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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of canakinumab in combination with docetaxel versus placebo in combination with docetaxel in subjects with non-small cell lung cancer (NSCLC) previously treated with PD-(L)1 inhibitors and platinum-based chemotherapy (CANOPY-2)

    Summary
    EudraCT number
    		 2018-002480-26
    Trial protocol
    		 GR   DE   FR   ES   BE   CZ   PL   NL   HU   DK   IT  
    Global end of trial date
    20 Dec 2021

    Results information
    Results version number
    		 v1
    This version publication date
    20 Sep 2022
    First version publication date
    20 Sep 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CACZ885V2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03626545
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, 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
    20 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the efficacy and safety of canakinumab in combination with docetaxel versus placebo in combination with docetaxel, as second or third-line treatment.
    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
    23 Jan 2019
    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: 8
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    China: 12
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Jordan: 2
    Country: Number of subjects enrolled
    Japan: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    245
    EEA total number of subjects
    146
    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)
    135
    From 65 to 84 years
    110
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Safety run-in (Part 1) was conducted in 6 centers across 4 countries and the Randomized part (Part 2) was conducted in 85 centers across 26 countries.

    Pre-assignment
    Screening details
    		 In the randomized part, a total of 352 subjects were screened. 237 subjects completed the screening phase and were randomized in a 1:1 ratio to treatment with either canakinumab plus docetaxel or placebo plus docetaxel. Three randomized subjects in the placebo plus docetaxel group were not treated

    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
    		 Investigator, Monitor, Carer, Data analyst, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safety run-in part: Canakinumab+docetaxel
    Arm description
    		 Participants were treated with full doses of docetaxel 75mg/m^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab, 200 mg, subcutaneous. The initial dose regimen was once every 3 weeks (on Day 1 of each 21-day cycle)

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75mg/m^2, intravenous, administered on Day 1 of each 21-day cycle

    Arm title
    		 Randomized part: Canakinumab + docetaxel
    Arm description
    		 Participants were randomized to receive canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75mg/m^2, intravenous, administered on Day 1 of each 21-day cycle

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab, 200 mg, subcutaneous, administered on Day 1 of each 21-day cycle

    Arm title
    		 Randomized part: Placebo + docetaxel
    Arm description
    		 Participants were randomized to receive placebo subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo, sub-cutaneous, every 3 weeks, administered on Day 1 of each 21-day cycle

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75mg/m^2, intravenous, administered on Day 1 of each 21-day cycle

    Number of subjects in period 1
    		Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Started
    8
    120
    117
    Completed
    0
    0
    0
    Not completed
    8
    120
    117
         Adverse event, serious fatal
    1
    1
    1
         Physician decision
    1
    18
    14
         Subject Decision
    -
    5
    5
         Adverse event, non-fatal
    3
    13
    10
         Protocol Deviation
    -
    1
    1
         Guardian Decision
    -
    -
    1
         Progressive disease
    3
    82
    85

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety run-in part: Canakinumab+docetaxel
    Reporting group description
    		 Participants were treated with full doses of docetaxel 75mg/m^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1).

    Reporting group title
    Randomized part: Canakinumab + docetaxel
    Reporting group description
    		 Participants were randomized to receive canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle

    Reporting group title
    Randomized part: Placebo + docetaxel
    Reporting group description
    		 Participants were randomized to receive placebo subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle

    Reporting group values
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel Total
    Number of subjects
    		 8 120 117 245
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 8 61 66 135
        From 65-84 years
    		 0 59 51 110
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 55.9 ( 4.19 ) 63.4 ( 9.13 ) 62.2 ( 10.05 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 2 38 32 72
        Male
    		 6 82 85 173
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 8 91 83 182
        Asian
    		 0 22 27 49
        Unknown
    		 0 4 7 11
        Black or African American
    		 0 3 0 3

    End points

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    End points reporting groups
    Reporting group title
    Safety run-in part: Canakinumab+docetaxel
    Reporting group description
    		 Participants were treated with full doses of docetaxel 75mg/m^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1).

    Reporting group title
    Randomized part: Canakinumab + docetaxel
    Reporting group description
    		 Participants were randomized to receive canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle

    Reporting group title
    Randomized part: Placebo + docetaxel
    Reporting group description
    		 Participants were randomized to receive placebo subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle

    Primary: Randomized part: Overall Survival (OS)

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    End point title
    		 Randomized part: Overall Survival (OS) [1]
    End point description
    OS is defined as the time from randomization to date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. If a subject was not known to have died, then OS was censored at the latest date the subject was known to be alive (on or before the cut-off date).
    End point type
    Primary
    End point timeframe
    From randomization until death or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approximately 18 months)
    Notes
    [1] - 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: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Months
        median (confidence interval 95%)
    10.55 (8.15 to 12.39)
    11.30 (8.54 to 13.80)
    Statistical analysis title
    		 Cox regression model for overall survival
    Comparison groups
    Randomized part: Canakinumab + docetaxel v Randomized part: Placebo + docetaxel
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.633
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.48

    Primary: Safety run-in part: Percentage of participants with dose limiting toxicities (DLTs)

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    End point title
    		 Safety run-in part: Percentage of participants with dose limiting toxicities (DLTs) [2] [3]
    End point description
    Percentage of participants with DLTs. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 42 days of docetaxel and canakinumab treatment.
    End point type
    Primary
    End point timeframe
    During the first 42 days of dosing
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this primary endpoint
    [3] - 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: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    7
    Units: Participants
    1
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    ORR is defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1 CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 10 months for the safety run-in part and 18 months for the randomized part)
    End point values
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    8
    120
    117
    Units: Percentage of participants
        number (confidence interval 95%)
    0.0 (-9999 to 9999)
    15.0 (9.1 to 22.7)
    13.7 (8.0 to 21.3)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    DOR is defined as the time from first documented response of CR or PR to date of first documented progression or death, by investigator's assessment according to RECIST 1.1 criteria. The DOR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    From first documented response of CR or PR to date of first documented progression, death or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approximately 10 months for the safety run-in and 18 months for the randomized)
    End point values
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    0 [4]
    18
    16
    Units: Months
        median (confidence interval 95%)
    ( to )
    4.14 (2.89 to 11.17)
    5.42 (4.17 to 9999)
    Notes
    [4] - No participants had CR or PR
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    DCR is defined as the percentage of participants with CR or PR or with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    Through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 10 months for the safety run-in part and 18 months for the randomized part)
    End point values
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    8
    120
    117
    Units: Percentage of participants
        number (confidence interval 95%)
    62.5 (24.5 to 91.5)
    65.8 (56.6 to 74.2)
    61.5 (52.1 to 70.4)
    No statistical analyses for this end point

