD-L1 ≥50%
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    814
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.823 [3]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.43
    Notes
    [3] - 1-sided p-value
    Statistical analysis title
    		 DFS in PD-L1 subgroups: Canakinumab vs Placebo
    Statistical analysis description
    PD-L1 ≥1% and <49%
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    814
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.036 [4]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.05
    Notes
    [4] - 1-sided p-value

    Secondary: Lung Cancer Specific Survival (LCSS)

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    End point title
    		 Lung Cancer Specific Survival (LCSS)
    End point description
    LCSS is defined as the time from date of randomization to the date of death due to lung cancer. The LCSS distribution was estimated using the Kaplan-Meier method, and Kaplan-Meier medians and 95% confidence intervals of the medians were presented for each treatment group. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 4.3 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
        median (confidence interval 95%)
    51.12 (44.71 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Disease free survival (DFS) by local investigator in CD8 subgroups

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    End point title
    		 Disease free survival (DFS) by local investigator in CD8 subgroups
    End point description
    DFS is the time from the date of randomization to the date of the first documented NSCLC disease recurrence as assessed by local investigator radiologically or death due to any cause. Disease recurrence included diagnoses of new primary lung malignancies. Clinical deterioration was not considered as a recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment was performed to confirm NSCLC recurrence. The median DFS was estimated using the Kaplan-Meier method. DFS was censored if no DFS event was observed prior to the analysis cut-off date or subjects who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date was the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy date. DFS analysis was performed by CD8 subgroups with the median of baseline CD8 expression as cut-off. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    429
    449
    Units: Months
    median (confidence interval 95%)
        CD8 < median (n= 213 / 225)
    26.58 (20.67 to 9999)
    9999 (25.03 to 9999)
        CD8 ≥ median (n= 216 / 224)
    46.95 (28.81 to 9999)
    9999 (23.89 to 9999)
    Statistical analysis title
    		 DFS in CD8 subgroups: Canakinumab vs Placebo
    Statistical analysis description
    CD8 ≥ median
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.303 [5]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.33
    Notes
    [5] - 1-sided p-value
    Statistical analysis title
    		 DFS in CD8 subgroups: Canakinumab vs Placebo
    Statistical analysis description
    CD8 < median
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.872 [6]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.72
    Notes
    [6] - 1-sided p-value

    Secondary: Canakinumab serum concentrations

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    End point title
    		 Canakinumab serum concentrations [7]
    End point description
    Serum concentrations of canakinumab were determined using an ELISA method.
    End point type
    Secondary
    End point timeframe
    Cycle 1 on day 1 (pre-dose), day 8 and 15; Cycle 2, 4, 6, 9 and 12 on day 1 (pre-dose). Cycle=21 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: Only participants who received canakinumab were included in this analysis
    End point values
    		 Canakinumab
    Number of subjects analysed
    664
    Units: ug/ml
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n= 664)
    0 ± 0
        Cycle 1 Day 8 (n= 569)
    18.1 ± 6.53
        Cycle 1 Day 15 (n= 611)
    16.9 ± 5.43
        Cycle 2 Day 1 (n= 636)
    15.0 ± 4.91
        Cycle 4 Day 1 (n= 611)
    29.7 ± 10.3
        Cycle 6 Day 1 (n= 559)
    34.7 ± 13.0
        Cycle 9 Day 1 (n=530)
    37.1 ± 14.5
        Cycle 12 Day 1 (n=502)
    38.6 ± 15.5
    No statistical analyses for this end point

    Secondary: Time to definitive 10 point deterioration of global health status/quality of life (QoL), shortness of breath and pain per EORTC QLQ-C30 questionnaire

