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    Clinical Trial Results:
    A Phase 3, Randomized, Open-label Study to Compare Adjuvant Immunotherapy of Bempegaldesleukin Combined with Nivolumab Versus Nivolumab After Complete Resection of Melanoma in Patients at High Risk for Recurrence (PIVOT-12).

    Summary
    EudraCT number
    		 2020-000917-34
    Trial protocol
    		 CZ   FR   GR   PL   AT   PT   DE   NL   GB   IT   RO  
    Global end of trial date
    22 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2023
    First version publication date
    16 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20-214-29/CA045-022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04410445
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 US IND No: 125471
    Sponsors
    Sponsor organisation name
    Nektar Therapeutics
    Sponsor organisation address
    455 Mission Bay Boulevard South, San Francisco, United States, CA 94158
    Public contact
    Clinical Trial Information Desk, Nektar Therapeutics, Nektar Therapeutics, +1 855 482 8676, studyinquiry@nektar.com
    Scientific contact
    Clinical Trial Information Desk, Nektar Therapeutics, Nektar Therapeutics, +1 855 482 8676, studyinquiry@nektar.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 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the efficacy, as measured by recurrence-free survival (RFS) by blinded independent central review (BICR), of bempegaldesleukin plus nivolumab versus nivolumab in patients with completely resected Stage IIIA (lymph node [LN] metastasis > 1 mm), Stage IIIB/C/D, or Stage IV (American Joint Committee on Cancer [AJCC] 8th edition) cutaneous melanoma with no evidence of disease (NED) who are at high risk for recurrence.
    Protection of trial subjects
    The conduct of the study was consistent with the principles that have their origin in the Declaration of Helsinki and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, and 312), with ICH GCP, as well as with any applicable regulatory authority, federal, state, and/or local laws and regulations. Patients were to be informed of all aspects of the study relevant to the patient’s decision to participate, and the ICF was to be presented to each patient in the language in which the patient was fluent. Informed consent was obtained and documented by each patient or patient’s legal representative prior to any protocol-specific procedures. Signed ICFs were retained by the Investigator with the study records. Each patient/legal representative was given a copy of the signed and dated ICF.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Bempegaldesleukin + nivolumab were compared with nivolumab after complete resection of melanoma in patients at high risk for recurrence. Nivolumab 480 mg IV infusion q4w (or 6.0 mg/kg IV infusion q4w for patients < 40 kg) were administrated as reference therapy.
    Actual start date of recruitment
    28 Jul 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 20
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Spain: 84
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Austria: 21
    Country: Number of subjects enrolled
    Czechia: 20
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    Germany: 90
    Country: Number of subjects enrolled
    Greece: 43
    Country: Number of subjects enrolled
    Italy: 74
    Country: Number of subjects enrolled
    Australia: 77
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    New Zealand: 33
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    United States: 141
    Worldwide total number of subjects
    765
    EEA total number of subjects
    439
    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)
    546
    From 65 to 84 years
    217
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 774 subjects were enrolled in the study (386 in the bempegaldesleukin + nivolumab arm and 388 in the nivolumab arm). 9 of 774 subjects were not treated. 765 subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment arms: - Arm A: bempegaldesleukin + nivolumab every 3 weeks (q3w) - Arm B: nivolumab monotherapy every 4 weeks (q4w).

    Pre-assignment
    Screening details
    		 This study was divided into a Screening period, a Treatment period, and a Long-Term Follow-Up period. The subjects who met all the inclusion and none of the exclusion criteria were selected to participate in the study.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: bempegaldesleukin + nivolumab
    Arm description
    		 Bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenous (IV) infusion + nivolumab 360 mg IV infusion (or 4.5 mg/kg IV infusion q3w for patients < 40 kg) were administrated every 3 weeks (q3w).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bempegaldesleukin
    Investigational medicinal product code
    Other name
    NKTR-214
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bempegaldesleukin 0.006 mg/kg intravenous (IV) infusion q3w. NKTR-214 was provided in 1.0 mg and 0.5 mg vials.

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 360 mg IV infusion q3w (or 4.5 mg/kg IV infusion q3w for patients < 40 kg).

    Arm title
    		 Arm B: nivolumab monotherapy
    Arm description
    		 Nivolumab 480 mg IV infusion (or 6.0 mg/kg IV infusion q4w for patients < 40 kg) was administrated every 4 weeks (q4w).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg IV infusion q4w (or 6.0 mg/kg IV infusion q4w for patients < 40 kg).