    Secondary: Randomized part: Progression-Free Survival (PFS)

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    End point title
    		 Randomized part: Progression-Free Survival (PFS) [5]
    End point description
    PFS is defined as the time from randomization to the date of the first documented radiological progression by investigator assessment according to RECIST 1.1 response criteria or death due to any cause. The PFS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. If a participant did not have disease progression or die at the analysis cut-off date, PFS was censored at the date of last adequate tumor assessment.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, death or final analysis data cutoff date (08-Jan-2021) whichever comes first (assessed up to approximately 18 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Months
        median (confidence interval 95%)
    4.17 (2.96 to 5.42)
    4.21 (3.06 to 5.13)
    No statistical analyses for this end point

    Secondary: Randomized part: Time to Response (TTR)

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    End point title
    		 Randomized part: Time to Response (TTR) [6]
    End point description
    TTR is defined as the time from the date of randomization to the date of first documented response of either CR or PR, by investigator's assessment according to RECIST 1.1 criteria. The TTR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. Subjects without a confirmed CR or PR at the time of the analysis cut-off date were censored at the study-maximum follow-up time for subjects with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last adequate tumor assessment for subjects without a PFS event. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    From randomization until first documented response or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approximately 18 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Randomized part: Time to definitive 10-point deterioration (TTD) symptom scores of chest pain, cough and dyspnea per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) Lung Cancer (LC13) questionnaire

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    End point title
    		 Randomized part: Time to definitive 10-point deterioration (TTD) symptom scores of chest pain, cough and dyspnea per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) Lung Cancer (LC13) questionnaire [7]
    End point description
    The EORTC QLQ-LC13 comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, dyspnea, and chest pain) and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie. hair loss, neuropathy, sore mouth, and dysphagia). Scores for each scale and single-item range from 0 to 100, with higher scores indicating higher level of symptoms. TTD for chest pain, cough and dyspnea is defined as the time from randomization to the date of event, which is defined as at least 10 points absolute worsening from baseline of the corresponding scale score, with no later change below this threshold ie.<10 points was observed or if this worsening was observed at the last assessment for the subject, or death due to any cause (whichever occurs earlier). If a subject did not have an event, TTD was censored at the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From baseline through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 18 months)
    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: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Months
    median (confidence interval 95%)
        Chest Pain
    7.23 (4.96 to 9999)
    13.14 (7.06 to 9999)
        Cough
    7.23 (5.09 to 9999)
    13.14 (7.85 to 9999)
        Dyspnea
    3.45 (2.14 to 4.83)
    4.27 (2.63 to 5.65)
    No statistical analyses for this end point

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

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    End point title
    		 Randomized part: Time to definitive 10-point deterioration in global health status (GHS)/quality of life (QoL), shortness of breath and pain per EORTC QLQ-C30 questionnaire [8]
    End point description
    The EORTC QLQ-C30 includes 5 functional scales (physical,role,cognitive,emotional and social), 3 symptom scales (fatigue,pain and nausea/vomiting), a GHS/QoL scale, and 6 single items (constipation,diarrhea,insomnia,shortness of breath,appetite loss and financial difficulties). For each scale and single-item, scores range between 0 and 100. A high score for functional scales/ GHS/QoL represents better functioning or QoL, a high score for symptom scales/single items represents significant symptomatology. TTD in GHS/QoL, shortness of breath and pain is defined as the time from randomization to the date of event, defined as at least 10 points absolute worsening from baseline of the corresponding scale score, with no later change below this threshold i.e.<10 points was observed or if this worsening was observed at the last assessment for the subject, or death due to any cause (whichever occurs earlier). If a subject did not have an event, TTD was censored at the last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From baseline through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 18 months)
    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: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Months
    median (confidence interval 95%)
        GHS/QOL
    4.83 (3.48 to 6.97)
    7.16 (4.80 to 13.14)
        Shortness of breath
    6.57 (4.60 to 7.89)
    5.78 (4.27 to 9999)
        Pain
    6.05 (4.47 to 7.72)
    8.54 (4.27 to 10.38)
    No statistical analyses for this end point

    Secondary: Randomized part: Change from baseline in GHS/QoL, shortness of breath and pain scores as per the EORTC QLQ C30 questionnaire

