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    Clinical Trial Results:
    VISION: An international, prospective, open label, multicenter, randomized Phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC)

    Summary
    EudraCT number
    		 2018-000459-41
    Trial protocol
    		 GB   DE   SE   FR   DK   NL   BE  
    Global end of trial date
    14 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2024
    First version publication date
    28 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PSMA-617-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03511664
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Novartis: CAAA617A12301
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.
    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
    29 May 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    France: 70
    Country: Number of subjects enrolled
    Netherlands: 38
    Country: Number of subjects enrolled
    Sweden: 33
    Country: Number of subjects enrolled
    United Kingdom: 47
    Country: Number of subjects enrolled
    United States: 553
    Country: Number of subjects enrolled
    Germany: 30
    Worldwide total number of subjects
    861
    EEA total number of subjects
    212
    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)
    217
    From 65 to 84 years
    630
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 86 sites across 9 countries. Belgium (3); Canada (7); Denmark (3); France (6); Netherlands (4); Sweden (5); UK (9); US (45); Germany (4, for the sub-study only)

    Pre-assignment
    Screening details
    		 Screening period of up to 28 days before starting randomized treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Participants in the Main Study were randomized in a 2:1 ratio to receive either 177Lu-PSMA-617 plus BSC/BSOC or BSC/BSOC only. The sub-study was conducted in a non-randomized cohort (AAA617+ BSC/BSOC)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC
    Arm description
    		 Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used
    Arm type
    		 Experimental

    Investigational medicinal product name
    Best supportive/best standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet, Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous use, Oral use, Other use
    Dosage and administration details
    Best supportive/best standard of care as defined by the local investigator

    Investigational medicinal product name
    177Lu-PSMA-617
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously once every 6 weeks (1 cycle) for a maximum of 6 cycles. After 4 cycles, patients were assessed for (1) evidence of response, (2) residual disease, and (3) tolerance to 177Lu-PSMA-617. If all 3 assessments were met the patient might received an additional 2 cycles of 177Lu-PSMA-617.

    Arm title
    		 Main Study: BS/BSOC alone
    Arm description
    		 Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
    Arm type
    		 Best supportive/best standard of care

    Investigational medicinal product name
    Best supportive/best standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet, Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous use, Oral use, Other use
    Dosage and administration details
    Best supportive/best standard of care as defined by the local investigator

    Arm title
    		 Sub Study: 177Lu-PSMA-617 + BS/BSOC
    Arm description
    		 non-randomized cohort (AAA617+ BSC/BSoC) at sites in Germany to provide a more complete assessment of the safety aspects of AAA617. Patients were treated and followed up similarly to the AAA617+BSC/BSOC (investigational arm) patients in the main study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Best supportive/best standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet, Radiopharmaceutical precursor, solution
    Routes of administration
    Intravenous use, Oral use, Other use
    Dosage and administration details
    Best supportive/best standard of care as defined by the local investigator

    Investigational medicinal product name
    177Lu-PSMA-617
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously once every 6 weeks (1 cycle) for a maximum of 6 cycles. After 4 cycles, patients were assessed for (1) evidence of response, (2) residual disease, and (3) tolerance to 177Lu-PSMA-617. If all 3 assessments were met the patient might received an additional 2 cycles of 177Lu-PSMA-617.

    Number of subjects in period 1
    		Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone Sub Study: 177Lu-PSMA-617 + BS/BSOC
    Started
    551
    280
    30
    FAS Safety Analysis Set
    529
    205
    30
    PFS-FAS Analysis Set
    385
    196
    0 [1]
    Response Evaluable Analysis Set
    319
    120
    0 [2]
    Completed
    28
    6
    4
    Not completed
    523
    274
    26
         Adverse event, serious fatal
    457
    201
    21
         Physician decision
    2
    1
    -
         Other protocol pre-specified reasons for d/c
    15
    4
    2
         Patient non-compliance
    1
    -
    -
         Withdrew consent
    40
    63
    3
         Lost to follow-up
    8
    5
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only apply to the Main Study
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only apply to the Main Study

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main Study: 177Lu-PSMA-617 + BS/BSOC
    Reporting group description
    		 Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used

    Reporting group title
    Main Study: BS/BSOC alone
    Reporting group description
    		 Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator

    Reporting group title
    Sub Study: 177Lu-PSMA-617 + BS/BSOC
    Reporting group description
    		 non-randomized cohort (AAA617+ BSC/BSoC) at sites in Germany to provide a more complete assessment of the safety aspects of AAA617. Patients were treated and followed up similarly to the AAA617+BSC/BSOC (investigational arm) patients in the main study

    Reporting group values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone Sub Study: 177Lu-PSMA-617 + BS/BSOC Total
    Number of subjects
    		 551 280 30 861
    Age Categorical
    Units: Participants
        < 65 years
    		 145 60 12 217
        ≥ 65-84 years
    		 398 214 18 630
        ≥ 85 years
    		 8 6 0 14
    Sex: Female, Male
    Units: Participants
        Female
    		 0 0 0 0
        Male
    		 551 280 30 861
    Race/Ethnicity, Customized
    Race 'Other' included Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native and more than one race reported.
    Units: Subjects
        White
    		 486 235 30 751
        Black or African American
    		 34 21 0 55
        Asian
    		 9 11 0 20
        Other
    		 2 0 0 2
        Missing
    		 20 13 0 33

    End points

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    End points reporting groups
    Reporting group title
    Main Study: 177Lu-PSMA-617 + BS/BSOC
    Reporting group description
    		 Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used

    Reporting group title
    Main Study: BS/BSOC alone
    Reporting group description
    		 Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator

    Reporting group title
    Sub Study: 177Lu-PSMA-617 + BS/BSOC
    Reporting group description
    		 non-randomized cohort (AAA617+ BSC/BSoC) at sites in Germany to provide a more complete assessment of the safety aspects of AAA617. Patients were treated and followed up similarly to the AAA617+BSC/BSOC (investigational arm) patients in the main study

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [1]
    End point description
    Overall Survival (OS) was defined as the time (in months) from the date of randomization to the date of death due to any cause. If the patient was not known to have died, then OS was censored. The censoring date was date of the last study visit, or contact, until the cut-off date. The cut-off date was not used for last contact date, unless the patient was seen or contacted on that date. Final OS was analyzed at the time of Primary analysis (Primary Analysis cut-off date = 27-Jan-2021) and an updated descriptive analysis of OS was re-run at the time of final analysis (Final Analysis cut-off date 14-Dec-2023).
    End point type
    Primary
    End point timeframe
    From date of randomization until date of death from any cause, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021) and up to 66 months (Final Analysis cut-off date = 14-Dec-2023)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    551
    280
    Units: Months
    median (confidence interval 95%)
        Primary OS Analysis
    15.3 (14.2 to 16.9)
    11.3 (9.8 to 13.5)
        Final OS analysis
    15.3 (14.2 to 16.9)
    11.5 (9.9 to 13.5)
    Statistical analysis title
    		 Final OS analysis
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    831
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.81
    Statistical analysis title
    		 Primary OS Analysis
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    831
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.74