    Number of subjects in period 1
    		Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Started
    378
    387
    Completed
    348
    363
    Not completed
    30
    24
         Consent withdrawn by subject
    27
    15
         Lost to follow-up
    3
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: bempegaldesleukin + nivolumab
    Reporting group description
    		 Bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenous (IV) infusion + nivolumab 360 mg IV infusion (or 4.5 mg/kg IV infusion q3w for patients < 40 kg) were administrated every 3 weeks (q3w).

    Reporting group title
    Arm B: nivolumab monotherapy
    Reporting group description
    		 Nivolumab 480 mg IV infusion (or 6.0 mg/kg IV infusion q4w for patients < 40 kg) was administrated every 4 weeks (q4w).

    Reporting group values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy Total
    Number of subjects
    		 378 387 765
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 268 278 546
        From 65-84 years
    		 109 108 217
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55 ± 14.21 56 ± 13.45 -
    Gender categorical
    Units: Subjects
        Female
    		 162 148 310
        Male
    		 216 239 455
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A total of 765 patients who received at least 1 dose of study drug (378 patients in the bempegaldesleukin + nivolumab arm; 387 patients in the nivolumab arm) were included in Safety population. Demographic and baseline characteristics are summarized for Safety population. All analyses were performed on the Safety Population.

    Subject analysis sets values
    		 Safety Population
    Number of subjects
    765
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    546
        From 65-84 years
    217
        85 years and over
    2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.5 ± 13.83
    Gender categorical
    Units: Subjects
        Female
    310
        Male
    455

    End points

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    End points reporting groups
    Reporting group title
    Arm A: bempegaldesleukin + nivolumab
    Reporting group description
    		 Bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenous (IV) infusion + nivolumab 360 mg IV infusion (or 4.5 mg/kg IV infusion q3w for patients < 40 kg) were administrated every 3 weeks (q3w).

    Reporting group title
    Arm B: nivolumab monotherapy
    Reporting group description
    		 Nivolumab 480 mg IV infusion (or 6.0 mg/kg IV infusion q4w for patients < 40 kg) was administrated every 4 weeks (q4w).

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A total of 765 patients who received at least 1 dose of study drug (378 patients in the bempegaldesleukin + nivolumab arm; 387 patients in the nivolumab arm) were included in Safety population. Demographic and baseline characteristics are summarized for Safety population. All analyses were performed on the Safety Population.

    Primary: Recurrence-free Survival (RFS) by BICR

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    End point title
    		 Recurrence-free Survival (RFS) by BICR [1]
    End point description
    RFS, defined as the time between the date of randomization and the date of first reccurence (local, regional, or distant metastasis by BICR), a new primary melanoma (by BICR), or all-cause death, whichever occurred first. For this outcome measure, zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early due to the closure of the bempegaldesleukin clinical development program due to lack of enhanced efficacy being observed in combination with nivolumab therapy over nivolumab monotherapy for metastatic melanoma. As consequence, no aggregate blinded independent central review data were available; no comparative analysis between bempegaldesleukin + nivolumab arm vs nivolumab arm were conducted for this efficacy endpoint.
    End point type
    Primary
    End point timeframe
    Patients were treated up to approximately 1 year (maximum of 17 cycles for the bempegaldesleukin + nivolumab arm and 13 cycles for the nivolumab arm).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the early termination of the study, as a consequence of the closure of the bempegaldesleukin clinical program, no BICR data were transferred and analysed, and primary endpoint data was not evaluable.
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy Safety Population
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Time
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    Notes
    [2] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    [3] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    [4] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival (OS) is defined as the time between the date of randomization and the date of death due to any cause. For this outcome measure, the results were not estimable due to insufficient number of events. The number 999 indicates the result was not estimable due to insufficient number of events. The study was terminated early due to the closure of the bempegaldesleukin clinical development program due to lack of enhanced efficacy being observed in combination with nivolumab therapy over nivolumab monotherapy for metastatic melanoma. No comparative analyses between bempegaldesleukin + nivolumab arm vs nivolumab arm were conducted for this efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    378 [5]
    387 [6]
    Units: Months
        number (confidence interval 95%)
    999 (16.9 to 999)
    999 (999 to 999)
    Notes
    [5] - Median and upper CI was not estimable due to insufficient number of events.
    [6] - Median and 95% CI was not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Distant Metastasis-free Survival (DMFS) by Investigator