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    End point title
    		 Randomized part: Change from baseline in GHS/QoL, shortness of breath and pain scores as per the EORTC QLQ C30 questionnaire [9]
    End point description
    The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties). For each scale and single-item, scores range between 0 and 100. A high score for functional scales/ GHS/QoL represents better functioning ability or QoL; a high score for symptom scales/single items represents significant symptomatology. Changes from baseline in GHS/QoL, shortness of breath and pain scores are presented. For QoL, a negative change from baseline indicates improvement; for shortness of breath and pain a positive change from baseline indicates improvement. Post-treatment efficacy follow up visits were conducted every 6 weeks (for the first 12 months since start of treatment) or every 12 weeks (after 12 months since start of treatment)
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment and 7 and 28 days post disease progression through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 18 months)
    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: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Score on a scale
    arithmetic mean (standard deviation)
        GHS/QoL: Week 3
    -0.5 ( 18.34 )
    1.8 ( 21.51 )
        GHS/QoL: Week 6
    -3.3 ( 17.48 )
    1.4 ( 22.19 )
        GHS/QoL: Week 9
    -2.7 ( 20.04 )
    -0.4 ( 23.50 )
        GHS/QoL: Week 12
    -7.4 ( 19.75 )
    2.5 ( 22.14 )
        GHS/QoL: Week 15
    -2.9 ( 19.85 )
    -4.2 ( 22.60 )
        GHS/QoL: Week 18
    -3.9 ( 22.75 )
    2.8 ( 24.69 )
        GHS/QoL: Week 21
    -3.5 ( 25.31 )
    -4.2 ( 27.25 )
        GHS/QoL: Week 24
    -3.6 ( 16.08 )
    -0.7 ( 24.90 )
        GHS/QoL: Week 27
    -4.7 ( 16.25 )
    -2.2 ( 26.51 )
        GHS/QoL: Week 30
    -3.7 ( 19.43 )
    -5.7 ( 30.31 )
        GHS/QoL: Week 33
    -3.2 ( 15.79 )
    0.4 ( 31.82 )
        GHS/QoL: Week 36
    -4.5 ( 15.97 )
    3.3 ( 27.06 )
        GHS/QoL: Week 39
    -5.8 ( 18.02 )
    1.2 ( 28.28 )
        GHS/QoL: Week 42
    -9.2 ( 16.41 )
    2.8 ( 29.15 )
        GHS/QoL: Week 45
    -3.6 ( 16.57 )
    -3.5 ( 22.32 )
        GHS/QoL: Week 48
    -8.3 ( 19.72 )
    -13.9 ( 13.82 )
        GHS/QoL: Week 51
    -8.3 ( 16.67 )
    -6.7 ( 21.80 )
        GHS/QoL: Week 54
    -6.9 ( 17.01 )
    -4.8 ( 31.86 )
        GHS/QoL: Week 57
    -12.5 ( 14.43 )
    -8.3 ( 36.32 )
        GHS/QoL: Week 60
    -8.3 ( 22.05 )
    2.1 ( 38.71 )
        GHS/QoL: Week 63
    -5.6 ( 17.35 )
    2.8 ( 4.81 )
        GHS/QoL: Week 66
    8.3 ( 11.79 )
    -8.3 ( 11.79 )
        GHS/QoL: Week 69
    16.7 ( 9999 )
    0.0 ( 23.57 )
        GHS/QoL: Week 72
    9999 ( 9999 )
    -8.3 ( 11.79 )
        GHS/QoL: Week 75
    9999 ( 9999 )
    -16.7 ( 9999 )
        GHS/QoL: Week 78
    9999 ( 9999 )
    -16.7 ( 9999 )
        GHS/QoL: post treatment efficacy 1
    -16.7 ( 11.79 )
    5.6 ( 9.62 )
        GHS/QoL: post treatment efficacy 2
    -16.7 ( 16.67 )
    16.7 ( 9999 )
        GHS/QoL: post treatment efficacy 3
    9999 ( 9999 )
    -8.3 ( 23.57 )
        GHS/QoL: post treatment efficacy 5
    9999 ( 9999 )
    25.0 ( 9999 )
        GHS/QoL: 7 days post disease progression
    -7.5 ( 26.65 )
    -4.6 ( 22.11 )
        GHS/QoL: 28 days post disease progression
    -3.7 ( 29.60 )
    -7.8 ( 20.08 )
        Shortness of breath: Week 3
    31.2 ( 28.30 )
    31.7 ( 30.02 )
        Shortness of breath: Week 6
    7.3 ( 24.99 )
    4.0 ( 28.06 )
        Shortness of breath: Week 9
    6.7 ( 27.13 )
    5.7 ( 28.36 )
        Shortness of breath: Week 12
    12.2 ( 25.61 )
    4.4 ( 29.73 )
        Shortness of breath: Week 15
    7.8 ( 21.69 )
    7.3 ( 29.58 )
        Shortness of breath: Week 18
    8.5 ( 26.54 )
    3.5 ( 30.93 )
        Shortness of breath: Week 21
    34.2 ( 29.71 )
    29.8 ( 27.72 )
        Shortness of breath: Week 24