    Primary: Radiographic progression-free survival (rPFS)

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    End point title
    		 Radiographic progression-free survival (rPFS) [2]
    End point description
    Radiographic progression-free survival (rPFS) was defined as the time (in months) from the date of randomization to the date of radiographic disease progression based on the central review assessment per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or death due to any cause. Patients who were alive without radiographic progression at the analysis data cut-off were censored for rPFS at the time of their last evaluable radiographic assessment. Date of censoring for rPFS: 1) The censoring date was the date when the last evaluable radiographic assessment (CT/MRI/bone scan) determined a lack of progression; 2) If there were no evaluable assessments, censoring occurred at the date of randomization; 3) Patients who had 2 or more consecutive missed tumor assessments immediately prior to PD or death were censored at the date of the last evaluable tumor assessment prior to those missing tumor assessments.
    End point type
    Primary
    End point timeframe
    From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Months
        median (confidence interval 99.2%)
    8.7 (7.9 to 10.8)
    3.4 (2.4 to 4.0)
    Statistical analysis title
    		 Radiographic progression-free survival (rPFS)
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    581
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    		 99.2%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.57

    Secondary: Number of participants with randomized/study treatment-emergent adverse events (TEAE)

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    End point title
    		 Number of participants with randomized/study treatment-emergent adverse events (TEAE)
    End point description
    In the Main Study, "randomized treatment" refers to the investigational arm (AAA617+BSC/BSoC) and the control arm (BSC/BSoC). In the sub-study, "study treatment" refers to the investigational arm (AAA617+BSC/BSoC) without randomization: 1) A randomized treatment-emergent adverse event (TEAE) is any adverse event that occurs from the start of randomized treatment to 30 days after the last administration of randomized treatment or prior to the initiation of subsequent anticancer treatment. 2) A study treatment-emergent adverse event (TEAE) is any adverse event that occurs from the start of study treatment to 30 days after the last administration of study treatment or prior to the initiation of subsequent anticancer treatment. The distribution of randomized/study treatment-emergent adverse events (TEAEs) was done via the analysis of frequencies for TEAEs and Serious Adverse Event (TESAEs), through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    From randomization till 30 days safety follow-up, assessed up to 66 months (Final Analysis cut-off date = 14-Dec-2023)
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone Sub Study: 177Lu-PSMA-617 + BS/BSOC
    Number of subjects analysed
    529
    205
    30
    Units: Participants
        TEAE
    518
    170
    30
        Serious TEAE
    195
    58
    9
        Grade 3/4/5 TEAE
    284
    79
    11
        Drug-related TEAE
    451
    59
    19
        Serious Drug-related TEAE
    51
    5
    2
        Drug-related grade 3/4/5 TEAE
    152
    8
    6
        TEAE leading to reduction of 177Lu-PSMA-617
    30
    0
    2
        TEAE leading to reduction of BSC/BSoC
    17
    7
    1
        TEAE leading to interruption of 177Lu-PSMA-617
    85
    2
    4
        TEAE leading to interruption of BSC/BSoC
    50
    14
    1
        TEAE leading to discontinuation of 177Lu-PSMA-617
    63
    1
    2
        TEAE leading to discontinuation of BSC/BSoC
    47
    16
    0
        Fatal TEAE
    19
    6
    2
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR) [3]
    End point description
    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). ORR was based on RECIST 1.1 response for patients with evaluable disease at baseline per central review assessment.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    319
    120
    Units: Participants
    95
    2
    Statistical analysis title
    		 Overall Response Rate (ORR)
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    24.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.05
         upper limit
    		 103.24

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR) [4]
    End point description
    Disease control rate (DCR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) according to RECIST v1.1 per central review assessment.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    319
    120
    Units: Participants
    284
    80
    Statistical analysis title
    		 Disease control rate (DCR)
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.18
         upper limit
    		 10.55

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR) [5]
    End point description
    Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented radiographic progression or death due to any cause as per central review assessment.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    95
    2
    Units: Months
        median (confidence interval 95%)
    9.8 (9.1 to 11.7)
    10.6 (0 to 999)
    No statistical analyses for this end point

    Secondary: Time to first Symptomatic Skeletal Event (SSE)

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    End point title
    		 Time to first Symptomatic Skeletal Event (SSE) [6]
    End point description
    Time to first Symptomatic Skeletal Event (SSE) was defined as the time (in months) from the date of randomization to the date of the SSE or death from any cause. The SSE date was the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death due to any cause, whichever occurred first. SSE data for this endpoint were collected up through EOT visit. The censoring date was date of the last study visit (on or before the EOT visit).
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Months
        median (confidence interval 95%)
    11.5 (10.3 to 13.2)
    6.8 (5.2 to 8.5)
    Statistical analysis title
    		 Time to first Symptomatic Skeletal Event (SSE)
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    581
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.62

    Secondary: Best percentage change from baseline in prostate-specific antigen (PSA) level

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    End point title
    		 Best percentage change from baseline in prostate-specific antigen (PSA) level [7]
    End point description
    Best percentage change from baseline in PSA level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    333
    138
    Units: Percentage change
        arithmetic mean (standard deviation)
    -20.9 ( 142.6 )
    50.4 ( 118.4 )
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS) [8]
    End point description
    Progression-free survival (PFS) was defined as the time (in months) from the date of randomization to the date of first evidence of radiographic, clinical or PSA progression or death due to any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Months
        median (confidence interval 95%)
    5.9 (5.2 to 6.6)
    2.4 (2.2 to 3.0)
    Statistical analysis title
    		 Progression-free survival (PFS)
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    581
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.38

    Secondary: Percentage of participants achieving prostate-specific antigen (PSA) response

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    End point title
    		 Percentage of participants achieving prostate-specific antigen (PSA) response [9]
    End point description
    PSA response was defined as the proportion of patients who had a >= 50% decrease in PSA from baseline confirmed by a PSA measurement >= 4 weeks later.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Percentage of participants
        number (confidence interval 95%)
    46.0 (40.9 to 51.1)
    7.1 (4.0 to 11.7)
    Statistical analysis title
    		 % of participants achieving PSA response
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    581
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.3
         upper limit
    		 20