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    End point title
    		 Time to definitive 10 point deterioration of global health status/quality of life (QoL), shortness of breath and pain per EORTC QLQ-C30 questionnaire
    End point description
    The EORTC QLQ-C30 was a questionnaire developed to assess the health-related quality of life of cancer participants. It assessed 15 domains consisting of 5 functional domains and 9 symptom domains and a global health status/QoL scale. All domain scores ranged from 0 to 100. A high score for the functional or global health status scales indicated a high level of functioning or QoL; a high score for a symptom scale indicated a high level of symptoms. The time to definitive 10 point deterioration of global health status/QoL, shortness of breath and pain was defined as the time from the date of randomization to the date of event, which was defined as at least 10 points relative to baseline worsening of the score with no later change below this threshold or death due to any cause, whichever occurred earlier. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
    median (confidence interval 95%)
        Global health status/QoL
    34.99 (29.93 to 9999)
    35.15 (35.15 to 9999)
        Shortness of breath
    9999 (-9999 to 9999)
    35.15 (34.99 to 9999)
        Pain
    29.93 (28.29 to 35.22)
    36.44 (34.99 to 9999)
    No statistical analyses for this end point

    Secondary: Canakinumab ADA incidence

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    End point title
    		 Canakinumab ADA incidence [8]
    End point description
    Canakinumab ADA incidence on-treatment was calculated as the percentage of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    From baseline up to 130 days after end of treatment, assessed up to approx. 1.5 years
    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: Only participants who received canakinumab were included in this analysis
    End point values
    		 Canakinumab
    Number of subjects analysed
    692
    Units: Participants
    7
    No statistical analyses for this end point

    Secondary: Canakinumab Anti-drug Antibody (ADA) prevalence at baseline

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    End point title
    		 Canakinumab Anti-drug Antibody (ADA) prevalence at baseline [9]
    End point description
    Canakinumab ADA prevalence at baseline was calculated as the percentage of participants who had an ADA positive result at baseline
    End point type
    Secondary
    End point timeframe
    Baseline
    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: Only participants who received canakinumab were included in this analysis
    End point values
    		 Canakinumab
    Number of subjects analysed
    692
    Units: Participants
    8
    No statistical analyses for this end point

    Secondary: Time to definitive 10 point deterioration symptom scores of pain,cough and dyspnea per European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung cancer (LC) 13 questionnaire

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    End point title
    		 Time to definitive 10 point deterioration symptom scores of pain,cough and dyspnea per European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung cancer (LC) 13 questionnaire
    End point description
    The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores ranged from 0 to 100. A high score indicated a high level of symptoms. The time to definitive 10 point deterioration symptom scores of pain, cough and dyspnea was defined as the time from the date of randomization to the date of event, which was defined as at least 10 points relative to baseline worsening of the EORTC QLQ-LC13 symptom score with no later change below this threshold or death due to any cause, whichever occurred earlier. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
    median (confidence interval 95%)
        Pain
    9999 (35.45 to 9999)
    9999 (-9999 to 9999)
        Cough
    9999 (35.06 to 9999)
    9999 (34.99 to 9999)
        Dyspnea
    28.88 (23.10 to 34.96)
    34.99 (23.13 to 9999)
    No statistical analyses for this end point

    Secondary: Time to first 10 point deterioration for symptom scores of pain, cough and dyspnea per EORTC QLQ-LC13 questionnaire

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    End point title
    		 Time to first 10 point deterioration for symptom scores of pain, cough and dyspnea per EORTC QLQ-LC13 questionnaire
    End point description
    The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) was used in conjunction with the EORTC QLQ-C30 and provided information on an additional 13 items specifically related to lung cancer. The lung cancer module incorporated one multi-item scale to assess dyspnea, and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All of the domain scores ranged from 0 to 100. A high score indicated a high level of symptoms. The time to first 10 point deterioration symptom scores of pain, cough and dyspnea was defined as the time from the date of randomization to the first onset of at least 10 points absolute increase from baseline (worsening) in symptoms scores or death due to any cause, whichever occurred earlier. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
    median (confidence interval 95%)
        Pain
    35.15 (26.58 to 9999)
    9999 (23.06 to 9999)
        Cough
    15.44 (10.38 to 23.06)
    15.01 (9.69 to 9999)
        Dyspnea
    4.17 (3.42 to 5.55)
    4.86 (3.48 to 6.97)
    No statistical analyses for this end point

    Secondary: Change from baseline in the utility score of the EuroQoL- 5 dimension- 5 level (EQ-5D-5L)