    4.8 ( 21.61 )
    6.9 ( 32.60 )
        Shortness of breath: Week 27
    13.0 ( 24.08 )
    -1.2 ( 36.38 )
        Shortness of breath: Week 30
    16.7 ( 20.61 )
    5.3 ( 38.10 )
        Shortness of breath: Week 33
    17.9 ( 22.01 )
    -1.7 ( 39.70 )
        Shortness of breath: Week 36
    9.1 ( 21.56 )
    -2.2 ( 32.04 )
        Shortness of breath: Week 39
    33.3 ( 27.22 )
    40.5 ( 26.73 )
        Shortness of breath: Week 42
    23.3 ( 27.44 )
    -6.7 ( 31.37 )
        Shortness of breath: Week 45
    9.5 ( 31.71 )
    8.3 ( 40.51 )
        Shortness of breath: Week 48
    22.2 ( 34.43 )
    3.7 ( 26.06 )
        Shortness of breath: Week 51
    16.7 ( 18.26 )
    0.0 ( 22.22 )
        Shortness of breath: Week 54
    11.1 ( 17.21 )
    9.5 ( 37.09 )
        Shortness of breath: Week 57
    8.3 ( 31.91 )
    20.0 ( 38.01 )
        Shortness of breath: Week 60
    0.0 ( 33.33 )
    16.7 ( 43.03 )
        Shortness of breath: Week 63
    0.0 ( 33.33 )
    0.0 ( 33.33 )
        Shortness of breath: Week 66
    -16.7 ( 23.57 )
    0.0 ( 47.14 )
        Shortness of breath: Week 69
    0.0 ( 9999 )
    -16.7 ( 70.71 )
        Shortness of breath: Week 72
    9999 ( 9999 )
    -16.7 ( 70.71 )
        Shortness of breath: Week 75
    9999 ( 9999 )
    33.3 ( 9999 )
        Shortness of breath: Week 78
    9999 ( 9999 )
    33.3 ( 9999 )
        Shortness of breath: post treatment efficacy 1
    33.3 ( 47.14 )
    33.3 ( 33.33 )
        Shortness of breath: post treatment efficacy 2
    0.0 ( 33.33 )
    0.0 ( 9999 )
        Shortness of breath: post treatment efficacy 3
    9999 ( 9999 )
    16.7 ( 23.57 )
        Shortness of breath: post treatment efficacy 5
    9999 ( 9999 )
    0.00 ( 9999 )
        Shortness of breath 7days postdisease progression
    8.6 ( 21.03 )
    8.0 ( 29.08 )
        Shortness of breath 28days postdisease progression
    3.7 ( 27.75 )
    15.7 ( 29.15 )
        Pain: Week 3
    -5.1 ( 21.07 )
    -2.0 ( 22.53 )
        Pain: Week 6
    -5.1 ( 20.33 )
    -1.6 ( 24.07 )
        Pain: Week 9
    -4.1 ( 19.33 )
    -3.1 ( 21.85 )
        Pain: Week 12
    2.2 ( 24.61 )
    -1.4 ( 27.32 )
        Pain: Week 15
    -0.7 ( 20.81 )
    0.7 ( 22.07 )
        Pain: Week 18
    2.3 ( 23.34 )
    0.7 ( 25.25 )
        Pain: Week 21
    3.3 ( 24.52 )
    0.0 ( 25.70 )
        Pain: Week 24
    25.2 ( 25.36 )
    19.1 ( 21.76 )
        Pain: Week 27
    1.4 ( 22.42 )
    1.2 ( 19.57 )
        Pain: Week 30
    2.8 ( 19.17 )
    4.0 ( 26.03 )
        Pain: Week 33
    -8.3 ( 19.46 )
    6.7 ( 21.22 )
        Pain: Week 36
    22.7 ( 17.12 )
    26.7 ( 23.40 )
        Pain: Week 39
    -10.0 ( 21.08 )
    10.7 ( 31.08 )
        Pain: Week 42
    -3.3 ( 10.54 )
    11.1 ( 30.65 )
        Pain: Week 45
    -11.9 ( 23.00 )
    15.3 ( 30.53 )
        Pain: Week 48
    -5.6 ( 22.77 )
    5.6 ( 20.41 )
        Pain: Week 51
    2.8 ( 24.53 )
    8.3 ( 18.00 )
        Pain: Week 54
    8.3 ( 20.41 )
    -2.4 ( 32.53 )
        Pain: Week 57
    0.0 ( 13.61 )
    6.7 ( 19.00 )
        Pain: Week 60
    16.7 ( 16.67 )
    0.0 ( 36.00 )
        Pain: Week 63
    5.6 ( 25.46 )
    -16.7 ( 16.7 )
        Pain: Week 66
    0.0 ( 0.00 )
    0.0 ( 0.00 )
        Pain: Week 69
    33.3 ( 9999 )
    8.3 ( 11.79 )
        Pain: Week 72
    9999 ( 9999 )
    0.0 ( 0.00 )
        Pain: Week 75
    9999 ( 9999 )
    0.0 ( 9999 )
        Pain: Week 78
    9999 ( 9999 )
    0.0 ( 9999 )
        Pain: post treatment efficacy 1
    -33.3 ( 23.57 )
    -11.1 ( 19.25 )
        Pain: post treatment efficacy 2
    0.0 ( 16.67 )
    0.0 ( 9999 )
        Pain: post treatment efficacy 3
    9999 ( 9999 )
    33.3 ( 0.00 )
        Pain: post treatment efficacy 5
    9999 ( 9999 )
    0.0 ( 9999 )
        Pain: 7 days post disease progression
    1.6 ( 18.44 )
    2.3 ( 31.41 )
        Pain: 28 days post disease progression
    9.3 ( 23.02 )
    13.7 ( 20.61 )
    No statistical analyses for this end point