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    End point title
    		 Distant Metastasis-free Survival (DMFS) by Investigator
    End point description
    For this outcome measure, the results were not estimable due to insufficient number of events. Distant Metastasis-free Survival (DMFS) measured by Investigator in patients who have stage IIIA (LN Metastasis > 1 mm) or IIIB/C/D Melanoma at study entry. Metastasis Free Survival is defined as the time between the date of randomization and the date of first distant metastasis or date of death due to any cause. The number 999 indicate the result was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    347
    355
    Units: Months
        number (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Time to Disease Progression After the Next Line of Treatment

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    End point title
    		 Time to Disease Progression After the Next Line of Treatment
    End point description
    Time to Disease Progression After the Next Line of Treatment measured for study patients following discontinuation of bempegaldesleukin plus nivolumab versus nivolumab. For this outcome measure, zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early due to the closure of the bempegaldesleukin clinical development program due to lack of enhanced efficacy being observed in combination with nivolumab therapy over nivolumab monotherapy for metastatic melanoma. No comparative analyses between bempegaldesleukin + nivolumab arm vs nivolumab arm were conducted for this efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: percent
    number (not applicable)
        Overall Number of Participants Analyzed
    Notes
    [7] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    [8] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    No statistical analyses for this end point

    Secondary: Recurrence-free Survival (RFS) by Investigator

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    End point title
    		 Recurrence-free Survival (RFS) by Investigator
    End point description
    RFS by Investigator Will be Measured Similarly to the Primary Endpoint, But Recurrence and New Primary Melanoma Will be Decided by the Investigator. For this outcome measure, the results were not estimable due to insufficient number of events. The number 999 indicates the result was not estimable due to insufficient number of events. The study was terminated early due to the closure of the bempegaldesleukin clinical development program due to lack of enhanced efficacy being observed in combination with nivolumab therapy over nivolumab monotherapy for metastatic melanoma. As a consequence no comparative analyses between bempegaldesleukin + nivolumab arm vs nivolumab arm were conducted for this efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    378 [9]
    387 [10]
    Units: Months
        number (confidence interval 95%)
    999 (999 to 999)
    999 (14.3 to 999)
    Notes
    [9] - Median and 95% CI was not estimable due to insufficient number of events.
    [10] - Median and upper CI was not estimable due to insufficient number of events.
    No statistical analyses for this end point

    Secondary: Patient Reported Outcomes

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    End point title
    		 Patient Reported Outcomes
    End point description
    Patient Reported Outcomes measured by changes from baseline in scores for the Global Health/Quality of Life and Physical Functioning Subscales of the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire. The EORTC QLQ-C30 comprises 30 items (i.e. single questions), 24 of which are aggregated into nine multi-item scales, that is, five functioning scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and one global health status scale. Due to the study termination, results for the mean change from baseline for GH/QoL and the physical functioning subscale were analyzed at approximately 6 months of treatment.
    End point type
    Secondary
    End point timeframe
    Approximately up to 6 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    378
    387
    Units: Score on a scale
    arithmetic mean (standard deviation)
        GH/QoL
    -3.71 ± 16.933
    -0.66 ± 17.871
        Physical Functioning Subscale
    -2.41 ± 12.168
    -1.13 ± 12.606
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    To evaluate safety and tolerability of (NKTR-214) 0.006 mg/kg in combination with nivolumab 360 mg IV infusion (or 4.5 mg/kg IV infusion q3w for patients <40 kg) and nivolumab 480 mg IV infusion (or 6.0 mg/kg IV infusion q4w for patients < 40 kg). Treatment-emergent adverse event (TEAE) is defined as an AE that was not present prior to treatment with study drug but appeared following treatment or was present at treatment start date but worsened during treatment-emergent period. The treatment-emergent period is defined as the period from the date of the first dose of study drug up to 30 days after the date of the last dose of study drug or the day prior to the initiation of subsequent anticancer treatment, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Approximately up to 21 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    378
    387
    Units: Participants
        Subjects who had a TEAE
    370
    330
        Subjects who had a Serious TEAE
    74
    33
        Subjects who had a TEAE of Grade 3 or Higher
    120
    50
        Subjects who had a TEAE Leading to Death
    1
    0
    No statistical analyses for this end point