    Secondary: Duration of PSA response

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    End point title
    		 Duration of PSA response [10]
    End point description
    Duration of PSA response was defined as the duration between the date of first document PSA response (i.e. >= 50% decrease in PSA from Baseline) and the earliest date of PSA progression, where date of PSA progression was defined as: 1) Where a decline from baseline was documented, date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained at least 3 weeks later. Rises in PSA within the first 12 weeks of the date of first dose of randomized treatment were ignored; 2) Where no decline from baseline was documented, PSA progression was defined as a >= 25% increase from the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks from the date of first dose of randomized treatment (without confirmation) as specified in the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines.
    End point type
    Secondary
    End point timeframe
    From date of first documented PSA response till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    177
    14
    Units: Months
        median (confidence interval 95%)
    8.9 (7.6 to 10.7)
    4.4 (2.6 to 10.8)
    No statistical analyses for this end point

    Secondary: Prostate-specific antigen 80 (PSA80) response

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    End point title
    		 Prostate-specific antigen 80 (PSA80) response [11]
    End point description
    PSA80 response was defined as the proportion of participants who had a >= 80% decrease in PSA from baseline confirmed by a PSA measurement >= 4 weeks later.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Percentage of participants
        number (confidence interval 95%)
    33.0 (28.3 to 37.9)
    2.0 (0.6 to 5.1)
    Statistical analysis title
    		 Prostate-specific antigen 80 (PSA80) response
    Comparison groups
    Main Study: 177Lu-PSMA-617 + BS/BSOC v Main Study: BS/BSOC alone
    Number of subjects included in analysis
    581
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    23.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.6
         upper limit
    		 65.1

    Secondary: Best percentage change from baseline in alkaline phosphatase (ALP) level

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    End point title
    		 Best percentage change from baseline in alkaline phosphatase (ALP) level [12]
    End point description
    Best percentage change from baseline in alkaline phosphatase (ALP) level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    372
    172
    Units: Percentage change
        arithmetic mean (standard deviation)
    -14.4 ( 46.3 )
    0.6 ( 33.8 )
    No statistical analyses for this end point

    Secondary: Time to worsening in BPI-SF pain intensity scale

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    End point title
    		 Time to worsening in BPI-SF pain intensity scale [13]
    End point description
    Time to worsening in BPI-SF pain intensity scale was defined as the time from randomization to the first occurring of an increase of worsening threshold (>=30% of baseline or >=2-point increase) at any time up through EOT visit compared to baseline, clinical disease progression, or death.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    328
    166
    Units: Months
        median (confidence interval 95%)
    5.9 (4.8 to 6.9)
    2.2 (1.8 to 2.8)
    No statistical analyses for this end point

    Secondary: Best percentage change from baseline in lactate dehydrogenase (LDH) level

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    End point title
    		 Best percentage change from baseline in lactate dehydrogenase (LDH) level [14]
    End point description
    Best percentage change from baseline in lactate dehydrogenase (LDH) level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    371
    168
    Units: Percentage change
        arithmetic mean (standard deviation)
    -23.1 ( 23.8 )
    -9.2 ( 28.2 )
    No statistical analyses for this end point

    Secondary: Time to improvement after worsening in BPI-SF pain intensity scale

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    End point title
    		 Time to improvement after worsening in BPI-SF pain intensity scale [15]
    End point description
    Time to improvement after worsening in BPI-SF pain intensity scale was defined as the time from worsening of Pain Intensity score to a Pain Intensity score <= baseline.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    144
    76
    Units: Months
        median (confidence interval 95%)
    2.8 (1.9 to 4.2)
    4.2 (2.8 to 11.3)
    No statistical analyses for this end point

    Secondary: Time to worsening in BPI-SF pain interference scale

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    End point title
    		 Time to worsening in BPI-SF pain interference scale [16]
    End point description
    Time to worsening in BPI-SF pain interference scale was defined as the time from randomization to the first occurring of 1) an increase of worsening threshold (>=30% of baseline or >=2-point increase) at any time up through EOT visit compared to baseline, 2) clinical disease progression, or 3) death.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    330
    166
    Units: Months
        median (confidence interval 95%)
    5.0 (4.2 to 6.1)
    2.3 (1.7 to 2.9)
    No statistical analyses for this end point

    Secondary: Time to improvement after worsening in BPI-SF pain interference scale

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    End point title
    		 Time to improvement after worsening in BPI-SF pain interference scale [17]
    End point description
    Time to improvement after worsening in BPI-SF pain interference scale was defined as the time from worsening of Pain Interference score to a Pain Interference score <= baseline.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    176
    72
    Units: Months
        median (confidence interval 95%)
    3.0 (2.8 to 4.4)
    2.8 (1.7 to 999)
    No statistical analyses for this end point

    Secondary: Time to worsening in BPI-SF worst pain intensity scale (time to disease related pain)

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    End point title
    		 Time to worsening in BPI-SF worst pain intensity scale (time to disease related pain) [18]
    End point description
    Time to worsening in BPI-SF worst pain intensity scale (time to disease related pain) was defined as the time from randomization to the first occurring of worsening exceeding the threshold threshold (>=30% of baseline or >=2 point increase) at any time up through EOT visit compared to baseline, clinical disease progression, or death.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    332
    169
    Units: Months
        median (confidence interval 95%)
    5.0 (4.2 to 5.9)
    2.0 (1.7 to 2.2)
    No statistical analyses for this end point

    Secondary: Change from Baseline in BPI-SF (Brief-Pain Inventory - Short Form) pain intensity scale

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    End point title
    		 Change from Baseline in BPI-SF (Brief-Pain Inventory - Short Form) pain intensity scale [19]
    End point description
    The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF consists of 4 questions regarding pain intensity (worst pain intensity, least pain intensity, average pain intensity and pain right now), 2 questions on the use of analgesics, and 7 questions on how the level pain has interfered with the subject’s life (General Activity, Mood, Walking Ability, Normal Work, Relations with other people, Sleep, Enjoyment of Life). Intensity items consist of an 11-response rating scale scored from 0 (“No Pain”) to 10 (“Pain As Bad As You Can Imagine”). BPI-SF Pain intensity is the mean of non-missing items of the 4 individual scales, if there are 3 or more items not missing; otherwise this scale is set to missing.
    End point type
    Secondary
    End point timeframe
    Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 2, Week 1, Day 1 change from BL
    -0.59 ( 2.037 )
    0.21 ( 2.404 )
        Cycle 3, Week 1, Day 1 change from BL
    -0.62 ( 1.924 )
    0.02 ( 2.033 )
        Cycle 4, Week 1, Day 1 change from BL
    -0.42 ( 2.017 )
    0.26 ( 2.383 )
        Cycle 5, Week 1, Day 1 change from BL
    -0.49 ( 1.957 )
    0.55 ( 3.144 )
        Cycle 6, Week 1, Day 1 change from BL
    -0.41 ( 1.897 )
    0.10 ( 2.740 )
        Cycle 7, Week 1, Day 1 change from BL
    -0.48 ( 2.011 )
    -0.32 ( 1.585 )
        Cycle 8, Week 1, Day 1 change from BL
    -0.18 ( 1.759 )
    -1.10 ( 2.205 )
        Cycle 9, Week 1, Day 1 change from BL
    -0.70 ( 2.157 )
    0.13 ( 1.780 )
        Cycle 10, Week 1, Day 1 change from BL
    0.02 ( 1.513 )
    0.50 ( 1.768 )
        Cycle 11, Week 1, Day 1 change from BL
    -0.40 ( 0.956 )
    0.75 ( 1.768 )
        Cycle 12, Week 1, Day 1 change from BL
    -1.00 ( 0.354 )
    999 ( 999 )
        Cycle 13, Week 1, Day 1 change from BL
    -0.75 ( 999 )
    999 ( 999 )
        End of Treatment (EoT) change from BL
    0.46 ( 2.415 )
    0.50 ( 2.405 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in BPI-SF (Brief-Pain Inventory - Short Form) pain interference scale