    Secondary: Randomized part: Change from baseline in chest pain, cough and dyspnea scores as per the EORTC-QLQ LC13 questionnaire

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    End point title
    		 Randomized part: Change from baseline in chest pain, cough and dyspnea scores as per the EORTC-QLQ LC13 questionnaire [10]
    End point description
    The EORTC QLQ-LC13 is a 13-item questionnaire. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, dyspnea, and chest pain) and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores for each scale and single-item range from 0 to 100, with higher scores indicating higher ("worse") level of symptoms. Changes from baseline in chest pain, cough and dyspnea scores are presented. A positive change from baseline indicates improvement. Post-treatment efficacy follow up visits were conducted every 6 weeks (for the first 12 months since start of treatment) or every 12 weeks (after 12 months since start of treatment)
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment and 7 and 28 days post disease progression through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 18 months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Chest pain: Week 3
    -2.2 ( 16.24 )
    -3.2 ( 24.48 )
        Chest pain: Week 6
    0.4 ( 19.73 )
    -3.9 ( 24.89 )
        Chest pain: Week 9
    0.5 ( 19.09 )
    -3.8 ( 22.37 )
        Chest pain: Week 12
    1.1 ( 23.16 )
    -3.3 ( 24.32 )
        Chest pain: Week 15
    0.7 ( 25.38 )
    -0.7 ( 24.05 )
        Chest pain: Week 18
    0.7 ( 21.59 )
    -4.1 ( 26.90 )
        Chest pain: Week 21
    2.5 ( 26.57 )
    0.9 ( 18.15 )
        Chest pain: Week 24
    1.9 ( 21.30 )
    -1.0 ( 17.38 )
        Chest pain: Week 27
    2.9 ( 19.88 )
    6.2 ( 27.79 )
        Chest pain: Week 30
    3.7 ( 19.43 )
    6.7 ( 23.57 )
        Chest pain: Week 33
    -5.1 ( 18.49 )
    0.0 ( 15.71 )
        Chest pain: Week 36
    -9.1 ( 15.57 )
    0.0 ( 21.82 )
        Chest pain: Week 39
    0.0 ( 22.22 )
    9.5 ( 30.46 )
        Chest pain: Week 42
    0.0 ( 15.71 )
    0.0 ( 17.82 )
        Chest pain: Week 45
    0.0 ( 19.25 )
    8.3 ( 15.08 )
        Chest pain: Week 48
    0.0 ( 21.08 )
    11.1 ( 16.67 )
        Chest pain: Week 51
    0.0 ( 21.08 )
    10.0 ( 22.50 )
        Chest pain: Week 54
    0.0 ( 21.08 )
    9.5 ( 31.71 )
        Chest pain: Week 57
    0.0 ( 0.00 )
    20.0 ( 18.26 )
        Chest pain: Week 60
    -11.1 ( 19.25 )
    25.0 ( 16.67 )
        Chest pain: Week 63
    0.0 ( 33.33 )
    0.0 ( 0.00 )
        Chest pain: Week 66
    0.0 ( 47.14 )
    0.0 ( 0.00 )
        Chest pain: Week 69
    0.0 ( 9999 )
    0.0 ( 0.00 )
        Chest pain: Week 72
    9999 ( 9999 )
    0.0 ( 0.00 )
        Chest pain: Week 75
    9999 ( 9999 )
    0.0 ( 9999 )
        Chest pain: Week 78
    9999 ( 9999 )
    33.3 ( 9999 )
        Chest pain: Efficacy follow-up visit 1
    0.0 ( 0.00 )
    -22.2 ( 19.25 )
        Chest pain: Efficacy follow-up visit 2
    11.1 ( 19.25 )
    0.0 ( 9999 )
        Chest pain: Efficacy follow-up visit 3
    9999 ( 9999 )
    16.7 ( 23.57 )
        Chest pain: Efficacy follow-up visit 5
    9999 ( 9999 )
    0.0 ( 9999 )
        Chest pain: 7 days post disease progression
    5.4 ( 17.42 )
    -5.7 ( 21.95 )
        Chest pain: 28 days post disease progression
    14.8 ( 26.13 )
    -2.1 ( 25.73 )
        Coughing: Week 3
    0.0 ( 21.54 )
    -3.2 ( 24.03 )
        Coughing: Week 6
    3.0 ( 26.42 )
    -4.7 ( 27.77 )
        Coughing: Week 9
    2.6 ( 32.44 )
    0.5 ( 25.69 )
        Coughing: Week 12
    4.8 ( 33.79 )
    0.0 ( 26.75 )
        Coughing: Week 15
    2.0 ( 27.82 )
    -0.7 ( 24.05 )
        Coughing: Week 18
    -1.3 ( 26.63 )
    0.0 ( 31.18 )
        Coughing: Week 21
    -4.2 ( 30.37 )
    -4.4 ( 28.13 )
        Coughing: Week 24
    -1.0 ( 31.81 )
    -3.9 ( 24.29 )
        Coughing: Week 27
    -4.3 ( 25.23 )
    -1.2 ( 28.47 )
        Coughing: Week 30
    -5.6 ( 36.60 )
    -4.0 ( 26.03 )
        Coughing: Week 33
    2.6 ( 16.45 )
    -3.5 ( 26.98 )
        Coughing: Week 36
    12.1 ( 16.82 )
    -6.7 ( 28.73 )
        Coughing: Week 39
    3.3 ( 18.92 )
    -4.8 ( 25.68 )
        Coughing: Week 42
    6.7 ( 26.29 )
    -8.9 ( 29.46 )
        Coughing: Week 45
    0.0 ( 19.25 )
    2.8 ( 17.16 )
        Coughing: Week 48
    11.1 ( 17.21 )
    3.7 ( 20.03 )
        Coughing: Week 51
    16.7 ( 18.26 )
    -3.3 ( 18.92 )
        Coughing: Week 54
    16.7 ( 18.26 )
    -4.8 ( 23.00 )
        Coughing: Week 57
    -8.3 ( 16.67 )
    6.7 ( 27.89 )
        Coughing: Week 60
    0.0 ( 0.00 )
    -8.3 ( 31.91 )
        Coughing: Week 63
    0.0 ( 0.00 )
    -11.1 ( 19.25 )
        Coughing: Week 66
    -16.7 ( 23.57 )
    -16.7 ( 23.57 )
        Coughing: Week 69
    0.0 ( 9999 )
    -33.3 ( 47.14 )
        Coughing: Week 72
    9999 ( 9999 )
    -33.3 ( 47.14 )
        Coughing: Week 75
    9999 ( 9999 )
    0.0 ( 9999 )
        Coughing: Week 78
    9999 ( 9999 )
    0.0 ( 9999 )
        Coughing: Efficacy follow-up visit 1
    0.0 ( 0.00 )
    0.0 ( 0.00 )
        Coughing: Efficacy follow-up visit 2
    -22.2 ( 19.25 )
    33.3 ( 9999 )
        Coughing: Efficacy follow-up visit 3
    9999 ( 9999 )
    -16.7 ( 23.57 )
        Coughing: Efficacy follow-up visit 5
    9999 ( 9999 )
    0.0 ( 9999 )
        Coughing: 7 days post disease progression
    -1.1 ( 25.07 )
    3.4 ( 31.30 )
        Coughing: 28 days post disease progression
    -3.7 ( 27.75 )
    -4.2 ( 31.91 )
        Dyspnea: Week 3
    4.8 ( 17.84 )
    2.9 ( 18.47 )
        Dyspnea: Week 6
    4.4 ( 16.83 )
    5.0 ( 19.59 )
        Dyspnea: Week 9
    4.8 ( 19.44 )
    5.2 ( 20.17 )
        Dyspnea: Week 12
    7.4 ( 19.25 )
    6.9 ( 20.57 )
        Dyspnea: Week 15
    6.5 ( 16.66 )
    10.9 ( 21.69 )
        Dyspnea: Week 18
    10.2 ( 19.98 )
    4.3 ( 22.43 )
        Dyspnea: Week 21
    8.9 ( 19.36 )
    6.7 ( 21.07 )
        Dyspnea: Week 24
    7.9 ( 23.89 )
    9.2 ( 20.19 )
        Dyspnea: Week 27
    10.1 ( 21.43 )
    8.6 ( 20.52 )
        Dyspnea: Week 30
    8.0 ( 14.66 )
    8.0 ( 21.40 )
        Dyspnea: Week 33
    13.7 ( 17.66 )
    7.0 ( 22.89 )
        Dyspnea: Week 36
    12.1 ( 22.47 )
    7.4 ( 21.28 )
        Dyspnea: Week 39
    14.4 ( 16.60 )
    10.3 ( 25.21 )
        Dyspnea: Week 42
    20.0 ( 27.62 )
    3.0 ( 23.18 )
        Dyspnea: Week 45
    20.6 ( 26.00 )
    13.0 ( 20.56 )
        Dyspnea: Week 48
    20.4 ( 30.97 )
    14.8 ( 13.61 )
        Dyspnea: Week 51
    22.2 ( 29.81 )
    7.8 ( 15.76 )
        Dyspnea: Week 54
    22.2 ( 26.29 )
    12.7 ( 13.50 )
        Dyspnea: Week 57
    19.4 ( 31.91 )
    11.1 ( 11.11 )
        Dyspnea: Week 60
    25.9 ( 44.91 )
    -2.8 ( 24.64 )
        Dyspnea: Week 63
    18.5 ( 44.91 )
    -3.7 ( 12.83 )
        Dyspnea: Week 66
    -11.1 ( 15.71 )
    0.0 ( 15.71 )
        Dyspnea: Week 69
    -22.2 ( 9999 )
    -11.1 ( 47.14 )
        Dyspnea: Week 72
    9999 ( 9999 )
    -11.1 ( 47.14 )
        Dyspnea: Week 75
    9999 ( 9999 )
    22.2 ( 9999 )
        Dyspnea: Week 78
    9999 ( 9999 )
    22.2 ( 9999 )
        Dyspnea: Efficacy follow-up visit 1
    16.7 ( 23.57 )
    3.7 ( 16.97 )
        Dyspnea: Efficacy follow-up visit 2
    -3.7 ( 44.91 )
    22.2 ( 9999 )
        Dyspnea: Efficacy follow-up visit 3
    9999 ( 9999 )
    16.7 ( 7.86 )
        Dyspnea: Efficacy follow-up visit 5
    9999 ( 9999 )
    -11.1 ( 9999 )
        Dyspnea: 7 days post disease progression
    5.0 ( 17.88 )
    2.3 ( 20.22 )
        Dyspnea: 28 days post disease progression
    3.7 ( 16.61 )
    10.4 ( 19.23 )
    No statistical analyses for this end point

    Secondary: Randomized part: Change from baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Health State Scores