    Secondary: Distant Metastasis-free Survival (DMFS) by Blinded Independent Central Review (BICR)

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    End point title
    		 Distant Metastasis-free Survival (DMFS) by Blinded Independent Central Review (BICR)
    End point description
    Distant Metastasis-free Survival (DMFS) measured by Blinded Independent Central Review (BICR) in Patients Who Have Stage IIIA (LN Metastasis > 1 mm) or IIIB/C/D Melanoma at Study Entry. Distant Metastasis Free Survival is defined as the time between the date of randomization and the date of first distant metastasis or date of death due to any cause. For this outcome measure, zero (”0”) participants were analysed in each Arm/Group.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Months
    number (not applicable)
        Overall Number of Participants Analyzed
    Notes
    [11] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    [12] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    No statistical analyses for this end point

    Secondary: The Predictive Strength of PD-L1 Expression as a Biomarker

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    End point title
    		 The Predictive Strength of PD-L1 Expression as a Biomarker
    End point description
    The Predictive Strength of PD-L1 Expression as a Biomarker was measured by the endpoint RFS by BICR based on PD-L1 expression level. For this outcome measure, zero (”0”) participants were analysed in each Arm/Group. The study was terminated early due to the closure of the bempegaldesleukin clinical development program due to lack of enhanced efficacy being observed in combination with nivolumab therapy over nivolumab monotherapy for metastatic melanoma. As a consequence, no aggregate blinded independent central review data were available; no comparative analyses between bempegaldesleukin + nivolumab arm vs nivolumab arm were conducted for this efficacy endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Participants
        Overall Number of Participants Analyzed
    Notes
    [13] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    [14] - Zero (”0”) participants were analyzed in each Arm/Group. The study was terminated early.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs will be reported starting immediately after the patient has been administered the first dose of study drug(s) until 100 days (+/- 7 days) after the last dose of all study drug(s).
    Adverse event reporting additional description
    All ongoing non-serious AEs will be followed until resolution, the patient is lost to follow-up, patient death, or until the last Safety Follow-Up Visit. If the AE has not completely resolved by the last Safety Follow-Up Visit, the final outcome of these ongoing AEs will be captured.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Arm A: bempegaldesleukin + nivolumab
    Reporting group description
    		 Bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenous (IV) infusion + nivolumab 360 mg IV infusion (or 4.5 mg/kg IV infusion q3w for patients < 40 kg) were administrated every 3 weeks (q3w).

    Reporting group title
    Arm B: nivolumab monotherapy
    Reporting group description
    		 Nivolumab 480 mg IV infusion (or 6.0 mg/kg IV infusion q4w for patients < 40 kg) was administrated every 4 weeks (q4w).