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    End point title
    		 Change from baseline in the utility score of the EuroQoL- 5 dimension- 5 level (EQ-5D-5L)
    End point description
    EQ-5D-5L was a standardized questionnaire that measured health-related QoL. EQ-5D-5L consisted of two components: a health state profile and a visual analogue scale. The health state profile included five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each with five levels ranging from 1 (no problems) to 5 (extreme problems). The EQ-5D-5L health state profile responses were converted into single index utility score, ranging from -1 to 1, where lower scores representing a higher level of dysfunction. A positive change from baseline indicated improvement. This endpoint was assessed throughout the study, including safety and efficacy follow-up (FU) visits. Safety FU visits: every 4 weeks after end of treatment up to 130 days post-last dose. Efficacy FU visits: at 18, 24, 30, 36 and 48 months post-randomization (if no recurrence observed during treatment or safety FU). 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 weeks for 14 months; end of treatment; every 4 weeks up to 130 days post-treatment; at 18,24,30,36 and 48 months post-randomization (if no recurrence); 7 and 28 days post-disease progression, up to approx. 4 years.
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    643
    629
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 3 (n= 643 /629)
    0.0 ± 0.11
    0.0 ± 0.12
        Week 6 (n= 626 /614)
    0.0 ± 0.13
    0.0 ± 0.12
        Week 9 (n= 619 /603)
    0.0 ± 0.13
    0.0 ± 0.13
        Week 12 (n= 619 /604)
    0.0 ± 0.12
    0.0 ± 0.12
        Week 15 (n= 581 /572)
    0.0 ± 0.13
    0.0 ± 0.12
        Week 18 (n= 564 /558)
    0.0 ± 0.13
    0.0 ± 0.13
        Week 21 (n= 555 /556)
    0.0 ± 0.13
    0.0 ± 0.14
        Week 24 (n=551 /550)
    0.0 ± 0.14
    0.0 ± 0.14
        Week 27 (n=528/532)
    0.0 ± 0.13
    0.0 ± 0.14
        Week 30 (n=523/504)
    0.0 ± 0.13
    0.0 ± 0.14
        Week 33 (n=509/506)
    0.0 ± 0.13
    0.0 ± 0.14
        Week 36 (n=502/502)
    0.0 ± 0.14
    0.0 ± 0.15
        Week 39 (n=461/471)
    0.0 ± 0.15
    0.0 ± 0.13
        Week 42 (n=451/452)
    0.0 ± 0.15
    0.0 ± 0.14
        Week 45 (440/428)
    0.0 ± 0.14
    0.0 ± 0.14
        Week 48 (n=423/422)
    0.0 ± 0.14
    0.0 ± 0.15
        Week 51 (n=385/406)
    0.0 ± 0.13
    0.0 ± 0.14
        Week 54 (n=17/11)
    0.0 ± 0.18
    0.1 ± 0.12
        Week 57 (n=1/1)
    0.0 ± 9999
    -0.1 ± 9999
        Week 60 (n=1/1)
    -0.2 ± 9999
    -0.1 ± 9999
        Safety FU 1 (n=431/443)
    0.0 ± 0.15
    0.0 ± 0.14
        Safety FU 2 (n=421/432)
    0.0 ± 0.14
    0.0 ± 0.14
        Safety FU 3 (n=420/418)
    0.0 ± 0.14
    0.0 ± 0.15
        Safety FU 4 (n=392/406)
    0.0 ± 0.15
    0.0 ± 0.16
        Safety FU 5 (n=392/397)
    0.0 ± 0.15
    0.0 ± 0.14
        Efficacy FU 1 (n=237/254)
    0.0 ± 0.16
    0.0 ± 0.16
        Efficacy FU 2 (n=179/178)
    0.0 ± 0.15
    0.0 ± 0.16
        Efficacy FU 3 (n=124/116)
    0.0 ± 0.14
    0.0 ± 0.15
        Efficacy FU 4 (n=67/72)
    0.0 ± 0.13
    0.0 ± 0.15
        Efficacy FU 5 (n=15/7)
    0.0 ± 0.10
    -0.1 ± 0.17
        7 days post disease progression (n=29/22)
    -0.1 ± 0.16
    -0.1 ± 0.22
        28 days post disease progression (n=86/79)
    -0.1 ± 0.18
    -0.1 ± 0.18
        Week 63 (n=1/0)
    0.0 ± 9999
    9999 ± 9999
        Week 69 (n= 1/0)
    0.0 ± 9999
    9999 ± 9999
    No statistical analyses for this end point