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    End point title
    		 Change from Baseline in BPI-SF (Brief-Pain Inventory - Short Form) pain interference scale [20]
    End point description
    The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF consists of 4 questions regarding pain intensity (worst pain intensity, least pain intensity, average pain intensity and pain right now), 2 questions on the use of analgesics, and 7 questions on how the level pain has interfered with the subject’s life (General Activity, Mood, Walking Ability, Normal Work, Relations with other people, Sleep, Enjoyment of Life). Interference items consist of scores from 0 (“Does Not Interfere”) to 10 (“Completely Interferes”). BPI-SF Interference scale is the mean of non-missing items of the 7 items on pain interference, if there are 4 or more items not missing; otherwise this scale is set to missing.
    End point type
    Secondary
    End point timeframe
    Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 2, Week 1, Day 1 change from BL
    -0.40 ( 2.167 )
    0.58 ( 2.700 )
        Cycle 3, Week 1, Day 1 change from BL
    -0.35 ( 2.348 )
    -0.15 ( 2.216 )
        Cycle 4, Week 1, Day 1 change from BL
    -0.33 ( 2.249 )
    0.21 ( 2.762 )
        Cycle 5, Week 1, Day 1 change from BL
    -0.32 ( 2.223 )
    0.52 ( 3.480 )
        Cycle 6, Week 1, Day 1 change from BL
    -0.28 ( 2.166 )
    0.49 ( 3.354 )
        Cycle 7, Week 1, Day 1 change from BL
    -0.22 ( 1.882 )
    0.06 ( 2.570 )
        Cycle 8, Week 1, Day 1 change from BL
    0.18 ( 1.926 )
    -0.26 ( 1.291 )
        Cycle 9, Week 1, Day 1 change from BL
    -0.15 ( 1.751 )
    0.12 ( 1.667 )
        Cycle 10, Week 1, Day 1 change from BL
    0.62 ( 2.141 )
    1.50 ( 1.313 )
        Cycle 11, Week 1, Day 1 change from BL
    -0.06 ( 1.334 )
    0.36 ( 4.748 )
        Cycle 12, Week 1, Day 1 change from BL
    -0.89 ( 0.914 )
    999 ( 999 )
        Cycle 13, Week 1, Day 1 change from BL
    -0.43 ( 999 )
    999 ( 999 )
        End of Treatment (EoT) change from BL
    0.73 ( 2.756 )
    0.29 ( 2.385 )
    No statistical analyses for this end point

    Secondary: Time to worsening in FACT-P total score

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    End point title
    		 Time to worsening in FACT-P total score [21]
    End point description
    Time to worsening was defined as the time from randomization to the first occurring of a >=10 point decrease in FACT-P total score compared to baseline, clinical disease progression, or death.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Months
        median (confidence interval 95%)
    5.7 (4.8 to 6.6)
    2.2 (1.8 to 2.8)
    No statistical analyses for this end point

    Secondary: Change from Baseline in FACT-P (Functional Assessment of Cancer Therapy – Prostate) Total Score

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    End point title
    		 Change from Baseline in FACT-P (Functional Assessment of Cancer Therapy – Prostate) Total Score [22]
    End point description
    The FACT-P total score (range 0-156) consist of five subscales (Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24)) and a functional well-being and prostate cancer subscale (range 0-48). Higher scores indicate higher degree of functioning and better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 2, Week 1, Day 1 change from BL
    3.6 ( 16.63 )
    -7.2 ( 17.85 )
        Cycle 3, Week 1, Day 1 change from BL
    3.8 ( 17.48 )
    -2.6 ( 14.00 )
        Cycle 4, Week 1, Day 1 change from BL
    5.4 ( 15.93 )
    -1.3 ( 18.40 )
        Cycle 5, Week 1, Day 1 change from BL
    4.0 ( 16.24 )
    -5.9 ( 27.83 )
        Cycle 6, Week 1, Day 1 change from BL
    4.1 ( 15.22 )
    -5.0 ( 26.87 )
        Cycle 7, Week 1, Day 1 change from BL
    4.9 ( 16.47 )
    -2.9 ( 17.89 )
        Cycle 8, Week 1, Day 1 change from BL
    3.8 ( 15.87 )
    -13.0 ( 32.76 )
        Cycle 9, Week 1, Day 1 change from BL
    3.8 ( 14.22 )
    6.9 ( 5.92 )
        Cycle 10, Week 1, Day 1 change from BL
    0.0 ( 18.27 )
    0.2 ( 14.14 )
        Cycle 11, Week 1, Day 1 change from BL
    -0.8 ( 20.99 )
    8.2 ( 33.71 )
        Cycle 12, Week 1, Day 1 change from BL
    10.3 ( 12.11 )
    999 ( 999 )
        Cycle 13, Week 1, Day 1 change from BL
    30.0 ( 999 )
    999 ( 999 )
        End of Treatment (EoT) change from BL
    -9.4 ( 21.64 )
    -10.4 ( 18.59 )
    No statistical analyses for this end point

    Secondary: Time to worsening in EQ-5D-5L utility score

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    End point title
    		 Time to worsening in EQ-5D-5L utility score [23]
    End point description
    Time to worsening for utility score was defined as time from randomization to the first occurrence of worsening in utility score relative to baseline (no change or any decrease), clinical disease progression, or death.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    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: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Months
        median (confidence interval 95%)
    1.0 (0.7 to 1.8)
    0.5 (0.4 to 1.0)
    No statistical analyses for this end point

    Secondary: Change from Baseline in the European Quality of Life (EuroQol) – 5 Domain 5 Level scale (EQ-5D-5L) utility score