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    End point title
    		 Randomized part: Change from baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Health State Scores [11]
    End point description
    The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment and 7 and 28 days post disease progression through final analysis data cutoff date of 08-Jan-2021 (assessed up to approximately 18 months)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    120
    117
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 3
    -0.017 ( 0.1960 )
    -0.007 ( 0.1731 )
        Week 6
    -0.016 ( 0.1972 )
    0.001 ( 0.2283 )
        Week 9
    -0.006 ( 0.1759 )
    0.011 ( 0.1865 )
        Week 12
    -0.028 ( 0.1849 )
    0.014 ( 0.2315 )
        Week 15
    -0.057 ( 0.2229 )
    -0.042 ( 0.1827 )
        Week 18
    -0.062 ( 0.1835 )
    0.009 ( 0.2810 )
        Week 21
    -0.097 ( 0.2234 )
    0.005 ( 0.1952 )
        Week 24
    -0.070 ( 0.2075 )
    0.027 ( 0.1900 )
        Week 27
    -0.043 ( 0.1820 )
    0.008 ( 0.2272 )
        Week 30
    -0.023 ( 0.2378 )
    -0.014 ( 0.2068 )
        Week 33
    -0.031 ( 0.2148 )
    0.029 ( 0.2361 )
        Week 36
    0.017 ( 0.1942 )
    0.050 ( 0.2743 )
        Week 39
    -0.007 ( 0.1898 )
    -0.012 ( 0.2842 )
        Week 42
    -0.010 ( 0.2286 )
    0.116 ( 0.2180 )
        Week 45
    0.017 ( 0.1866 )
    -0.036 ( 0.1801 )
        Week 48
    -0.087 ( 0.3178 )
    0.003 ( 0.2424 )
        Week 51
    -0.151 ( 0.2663 )
    0.071 ( 0.2197 )
        Week 54
    -0.102 ( 0.3527 )
    0.056 ( 0.2011 )
        Week 57
    0.476 ( 0.2190 )
    0.652 ( 0.1308 )
        Week 60
    -0.193 ( 0.3653 )
    0.149 ( 0.1616 )
        Week 63
    -0.140 ( 0.3435 )
    0.165 ( 0.1717 )
        Week 66
    0.034 ( 0.0481 )
    0.124 ( 0.0085 )
        Week 69
    0.000 ( 9999 )
    0.340 ( 0.1230 )
        Week 72
    9999 ( 9999 )
    0.168 ( 0.0530 )
        Week 75
    9999 ( 9999 )
    0.130 ( 9999 )
        Week 78
    9999 ( 9999 )
    0.130 ( 9999 )
        Efficacy follow-up visit 1
    0.100 ( 0.0955 )
    -0.026 ( 0.0368 )
        Efficacy follow-up visit 2
    0.644 ( 0.1749 )
    0.704 ( 9999 )
        Efficacy follow-up visit 3
    9999 ( 9999 )
    0.601 ( 0.0990 )
        Efficacy follow-up visit 5
    9999 ( 9999 )
    1.000 ( 9999 )
        7 days post disease progression
    0.639 ( 0.2558 )
    0.657 ( 0.2654 )
        28 days post disease progression
    0.692 ( 0.1633 )
    0.692 ( 0.2149 )
    No statistical analyses for this end point

    Secondary: Safety run-in part: Maximum plasma concentration (Cmax) of canakinumab

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    End point title
    		 Safety run-in part: Maximum plasma concentration (Cmax) of canakinumab [12]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. Cmax of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    6
    Units: microgram/milliliter (ug/mL)
        geometric mean (geometric coefficient of variation)
    13.4 ( 29.9 )
    No statistical analyses for this end point

    Secondary: Safety run-in part: Time of maximum plasma concentration (Tmax) of canakinumab

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    End point title
    		 Safety run-in part: Time of maximum plasma concentration (Tmax) of canakinumab [13]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. Tmax of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    6
    Units: Hours (h)
        median (full range (min-max))
    169 (48.2 to 336)
    No statistical analyses for this end point

    Secondary: Safety run-in part: Area Under the plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of canakinumab

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    End point title
    		 Safety run-in part: Area Under the plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of canakinumab [14]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. AUClast of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days
    Notes
    [14] - 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: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    6
    Units: hour*microgram/mililiter (hr*ug/mL)
        geometric mean (geometric coefficient of variation)
    5470 ( 30.5 )
    No statistical analyses for this end point

    Secondary: Safety run-in part: Cmax of docetaxel

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    End point title
    		 Safety run-in part: Cmax of docetaxel [15]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. Cmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days
    Notes
    [15] - 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: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    8
    Units: nanogram/miliLiter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    476 ( 182.5 )
        Cycle 2 Day 1
    1630 ( 117.2 )
    No statistical analyses for this end point

    Secondary: Safety run-in part: Tmax of docetaxel

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    End point title
    		 Safety run-in part: Tmax of docetaxel [16]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. Tmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    8
    Units: Hour (hr)
    median (full range (min-max))
        Cycle 1 Day 1
    1.08 (0.917 to 6.12)
        Cycle 2 Day 1
    1.00 (0.917 to 1.00)
    No statistical analyses for this end point

    Secondary: Safety run-in part: AUClast of docetaxel

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    End point title
    		 Safety run-in part: AUClast of docetaxel [17]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. AUClast of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the safety run-in part only. Arms of the randomized part are not included in this analysis
    End point values
    		 Safety run-in part: Canakinumab+docetaxel
    Number of subjects analysed
    8
    Units: Hour *nanogram/miliLiter (hr*ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    884 ( 70.8 )
        Cycle 2 Day 1
    2120 ( 86.5 )
    No statistical analyses for this end point

    Secondary: Randomized part: Pre-dose plasma trough concentration (CTrough) of canakinumab

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    End point title
    		 Randomized part: Pre-dose plasma trough concentration (CTrough) of canakinumab [18]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. CTrough of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1 and Cycle 18 Day 1 through final analysis data cutoff date of 08-Jan-2021. Each cycle is 21 days.
    Notes
    [18] - 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: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel
    Number of subjects analysed
    112
    Units: microgram/miliLiter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 4 Day 1
    20.5 ( 36.6 )
        Cycle 6 Day 1
    23.7 ( 32.3 )
        Cycle 12 Day 1
    25.6 ( 56.7 )
        Cycle 18 Day 1
    28.3 ( 118.0 )
    No statistical analyses for this end point

    Secondary: Randomized part: Cmax of docetaxel

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    End point title
    		 Randomized part: Cmax of docetaxel [19]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. Cmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    31
    29
    Units: nanogram/miliLiter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    1570 ( 116.3 )
    1190 ( 265.3 )
        Cycle 4 Day 1
    1530 ( 118.7 )
    940 ( 215.8 )
    No statistical analyses for this end point

    Secondary: Randomized part: Tmax of docetaxel

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    End point title
    		 Randomized part: Tmax of docetaxel [20]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. Tmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days
    Notes
    [20] - 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: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    31
    29
    Units: Hour
    median (full range (min-max))
        Cycle 1 Day 1
    1.09 (0.517 to 5.83)
    1.10 (0.933 to 6.08)
        Cycle 4 Day 1
    1.15 (0.0833 to 3.83)
    1.08 (1.00 to 1.42)
    No statistical analyses for this end point