    Secondary: Time to first 10 point deterioration of global health status/QoL, shortness of breath and pain per EORTC QLQ-C30 questionnaire

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    End point title
    		 Time to first 10 point deterioration of global health status/QoL, shortness of breath and pain per EORTC QLQ-C30 questionnaire
    End point description
    The EORTC QLQ-C30 was a questionnaire developed to assess the health-related quality of life of cancer participants. It assessed 15 domains consisting of 5 functional domains (physical, role, emotional, cognitive, social) and 9 symptom domains (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global health status/QoL scale. All domain scores ranged from 0 to 100. A high score for the functional or global health status scales indicated a high level of functioning or QoL; a high score for a symptom scale indicated a high level of symptoms. The time to first 10 point deterioration of global health status/QoL, shortness of breath and pain scores was defined as the time from the date of randomization to the first onset of at least 10 points absolute increase from baseline (worsening) in symptoms scores or death due to any cause, whichever occurred earlier. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 4 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Months
    median (confidence interval 95%)
        Global health status/QoL
    9.23 (7.10 to 11.76)
    9.07 (7.62 to 11.76)
        Shortness of breath
    29.14 (23.03 to 9999)
    9999 (23.13 to 9999)
        Pain
    5.49 (4.21 to 6.90)
    5.62 (4.17 to 7.62)
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    Pre-treatment deaths were collected from day of participant’s informed consent to the day before first dose of study medication. On-treatment deaths were collected from start of treatment to 130 days after last dose. Post-treatment follow-up deaths were collected from day 131 after last dose of study treatment to end of study.
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment: Up to 28 days prior to treatment. On-treatment: Up to approx. 1.5 years. Post-treatment follow-up: Up to approx. 4.3 years
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    693
    689
    Units: Participants
        Pre-treatment deaths
    0
    0
        On-treatment deaths
    9
    17
        Post-treatment follow-up deaths
    53
    51
        All deaths
    62
    68
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment to 130 days after last dose of study medication (on-treatment), up to approx. 1.5 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Canakinumab
    Reporting group description
    		 Canakinumab