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    End point title
    		 Change from Baseline in the European Quality of Life (EuroQol) – 5 Domain 5 Level scale (EQ-5D-5L) utility score [24]
    End point description
    The EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3=moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions. A utility score was obtained by using a weighted combination of the levels of the five dimension-scales. The weights were based on value sets which were country-specific for the U.K. Utility scores ranges from the lowest possible score for a living patient of -0.594 (when all responses are ‘5’) to 1 (when all responses are ‘1’).If a patient died, he was assigned a score of 0 on the date of death.
    End point type
    Secondary
    End point timeframe
    Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 2, Week 1, Day 1 change from BL
    0.0221 ( 0.17693 )
    -0.0897 ( 0.24973 )
        Cycle 3, Week 1, Day 1 change from BL
    0.0297 ( 0.18817 )
    -0.0331 ( 0.14155 )
        Cycle 4, Week 1, Day 1 change from BL
    0.0292 ( 0.17713 )
    -0.0818 ( 0.23752 )
        Cycle 5, Week 1, Day 1 change from BL
    0.0398 ( 0.16827 )
    -0.0673 ( 0.28633 )
        Cycle 6, Week 1, Day 1 change from BL
    0.0342 ( 0.17950 )
    -0.0110 ( 0.17842 )
        Cycle 7, Week 1, Day 1 change from BL
    0.0252 ( 0.16127 )
    -0.0088 ( 0.09081 )
        Cycle 8, Week 1, Day 1 change from BL
    0.0285 ( 0.18017 )
    -0.0296 ( 0.14964 )
        Cycle 9, Week 1, Day 1 change from BL
    0.0100 ( 0.17447 )
    0.0087 ( 0.08167 )
        Cycle 10, Week 1, Day 1 change from BL
    0.0134 ( 0.15764 )
    -0.0655 ( 0.09263 )
        Cycle 11, Week 1, Day 1 change from BL
    0.0464 ( 0.16858 )
    0.0250 ( 0.19940 )
        Cycle 12, Week 1, Day 1 change from BL
    0.1118 ( 0.13833 )
    999 ( 999 )
        Cycle 13, Week 1, Day 1 change from BL
    0.0640 ( 999 )
    999 ( 999 )
        End of Treatment (EoT) change from BL
    -0.0939 ( 0.22698 )
    -0.0900 ( 0.21223 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the European Quality of Life (EuroQol) – 5 Domain 5 Level scale (EQ-5D-5L) EQ-VAS

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    End point title
    		 Change from Baseline in the European Quality of Life (EuroQol) – 5 Domain 5 Level scale (EQ-5D-5L) EQ-VAS [25]
    End point description
    The EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ VAS records the patient’s self-rated health on a vertical visual analogue 0-100 scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. The higher the EQ-VAS score, the better the QoL.
    End point type
    Secondary
    End point timeframe
    Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 2, Week 1, Day 1 change from BL
    1.8 ( 19.98 )
    -7.2 ( 20.31 )
        Cycle 3, Week 1, Day 1 change from BL
    1.4 ( 19.82 )
    -3.8 ( 21.50 )
        Cycle 4, Week 1, Day 1 change from BL
    2.8 ( 19.18 )
    -1.7 ( 18.73 )
        Cycle 5, Week 1, Day 1 change from BL
    4.0 ( 17.30 )
    -8.5 ( 28.88 )
        Cycle 6, Week 1, Day 1 change from BL
    2.1 ( 19.61 )
    3.2 ( 19.43 )
        Cycle 7, Week 1, Day 1 change from BL
    3.6 ( 20.64 )
    5.9 ( 12.79 )
        Cycle 8, Week 1, Day 1 change from BL
    0.6 ( 17.18 )
    13.8 ( 16.60 )
        Cycle 9, Week 1, Day 1 change from BL
    0.1 ( 19.68 )
    6.3 ( 20.82 )
        Cycle 10, Week 1, Day 1 change from BL
    2.9 ( 13.97 )
    -8.0 ( 2.83 )
        Cycle 11, Week 1, Day 1 change from BL
    5.8 ( 10.33 )
    -9.0 ( 28.28 )
        Cycle 12, Week 1, Day 1 change from BL
    4.5 ( 13.03 )
    999 ( 999 )
        Cycle 13, Week 1, Day 1 change from BL
    -5.0 ( 999 )
    999 ( 999 )
        End of Treatment (EoT) change from BL
    -8.9 ( 22.07 )
    -10.1 ( 21.49 )
    No statistical analyses for this end point

    Secondary: Number of participants hospitalized as in-patient

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    End point title
    		 Number of participants hospitalized as in-patient [26]
    End point description
    The number of hospitalizations (yes/no) (admitted as in-patient) was collected as part of the hospital admission for health economic evaluations.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Participants
        Yes
    157
    59
        No
    228
    137
    No statistical analyses for this end point

    Secondary: Duration of time in hospital following 177Lu-PSMA-617 administration

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    End point title
    		 Duration of time in hospital following 177Lu-PSMA-617 administration [27]
    End point description
    The duration of time in hospital following 177Lu-PSMA-617 administration (hours) was the time span of patient discharged as captured on the 177Lu-PSMA-617 administration Case Report Form (CRF).
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    341
    0 [28]
    Units: Hours
        arithmetic mean (standard deviation)
    28.25 ( 46.578 )
    ( )
    Notes
    [28] - This endpoint only apply to the Main Study "177Lu-PSMA-617 + BS/BSOC" arm
    No statistical analyses for this end point

    Secondary: Concomitant drug use for health economics analysis

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    End point title
    		 Concomitant drug use for health economics analysis [29]
    End point description
    The list of concomitant drugs as captured on the concomitant medication/therapy CRF page to include in each category was pre-specified and flagged prior to the pre planned analyses. (1) Bisphosphonates (including but not limited to zoledronic acid, alendronic acid, etc.), denosumab, and other bone targeted therapies), (2) Corticosteroids for systemic use (3), Antifungals for systemic use (i.e. ketoconazole), (4) ESA (erythropoietin stimulating agents, i.e. epoetin alfa), (5) Granulocyte macrophage colony-stimulating factor (GM-CSF), (6) Novel androgen axis drugs (NAADs; i.e. enzalutamide, abiraterone, apalutamide), (7) Antiemetics and (8) Opioid analgesics use for cancer-related pain.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Participants
        Bisphosphonates|Yes
    169
    88
        Corticosteroids|Yes
    246
    113
        Antifungals|Yes
    1
    4
        Erythropoietin Stimulating Agents|Yes
    8
    2
        GM-CSF|Yes
    7
    3
        Novel Androgen Axis Drugs|Yes
    188
    115
        Antiemetics|Yes
    232
    45
        Opioid analgesics|Yes
    199
    96
        Bisphosphonates|No
    216
    108
        Corticosteroids|No
    139
    83
        Antifungals|No
    384
    192
        Erythropoietin Stimulating Agents|No
    377
    194
        GM-CSF|No
    378
    193
        Novel Androgen Axis Drugs|No
    197
    81
        Antiemetics|No
    153
    151
        Opioid analgesics|No
    186
    100
    No statistical analyses for this end point