    Secondary: Randomized part: AUClast of docetaxel

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    End point title
    		 Randomized part: AUClast of docetaxel [21]
    End point description
    Venous whole blood samples were collected for pharmacokinetics characterization. AUClast of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    31
    29
    Units: hour*nanogram/miliLiter (h*ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    2530 ( 79.3 )
    1790 ( 157.4 )
        Cycle 4 Day 1
    2210 ( 66.4 )
    1530 ( 130.9 )
    No statistical analyses for this end point

    Secondary: Randomized part: Canakinumab Antidrug antibodies (ADA) at baseline

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    End point title
    		 Randomized part: Canakinumab Antidrug antibodies (ADA) at baseline [22]
    End point description
    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
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel
    Number of subjects analysed
    120
    Units: Participants
    1
    No statistical analyses for this end point

    Secondary: Randomized part: Canakinumab ADA incidence on-treatment

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    End point title
    		 Randomized part: Canakinumab ADA incidence on-treatment [23]
    End point description
    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 is at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    Pre-dose at Cycle 1 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1 , end of treatment, and 130 days after end of treatment through final analysis data cutoff date of 08-Jan-2021 (assessed up to 18 months). Each cycle is 21 days
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint refers to the randomized part only. The arm of the safety run-in part is not included in this analysis
    End point values
    		 Randomized part: Canakinumab + docetaxel
    Number of subjects analysed
    120
    Units: Participants
    0
    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 screening to the first day of treatment, for a maximum duration of 28 days. On-treatment deaths due to any cause were collected from first dose of study treatment to 130 days after the last dose of study treatment. Post-treatment deaths were collected from day 131 after last dose of study treatment to end of study. All deaths refer to the sum of pre-treatment, on-treatment and post-treatment deaths.
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment: up to 28 days before Day 1;On-treatment: up to approximately 10 months (safety run-in) or 25 months (randomized); All deaths: Up to approximately 16 months (safety run in) or 25 months (randomized)
    End point values
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab + docetaxel Randomized part: Placebo + docetaxel
    Number of subjects analysed
    8
    120
    117
    Units: Participants
        Pre-treatment deaths
    0
    0
    1
        On-treatment deaths
    6
    45
    37
        Post-treatment deaths
    2
    40
    38
        All deaths
    8
    85
    76
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first administration of study treatment to 130 days after date of last administration, up to approximately 10 months (safety run-in part) or 25 months (randomized part)
    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
    23.1
    Reporting groups
    Reporting group title
    Safety run-in part: Canakinumab+docetaxel
    Reporting group description
    		 Participants were treated with full doses of docetaxel 75mg/m^2 intravenous and canakinumab 200 mg subcutaneous on Day 1 of each 21-Day cycle (dose level 1).

    Reporting group title
    Randomized part: Canakinumab+Docetaxel
    Reporting group description
    		 Participants were randomized to receive canakinumab subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle

    Reporting group title
    Randomized part: Placebo+Docetaxel
    Reporting group description
    		 Participants were randomized to receive placebo subcutaneous at RP3R and docetaxel at 75 mg/m^2 on Day 1 of each 21-Day cycle