    Serious adverse events
    		 Placebo Canakinumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    146 / 689 (21.19%)
    141 / 692 (20.38%)
         number of deaths (all causes)
    17
    9
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 689 (0.00%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 689 (0.15%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm swelling
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 689 (0.00%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer stage 0
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (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 ischaemia
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 689 (0.29%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 689 (0.15%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 689 (0.44%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 689 (0.29%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 689 (0.00%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 689 (0.00%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 689 (0.29%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 689 (0.00%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 689 (0.29%)
    7 / 692 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 689 (0.15%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    3 / 689 (0.44%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    2 / 689 (0.29%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 689 (0.29%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 689 (0.00%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 689 (0.58%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 689 (0.58%)
    4 / 692 (0.58%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral nerve palsy
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulnar nerve palsy
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhegmatogenous retinal detachment
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 689 (0.29%)
    3 / 692 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 689 (0.29%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 689 (0.44%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (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 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         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
    Tenosynovitis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 689 (0.44%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 689 (0.00%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    48 / 689 (6.97%)
    48 / 692 (6.94%)
         occurrences causally related to treatment / all
    2 / 50
    0 / 50
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Appendicitis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 689 (0.15%)
    2 / 692 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 689 (0.58%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection parasitic
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 689 (1.31%)
    13 / 692 (1.88%)
         occurrences causally related to treatment / all
    2 / 10
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 689 (0.29%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tuberculosis
         subjects affected / exposed
    0 / 689 (0.00%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 689 (0.15%)
    0 / 692 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 689 (0.15%)
    1 / 692 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Placebo Canakinumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    455 / 689 (66.04%)
    465 / 692 (67.20%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    49 / 689 (7.11%)
    65 / 692 (9.39%)
         occurrences all number
    68
    102
    Amylase increased
         subjects affected / exposed
    51 / 689 (7.40%)
    52 / 692 (7.51%)
         occurrences all number
    70
    83
    Lipase increased
         subjects affected / exposed
    47 / 689 (6.82%)
    47 / 692 (6.79%)
         occurrences all number
    79
    68
    Neutrophil count decreased
         subjects affected / exposed
    13 / 689 (1.89%)
    45 / 692 (6.50%)
         occurrences all number
    23
    105
    Weight increased
         subjects affected / exposed
    48 / 689 (6.97%)
    63 / 692 (9.10%)
         occurrences all number
    68
    90
    White blood cell count decreased
         subjects affected / exposed
    18 / 689 (2.61%)
    35 / 692 (5.06%)
         occurrences all number
    30
    93
    Aspartate aminotransferase increased
         subjects affected / exposed
    37 / 689 (5.37%)
    53 / 692 (7.66%)
         occurrences all number
    45
    76
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 689 (3.48%)
    35 / 692 (5.06%)
         occurrences all number
    27
    40
    Nervous system disorders
    Headache
         subjects affected / exposed
    60 / 689 (8.71%)
    31 / 692 (4.48%)
         occurrences all number
    72
    37
    Paraesthesia
         subjects affected / exposed
    44 / 689 (6.39%)
    29 / 692 (4.19%)
         occurrences all number
    48
    32
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    50 / 689 (7.26%)
    46 / 692 (6.65%)
         occurrences all number
    56
    57
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    43 / 689 (6.24%)
    28 / 692 (4.05%)
         occurrences all number
    47
    30
    Fatigue
         subjects affected / exposed
    60 / 689 (8.71%)
    70 / 692 (10.12%)
         occurrences all number
    84
    92
    Asthenia
         subjects affected / exposed
    33 / 689 (4.79%)
    47 / 692 (6.79%)
         occurrences all number
    38
    61
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    42 / 689 (6.10%)
    34 / 692 (4.91%)
         occurrences all number
    56
    38
    Diarrhoea
         subjects affected / exposed
    48 / 689 (6.97%)
    57 / 692 (8.24%)
         occurrences all number
    66
    84
    Nausea
         subjects affected / exposed
    51 / 689 (7.40%)
    46 / 692 (6.65%)
         occurrences all number
    61
    63
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    108 / 689 (15.67%)
    89 / 692 (12.86%)
         occurrences all number
    143
    117
    Dyspnoea
         subjects affected / exposed
    50 / 689 (7.26%)
    67 / 692 (9.68%)
         occurrences all number
    55
    80
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    34 / 689 (4.93%)
    35 / 692 (5.06%)
         occurrences all number
    37
    43
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    88 / 689 (12.77%)
    74 / 692 (10.69%)
         occurrences all number
    108
    83
    Back pain
         subjects affected / exposed
    56 / 689 (8.13%)
    61 / 692 (8.82%)
         occurrences all number
    68
    64
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    33 / 689 (4.79%)
    44 / 692 (6.36%)
         occurrences all number
    38
    49
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 689 (4.50%)
    37 / 692 (5.35%)
         occurrences all number
    36
    45

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2018
    Included a biomarker sub-study which collected pre- and post- resection surgery blood samples. Central ECG collection was replaced by local ECG at screening and as clinically indicated. Updated dose interruption schedule related to Drug Induced Liver Injury (DILI). Updated the contraception language. Reduced number of C1D2 and C1D3 pharmacokinetics samples. Made clarifications, editorial and typographic changes
    05 Feb 2020
    Allowed sites the flexibility to perform hematology, chemistry, and coagulation based on local laboratory results allowed for same-day safety evaluations. The remaining blood specimens collected as part of safety monitoring (e.g., HIV screen, HbsAg, HCV antibody) continued to be performed by central laboratory. Additional minor protocol language clarification updates were made throughout the amendment.
    03 Feb 2022
    Second DFS IA removal. Inclusion as a secondary endpoint the comparison between the canakinumab and placebo arms of DFS by investigator local assessment and OS in subgroups defined respectively by PD-L1 and CD8 expression Time to first 10-point deterioration addition for symptoms and global health status/QoL as a secondary patient-reported outcomes variable of interest Disruption proofing language addition

    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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