    Secondary: Therapeutic interventions for health economics analysis

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    End point title
    		 Therapeutic interventions for health economics analysis [30]
    End point description
    The list of therapeutic interventions was pre-specified and flagged prior to the pre planned analyses as captured on: 1) the concurrent radiotherapy CRF page to include local external beam radiotherapy (inclusive of palliative external radiation), 2) on the concomitant medication/therapy CRF page to include blood transfusion (full blood or derivates).
    End point type
    Secondary
    End point timeframe
    From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to study arms for the Main Study
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone
    Number of subjects analysed
    385
    196
    Units: Participants
        Local external beam therapy|Yes
    63
    37
        Blood transfusion|Yes
    74
    13
        Local external beam therapy|No
    322
    159
        Blood transfusion|No
    311
    183
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    Pre-treatment deaths were collected from day of participant’s informed consent to the day before first dose of study medication. On-treatment deaths were collected from first dose of study medication to 30 days after last dose of study medication (on-treatment), up to approximately 43 months. ​ Deaths were collected in the post treatment survival follow up from 31 days after last dose of study medication until the end of the study, up to approximately 66 months. These are not considered AEs​
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment deaths: Up to 28 days prior to treatment. On-treatment deaths: Up to approximately 43 months. Post-treatment deaths: Up to approximately 66 months
    End point values
    		 Main Study: 177Lu-PSMA-617 + BS/BSOC Main Study: BS/BSOC alone Sub Study: 177Lu-PSMA-617 + BS/BSOC
    Number of subjects analysed
    551
    280
    30
    Units: Participants
        Pre-treatment deaths
    0
    0
    0
        On-treatment deaths
    68
    19
    5
        Post-treatment deaths
    389
    182
    16
        All deaths
    457
    201
    21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from first dose of study medication until the last dose plus 30 days post-treat follow-up, assessed up to approximately 43 months.
    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
    26.1
    Reporting groups
    Reporting group title
    -Main Study-@Lu-PSMA-617+@BSC/BSOC
    Reporting group description
    		 -Main Study-@Lu-PSMA-617+@BSC/BSOC

    Reporting group title
    -Sub Study-@Lu-PSMA-617+@BSC/BSOC
    Reporting group description
    		 -Sub Study-@Lu-PSMA-617+@BSC/BSOC

    Reporting group title
    -Main Study-@BSC/BSOC@only
    Reporting group description
    		 -Main Study-@BSC/BSOC@only