    Serious adverse events
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab+Docetaxel Randomized part: Placebo+Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    55 / 120 (45.83%)
    50 / 114 (43.86%)
         number of deaths (all causes)
    6
    45
    37
         number of deaths resulting from adverse events
    1
    3
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    6 / 120 (5.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 120 (3.33%)
    5 / 114 (4.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 120 (2.50%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    3 / 114 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 120 (2.50%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    6 / 120 (5.00%)
    8 / 114 (7.02%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 120 (3.33%)
    5 / 114 (4.39%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestine ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    3 / 114 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 8 (25.00%)
    13 / 120 (10.83%)
    8 / 114 (7.02%)
         occurrences causally related to treatment / all
    0 / 2
    6 / 13
    2 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 120 (2.50%)
    4 / 114 (3.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 120 (1.67%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 120 (2.50%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    Spinal cord infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    4 / 114 (3.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulvovaginitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety run-in part: Canakinumab+docetaxel Randomized part: Canakinumab+Docetaxel Randomized part: Placebo+Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    111 / 120 (92.50%)
    109 / 114 (95.61%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    2 / 114 (1.75%)
         occurrences all number
    1
    0
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    6 / 120 (5.00%)
    5 / 114 (4.39%)
         occurrences all number
    1
    8
    6
    Phlebitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 8 (25.00%)
    28 / 120 (23.33%)
    37 / 114 (32.46%)
         occurrences all number
    4
    36
    54
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    5 / 120 (4.17%)
    10 / 114 (8.77%)
         occurrences all number
    0
    5
    13
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    33 / 120 (27.50%)
    19 / 114 (16.67%)
         occurrences all number
    1
    44
    23
    Influenza like illness
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 120 (0.83%)
    3 / 114 (2.63%)
         occurrences all number
    2
    1
    3
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    7 / 114 (6.14%)
         occurrences all number
    0
    8
    10
    Mucosal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 120 (3.33%)
    12 / 114 (10.53%)
         occurrences all number
    0
    4
    13
    Oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 120 (4.17%)
    2 / 114 (1.75%)
         occurrences all number
    1
    5
    2
    Oedema peripheral
         subjects affected / exposed
    3 / 8 (37.50%)
    22 / 120 (18.33%)
    25 / 114 (21.93%)
         occurrences all number
    3
    26
    33
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    14 / 120 (11.67%)
    18 / 114 (15.79%)
         occurrences all number
    1
    20
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    16 / 120 (13.33%)
    19 / 114 (16.67%)
         occurrences all number
    2
    17
    23
    Dyspnoea
         subjects affected / exposed
    2 / 8 (25.00%)
    27 / 120 (22.50%)
    26 / 114 (22.81%)
         occurrences all number
    2
    28
    28
    Dyspnoea exertional
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 120 (2.50%)
    5 / 114 (4.39%)
         occurrences all number
    1
    3
    5
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    5 / 120 (4.17%)
    6 / 114 (5.26%)
         occurrences all number
    0
    6
    6
    Haemoptysis
         subjects affected / exposed
    1 / 8 (12.50%)
    10 / 120 (8.33%)
    10 / 114 (8.77%)
         occurrences all number
    2
    12
    18
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 120 (3.33%)
    6 / 114 (5.26%)
         occurrences all number
    1
    5
    6
    Productive cough
         subjects affected / exposed
    1 / 8 (12.50%)
    6 / 120 (5.00%)
    3 / 114 (2.63%)
         occurrences all number
    1
    6
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 120 (4.17%)
    2 / 114 (1.75%)
         occurrences all number
    1
    6
    2
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 120 (5.83%)
    8 / 114 (7.02%)
         occurrences all number
    1
    7
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    3 / 114 (2.63%)
         occurrences all number
    0
    8
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    0 / 114 (0.00%)
         occurrences all number
    0
    7
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 120 (4.17%)
    6 / 114 (5.26%)
         occurrences all number
    2
    5
    9
    Haemoglobin decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 120 (0.83%)
    2 / 114 (1.75%)
         occurrences all number
    1
    1
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    17 / 120 (14.17%)
    11 / 114 (9.65%)
         occurrences all number
    0
    27
    34
    SARS-CoV-2 test negative
         subjects affected / exposed
    0 / 8 (0.00%)
    10 / 120 (8.33%)
    13 / 114 (11.40%)
         occurrences all number
    0
    10
    14
    White blood cell count decreased
         subjects affected / exposed
    2 / 8 (25.00%)
    12 / 120 (10.00%)
    8 / 114 (7.02%)
         occurrences all number
    3
    24
    15
    Weight decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    9 / 120 (7.50%)
    8 / 114 (7.02%)
         occurrences all number
    1
    9
    9
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 120 (0.83%)
    2 / 114 (1.75%)
         occurrences all number
    1
    1
    2
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    8 / 120 (6.67%)
    3 / 114 (2.63%)
         occurrences all number
    0
    8
    5
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    8 / 120 (6.67%)
    6 / 114 (5.26%)
         occurrences all number
    0
    11
    7
    Neuropathy peripheral
         subjects affected / exposed
    1 / 8 (12.50%)
    9 / 120 (7.50%)
    15 / 114 (13.16%)
         occurrences all number
    1
    9
    23
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    12 / 120 (10.00%)
    8 / 114 (7.02%)
         occurrences all number
    0
    12
    11
    Taste disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 120 (0.83%)
    0 / 114 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    32 / 120 (26.67%)
    33 / 114 (28.95%)
         occurrences all number
    1
    47
    41
    Leukopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    6 / 120 (5.00%)
    15 / 114 (13.16%)
         occurrences all number
    2
    7
    39
    Neutropenia
         subjects affected / exposed
    2 / 8 (25.00%)
    22 / 120 (18.33%)
    25 / 114 (21.93%)
         occurrences all number
    2
    28
    42
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 120 (5.83%)
    4 / 114 (3.51%)
         occurrences all number
    1
    8
    4
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    22 / 120 (18.33%)
    24 / 114 (21.05%)
         occurrences all number
    0
    23
    33
    Diarrhoea
         subjects affected / exposed
    3 / 8 (37.50%)
    41 / 120 (34.17%)
    31 / 114 (27.19%)
         occurrences all number
    3
    68
    45
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    0 / 114 (0.00%)
         occurrences all number
    0
    7
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    28 / 120 (23.33%)
    29 / 114 (25.44%)
         occurrences all number
    1
    40
    36
    Odynophagia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 120 (0.83%)
    1 / 114 (0.88%)
         occurrences all number
    1
    1
    1
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    9 / 120 (7.50%)
    6 / 114 (5.26%)
         occurrences all number
    0
    9
    12
    Vomiting
         subjects affected / exposed
    2 / 8 (25.00%)
    15 / 120 (12.50%)
    14 / 114 (12.28%)
         occurrences all number
    2
    23
    15
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 8 (12.50%)
    31 / 120 (25.83%)
    44 / 114 (38.60%)
         occurrences all number
    1
    31
    45
    Dry skin
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 120 (3.33%)
    7 / 114 (6.14%)
         occurrences all number
    0
    4
    7
    Nail disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    8 / 114 (7.02%)
         occurrences all number
    0
    7
    11
    Night sweats
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    10 / 120 (8.33%)
    9 / 114 (7.89%)
         occurrences all number
    0
    10
    9
    Psoriasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    1
    0
    1
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    12 / 120 (10.00%)
    10 / 114 (8.77%)
         occurrences all number
    0
    15
    11
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    11 / 120 (9.17%)
    10 / 114 (8.77%)
         occurrences all number
    0
    12
    11
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    8 / 120 (6.67%)
    6 / 114 (5.26%)
         occurrences all number
    1
    10
    7
    Muscular weakness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 120 (0.83%)
    6 / 114 (5.26%)
         occurrences all number
    0
    1
    6
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    9 / 120 (7.50%)
    9 / 114 (7.89%)
         occurrences all number
    0
    10
    11
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    6 / 120 (5.00%)
    7 / 114 (6.14%)
         occurrences all number
    0
    6
    10
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 120 (3.33%)
    3 / 114 (2.63%)
         occurrences all number
    2
    4
    3
    Folliculitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    1 / 114 (0.88%)
         occurrences all number
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 120 (4.17%)
    2 / 114 (1.75%)
         occurrences all number
    1
    7
    2
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    4 / 114 (3.51%)
         occurrences all number
    0
    7
    4
    Respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    7 / 120 (5.83%)
    3 / 114 (2.63%)
         occurrences all number
    1
    11
    8
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    5 / 120 (4.17%)
    6 / 114 (5.26%)
         occurrences all number
    0
    7
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    8 / 120 (6.67%)
    7 / 114 (6.14%)
         occurrences all number
    0
    9
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    32 / 120 (26.67%)
    31 / 114 (27.19%)
         occurrences all number
    0
    41
    37
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    5 / 114 (4.39%)
         occurrences all number
    0
    9
    12
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    8 / 120 (6.67%)
    7 / 114 (6.14%)
         occurrences all number
    0
    9
    8
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 120 (5.83%)
    7 / 114 (6.14%)
         occurrences all number
    0
    7
    9
    Steroid diabetes
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 120 (0.00%)
    0 / 114 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2019
    The primary purpose of this amendment was to revise some eligibility criteria either for clarification purpose or in order to allow more flexibility for the enrollment/randomization. In addition, guidelines for dose modifications for canakinumab and follow up on potential DILI were updated based on the new Novartis Hepatotoxicity Clinical safety Guidelines (2018)
    10 Jun 2020
    The primary purpose of this amendment was that if OS meets statistical significance at either the interim analysis or the final analysis and the study was unblinded, all subjects on study treatment were allowed to enter into an OLE, irrespective of the treatment arm assignment, and receive open label drug canakinumab

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 9999 as data points in this record are not an accurate representation of the clinical trial results
    For support, Contact us.
    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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