    Serious adverse events
    		 -Main Study-@Lu-PSMA-617+@BSC/BSOC -Sub Study-@Lu-PSMA-617+@BSC/BSOC -Main Study-@BSC/BSOC@only
    Total subjects affected by serious adverse events
         subjects affected / exposed
    195 / 529 (36.86%)
    9 / 30 (30.00%)
    58 / 205 (28.29%)
         number of deaths (all causes)
    68
    5
    19
         number of deaths resulting from adverse events
    5
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 30 (3.33%)
    0 / 205 (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
    Metastases to central nervous system
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Orthostatic hypotension
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Deep vein thrombosis
         subjects affected / exposed
    3 / 529 (0.57%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 529 (0.76%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Surgical and medical procedures
    Euthanasia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Neck dissection
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pain management
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Fatigue
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 30 (3.33%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Generalised oedema
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Disease progression
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Oedema
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    5 / 529 (0.95%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 529 (1.51%)
    1 / 30 (3.33%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Penile pain
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Dyspnoea
         subjects affected / exposed
    5 / 529 (0.95%)
    1 / 30 (3.33%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Hypoxia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pleural effusion
         subjects affected / exposed
    2 / 529 (0.38%)
    1 / 30 (3.33%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 529 (1.13%)
    1 / 30 (3.33%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    3 / 529 (0.57%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mixed anxiety and depressive disorder
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Fall
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Femur fracture
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Rib fracture
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    4 / 529 (0.76%)
    0 / 30 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    Wound complication
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Vascular malformation
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Arrhythmia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Atrial fibrillation
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Cardiac failure
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Cerebral infarction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Diplegia
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Dysarthria
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Encephalopathy
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglossal nerve paralysis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Ischaemic stroke
         subjects affected / exposed
    3 / 529 (0.57%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pachymeningitis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Paraesthesia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 30 (3.33%)
    0 / 205 (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
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Tremor
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Seizure
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    6 / 529 (1.13%)
    0 / 30 (0.00%)
    11 / 205 (5.37%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord disorder
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         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
    4 / 529 (0.76%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Radiculopathy
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 529 (2.84%)
    2 / 30 (6.67%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    11 / 15
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Febrile neutropenia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    6 / 529 (1.13%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 529 (0.57%)
    2 / 30 (6.67%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         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
         subjects affected / exposed
    4 / 529 (0.76%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Ascites
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Constipation
         subjects affected / exposed
    5 / 529 (0.95%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 30 (3.33%)
    0 / 205 (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
    Duodenal ulcer
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Dysphagia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Haematemesis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Rectal haemorrhage
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Intestinal perforation
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Large intestinal obstruction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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 gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 529 (0.57%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 529 (0.95%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Cholecystitis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Cholestasis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Hepatic cytolysis
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Hepatic lesion
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Bile duct stenosis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    10 / 529 (1.89%)
    0 / 30 (0.00%)
    6 / 205 (2.93%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Urinary tract obstruction
         subjects affected / exposed
    4 / 529 (0.76%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    11 / 529 (2.08%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    2 / 12
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant urinary tract obstruction
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Renal tubular acidosis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Urinary retention
         subjects affected / exposed
    5 / 529 (0.95%)
    1 / 30 (3.33%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 30 (3.33%)
    0 / 205 (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
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Arthralgia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    10 / 529 (1.89%)
    1 / 30 (3.33%)
    3 / 205 (1.46%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    6 / 529 (1.13%)
    1 / 30 (3.33%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Neck pain
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pain in extremity
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pathological fracture
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Spinal stenosis
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 30 (3.33%)
    0 / 205 (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
    Spinal pain
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Appendicitis
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    COVID-19
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Diverticulitis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Escherichia sepsis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Fungaemia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Herpes zoster
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 529 (0.57%)
    0 / 30 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Klebsiella sepsis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Extradural abscess
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Osteomyelitis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pharyngitis
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 529 (1.32%)
    0 / 30 (0.00%)
    3 / 205 (1.46%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Pyelonephritis acute
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Wound infection
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Urinary tract infection
         subjects affected / exposed
    13 / 529 (2.46%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 529 (0.57%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Sepsis
         subjects affected / exposed
    10 / 529 (1.89%)
    0 / 30 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Decreased appetite
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (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
    Dehydration
         subjects affected / exposed
    5 / 529 (0.95%)
    1 / 30 (3.33%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 529 (0.00%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 30 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 30 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 -Main Study-@Lu-PSMA-617+@BSC/BSOC -Sub Study-@Lu-PSMA-617+@BSC/BSOC -Main Study-@BSC/BSOC@only
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    502 / 529 (94.90%)
    28 / 30 (93.33%)
    151 / 205 (73.66%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 529 (5.67%)
    0 / 30 (0.00%)
    12 / 205 (5.85%)
         occurrences all number
    36
    0
    12
    General disorders and administration site conditions
    Extravasation
         subjects affected / exposed
    0 / 529 (0.00%)
    2 / 30 (6.67%)
    0 / 205 (0.00%)
         occurrences all number
    0
    2
    0
    Fatigue
         subjects affected / exposed
    228 / 529 (43.10%)
    5 / 30 (16.67%)
    47 / 205 (22.93%)
         occurrences all number
    264
    5
    49
    General physical health deterioration
         subjects affected / exposed
    2 / 529 (0.38%)
    2 / 30 (6.67%)
    2 / 205 (0.98%)
         occurrences all number
    2
    2
    3
    Oedema peripheral
         subjects affected / exposed
    51 / 529 (9.64%)
    3 / 30 (10.00%)
    13 / 205 (6.34%)
         occurrences all number
    53
    3
    15
    Pain
         subjects affected / exposed
    28 / 529 (5.29%)
    2 / 30 (6.67%)
    10 / 205 (4.88%)
         occurrences all number
    30
    2
    11
    Pyrexia
         subjects affected / exposed
    30 / 529 (5.67%)
    1 / 30 (3.33%)
    7 / 205 (3.41%)
         occurrences all number
    35
    1
    7
    Asthenia
         subjects affected / exposed
    34 / 529 (6.43%)
    1 / 30 (3.33%)
    16 / 205 (7.80%)
         occurrences all number
    48
    1
    19
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    8 / 529 (1.51%)
    2 / 30 (6.67%)
    1 / 205 (0.49%)
         occurrences all number
    8
    2
    1
    Dyspnoea
         subjects affected / exposed
    51 / 529 (9.64%)
    2 / 30 (6.67%)
    19 / 205 (9.27%)
         occurrences all number
    58
    2
    19
    Cough
         subjects affected / exposed
    42 / 529 (7.94%)
    0 / 30 (0.00%)
    13 / 205 (6.34%)
         occurrences all number
    43
    0
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    28 / 529 (5.29%)
    2 / 30 (6.67%)
    9 / 205 (4.39%)
         occurrences all number
    28
    2
    10
    Investigations
    Weight decreased
         subjects affected / exposed
    58 / 529 (10.96%)
    1 / 30 (3.33%)
    20 / 205 (9.76%)
         occurrences all number
    58
    1
    22
    Blood creatinine increased
         subjects affected / exposed
    30 / 529 (5.67%)
    3 / 30 (10.00%)
    4 / 205 (1.95%)
         occurrences all number
    34
    3
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    20 / 529 (3.78%)
    2 / 30 (6.67%)
    2 / 205 (0.98%)
         occurrences all number
    23
    3
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    38 / 529 (7.18%)
    0 / 30 (0.00%)
    12 / 205 (5.85%)
         occurrences all number
    51
    0
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    42 / 529 (7.94%)
    1 / 30 (3.33%)
    9 / 205 (4.39%)
         occurrences all number
    46
    1
    10
    Headache
         subjects affected / exposed
    36 / 529 (6.81%)
    2 / 30 (6.67%)
    4 / 205 (1.95%)
         occurrences all number
    40
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    161 / 529 (30.43%)
    9 / 30 (30.00%)
    26 / 205 (12.68%)
         occurrences all number
    205
    10
    31
    Thrombocytopenia
         subjects affected / exposed
    91 / 529 (17.20%)
    4 / 30 (13.33%)
    9 / 205 (4.39%)
         occurrences all number
    109
    6
    9
    Neutropenia
         subjects affected / exposed
    45 / 529 (8.51%)
    0 / 30 (0.00%)
    3 / 205 (1.46%)
         occurrences all number
    68
    0
    4
    Lymphopenia
         subjects affected / exposed
    75 / 529 (14.18%)
    5 / 30 (16.67%)
    8 / 205 (3.90%)
         occurrences all number
    102
    5
    10
    Leukopenia
         subjects affected / exposed
    66 / 529 (12.48%)
    3 / 30 (10.00%)
    4 / 205 (1.95%)
         occurrences all number
    93
    4
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    103 / 529 (19.47%)
    3 / 30 (10.00%)
    23 / 205 (11.22%)
         occurrences all number
    143
    3
    25
    Abdominal pain
         subjects affected / exposed
    30 / 529 (5.67%)
    0 / 30 (0.00%)
    6 / 205 (2.93%)
         occurrences all number
    33
    0
    6
    Vomiting
         subjects affected / exposed
    97 / 529 (18.34%)
    4 / 30 (13.33%)
    12 / 205 (5.85%)
         occurrences all number
    126
    4
    12
    Toothache
         subjects affected / exposed
    4 / 529 (0.76%)
    2 / 30 (6.67%)
    0 / 205 (0.00%)
         occurrences all number
    4
    2
    0
    Nausea
         subjects affected / exposed
    187 / 529 (35.35%)
    11 / 30 (36.67%)
    33 / 205 (16.10%)
         occurrences all number
    266
    11
    40
    Flatulence
         subjects affected / exposed
    1 / 529 (0.19%)
    2 / 30 (6.67%)
    1 / 205 (0.49%)
         occurrences all number
    1
    2
    1
    Dry mouth
         subjects affected / exposed
    205 / 529 (38.75%)
    5 / 30 (16.67%)
    1 / 205 (0.49%)
         occurrences all number
    231
    5
    2
    Diarrhoea
         subjects affected / exposed
    101 / 529 (19.09%)
    3 / 30 (10.00%)
    5 / 205 (2.44%)
         occurrences all number
    128
    3
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 529 (0.76%)
    2 / 30 (6.67%)
    0 / 205 (0.00%)
         occurrences all number
    5
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    37 / 529 (6.99%)
    2 / 30 (6.67%)
    8 / 205 (3.90%)
         occurrences all number
    38
    2
    8
    Urinary retention
         subjects affected / exposed
    8 / 529 (1.51%)
    3 / 30 (10.00%)
    4 / 205 (1.95%)
         occurrences all number
    8
    4
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    117 / 529 (22.12%)
    3 / 30 (10.00%)
    26 / 205 (12.68%)
         occurrences all number
    154
    4
    30
    Back pain
         subjects affected / exposed
    122 / 529 (23.06%)
    4 / 30 (13.33%)
    29 / 205 (14.15%)
         occurrences all number
    141
    4
    29
    Bone pain
         subjects affected / exposed
    54 / 529 (10.21%)
    3 / 30 (10.00%)
    15 / 205 (7.32%)
         occurrences all number
    60
    3
    16
    Osteonecrosis of jaw
         subjects affected / exposed
    7 / 529 (1.32%)
    2 / 30 (6.67%)
    1 / 205 (0.49%)
         occurrences all number
    7
    2
    1
    Pain in extremity
         subjects affected / exposed
    45 / 529 (8.51%)
    2 / 30 (6.67%)
    12 / 205 (5.85%)
         occurrences all number
    55
    2
    15
    Infections and infestations
    Cystitis
         subjects affected / exposed
    6 / 529 (1.13%)
    2 / 30 (6.67%)
    0 / 205 (0.00%)
         occurrences all number
    7
    2
    0
    Urinary tract infection
         subjects affected / exposed
    54 / 529 (10.21%)
    1 / 30 (3.33%)
    1 / 205 (0.49%)
         occurrences all number
    71
    1
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    3 / 529 (0.57%)
    2 / 30 (6.67%)
    1 / 205 (0.49%)
         occurrences all number
    3
    2
    1
    Decreased appetite
         subjects affected / exposed
    112 / 529 (21.17%)
    2 / 30 (6.67%)
    30 / 205 (14.63%)
         occurrences all number
    132
    2
    32
    Hypocalcaemia
         subjects affected / exposed
    36 / 529 (6.81%)
    1 / 30 (3.33%)
    7 / 205 (3.41%)
         occurrences all number
    42
    1
    10
    Hypophosphataemia
         subjects affected / exposed
    28 / 529 (5.29%)
    0 / 30 (0.00%)
    7 / 205 (3.41%)
         occurrences all number
    31
    0
    9
    Hypokalaemia
         subjects affected / exposed
    39 / 529 (7.37%)
    0 / 30 (0.00%)
    7 / 205 (3.41%)
         occurrences all number
    48
    0
    8

    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
    Amendment 2.0: • Incorporated GB and DE only amendment changes. • Added statement of compliance as required by Sweden. • Incorporated the addition of the alternative primary endpoint of rPFS and update to 1 rPFS analysis and 1 overall survival analysis. • Clarified inclusion of and timing of start for best supportive/best standard of care. • Clarified inclusion/exclusion criteria. • Clarified procedures and timing. • Clarified progression of disease is not considered an AE or SAE. • Clarified start and end timing for 68Ga-PSMA-11 TEAEs, 177Lu-PSMA-617 TEAEs and best supportive/best standard of care dosing and intervention TEAEs.
    01 Apr 2019
    Amendment 3.0: • Updated sponsor name. • Updated background information data. • Clarified rPFS is an alternate primary endpoint. • Clarified inclusion/exclusion criteria and added specific criteria regarding best supportive/best standard of care options to be identified for patients as part of eligibility. • After Cycle 6, visits are now every 12 weeks (+/- 4 days). • Additional details regarding long-term follow were added including a second consent to be signed by patients who withdraw consent or leave the active part of the study for any reason other than radiographic disease progression. This now includes radiographic follow up. • Plasma testosterone was added as an acceptable form of testosterone testing. • Window for QOL and Pain questionnaires added. • Updated reference section
    08 Jul 2019
    Amendment 4.0: • Increased total number of patients randomized in the study by 64 to ensure sufficient events in order to maintain power for total enrollment of 814 patients. • Details for confirmatory analysis of OS (based on all randomized patients on an Intent to Treat (ITT) basis i.e., all patients enrolled since the start of the study) and the rPFS analysis based on randomized patients on or after March 5th, 2019 were added. • Adjusted the allocation of alpha between rPFS and OS while still maintaining the original power for both rPFS (approximately 85%) and OS (90%). Allocated alpha=0.004 to rPFS, 0.001 to interim OS and alpha of 0.02 to 0.025 for OS. Previously, allocation was rPFS=0.001 and OS=0.023. • Additional imaging analyses details were added for study 68Ga PSMA 11 scan data and the role of the Independent Review with reviewer variability assessment, as well as Quantitative Analysis was added to assess tumor burden and tumor characteristics with rPFS, OS, and other response measures, as determined by PCWG3 criteria. • Further clarification on the start and end timing for 68Ga-PSMA-11 TEAEs, 177Lu-PSMA-617 TEAEs and best supportive/best standard of care dosing and intervention TEAEs. • Additional wording to clarify intent to collect radiographic imaging for patients who stop treatment for reasons other than radiographic progression.
    26 Apr 2021
    Amendment 5.0: • Extend Long-Term Follow-Up for up to an additional 12 months after V5.0 of the protocol is implemented at each site. • Reduce the procedures required for each Long-Term Follow-Up visit. • Add the requirement to report Serious Adverse Events related to the study drug during Long-Term Follow-Up as well as reporting details of renal toxicities and secondary malignancies. • Updated Serious Adverse Event reporting to reflect the change to Novartis Safety vs PrimeVigilance. • Update footers and headers so that all pages read V5.0. In V4.0 pages 73 to 95 still read “V3.0”. No change was made to the content of these pages from V3.0 to V4.0; the error was typographical.
    26 May 2022
    Amendment 6.0: • Extend the Long-Term Follow-Up for patients on this study to ensure consistent collection of long-term safety data until a new long-term safety follow-up study is available (to comply with FDA Postmarketing Requirement; estimated in 2Q2023).
    14 Sep 2022
    Amendment 7.0: The purpose of this protocol amendment V7 is to document the gap between the last visit of the patient under protocol amendment V5 and the first visit of the patient under protocol amendment V6 as there might be a time gap due to late finalization of protocol amendment V6. Details of the protocol amendments are as follows: · V5 extended the long-term follow-up by one year. · V6 extended further the long-term follow-up until a separate long-term follow-up study is available. Despite the time gap between these two protocol amendments V5 and V6, we suggest to continue the patient on the trial in order to comply with FDA post marketing requirements, so we continue to collect long-term safety data (with the same patient ID) for reconsented patient. An additional addendum of the informed consent is released with this protocol amendment V7 to document the patient's understanding to continue on study.

    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 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/#/ for complete 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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