    Serious adverse events
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 378 (19.58%)
    33 / 387 (8.53%)
         number of deaths (all causes)
    9
    4
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor venous access
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 378 (1.59%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    3 / 378 (0.79%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Capillary permeability increased
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haemorrhage
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 378 (1.06%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    3 / 378 (0.79%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune myocarditis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 378 (0.79%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune neuropathy
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 378 (0.79%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    3 / 378 (0.79%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 378 (0.53%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Primary adrenal insufficiency
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune myositis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Coronavirus infection
         subjects affected / exposed
    3 / 378 (0.79%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 378 (0.26%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 378 (0.26%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 378 (0.00%)
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 378 (0.53%)
    0 / 387 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 378 (0.00%)
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: bempegaldesleukin + nivolumab Arm B: nivolumab monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    369 / 378 (97.62%)
    329 / 387 (85.01%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    40 / 378 (10.58%)
    3 / 387 (0.78%)
         occurrences all number
    65
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    160 / 378 (42.33%)
    22 / 387 (5.68%)
         occurrences all number
    417
    27
    Fatigue
         subjects affected / exposed
    154 / 378 (40.74%)
    112 / 387 (28.94%)
         occurrences all number
    262
    128
    Influenza like illness
         subjects affected / exposed
    114 / 378 (30.16%)
    11 / 387 (2.84%)
         occurrences all number
    327
    13
    Asthenia
         subjects affected / exposed
    70 / 378 (18.52%)
    38 / 387 (9.82%)
         occurrences all number
    136
    50
    Chills
         subjects affected / exposed
    55 / 378 (14.55%)
    7 / 387 (1.81%)
         occurrences all number
    80
    9
    Face oedema
         subjects affected / exposed
    21 / 378 (5.56%)
    1 / 387 (0.26%)
         occurrences all number
    35
    1
    Oedema peripheral
         subjects affected / exposed
    21 / 378 (5.56%)
    7 / 387 (1.81%)
         occurrences all number
    42
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    52 / 378 (13.76%)
    16 / 387 (4.13%)
         occurrences all number
    58
    18
    Dyspnoea
         subjects affected / exposed
    40 / 378 (10.58%)
    14 / 387 (3.62%)
         occurrences all number
    56
    14
    Nasal congestion
         subjects affected / exposed
    22 / 378 (5.82%)
    4 / 387 (1.03%)
         occurrences all number
    31
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    26 / 378 (6.88%)
    22 / 387 (5.68%)
         occurrences all number
    30
    23
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    37 / 378 (9.79%)
    24 / 387 (6.20%)
         occurrences all number
    47
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    27 / 378 (7.14%)
    22 / 387 (5.68%)
         occurrences all number
    36
    22
    Nervous system disorders
    Headache
         subjects affected / exposed
    85 / 378 (22.49%)
    46 / 387 (11.89%)
         occurrences all number
    139
    50
    Dizziness
         subjects affected / exposed
    37 / 378 (9.79%)
    18 / 387 (4.65%)
         occurrences all number
    47
    21
    Paraesthesia
         subjects affected / exposed
    20 / 378 (5.29%)
    4 / 387 (1.03%)
         occurrences all number
    24
    4
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    45 / 378 (11.90%)
    7 / 387 (1.81%)
         occurrences all number
    53
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    106 / 378 (28.04%)
    50 / 387 (12.92%)
         occurrences all number
    182
    57
    Diarrhoea
         subjects affected / exposed
    101 / 378 (26.72%)
    68 / 387 (17.57%)
         occurrences all number
    138
    94
    Vomiting
         subjects affected / exposed
    52 / 378 (13.76%)
    17 / 387 (4.39%)
         occurrences all number
    85
    22
    Abdominal pain upper
         subjects affected / exposed
    34 / 378 (8.99%)
    12 / 387 (3.10%)
         occurrences all number
    39
    12
    Dry mouth
         subjects affected / exposed
    33 / 378 (8.73%)
    15 / 387 (3.88%)
         occurrences all number
    34
    15
    Abdominal pain
         subjects affected / exposed
    24 / 378 (6.35%)
    18 / 387 (4.65%)
         occurrences all number
    33
    20
    Constipation
         subjects affected / exposed
    23 / 378 (6.08%)
    27 / 387 (6.98%)
         occurrences all number
    24
    28
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    95 / 378 (25.13%)
    54 / 387 (13.95%)
         occurrences all number
    119
    57
    Rash
         subjects affected / exposed
    75 / 378 (19.84%)
    34 / 387 (8.79%)
         occurrences all number
    103
    35
    Rash maculo-papular
         subjects affected / exposed
    55 / 378 (14.55%)
    21 / 387 (5.43%)
         occurrences all number
    103
    35
    Erythema
         subjects affected / exposed
    46 / 378 (12.17%)
    4 / 387 (1.03%)
         occurrences all number
    60
    4
    Dry skin
         subjects affected / exposed
    31 / 378 (8.20%)
    9 / 387 (2.33%)
         occurrences all number
    34
    9
    Pruritus generalised
         subjects affected / exposed
    37 / 378 (9.79%)
    9 / 387 (2.33%)
         occurrences all number
    46
    9
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    80 / 378 (21.16%)
    35 / 387 (9.04%)
         occurrences all number
    80
    35
    Hypothyroidism
         subjects affected / exposed
    65 / 378 (17.20%)
    39 / 387 (10.08%)
         occurrences all number
    66
    40
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    83 / 378 (21.96%)
    49 / 387 (12.66%)
         occurrences all number
    140
    54
    Myalgia
         subjects affected / exposed
    67 / 378 (17.72%)
    23 / 387 (5.94%)
         occurrences all number
    110
    25
    Back pain
         subjects affected / exposed
    33 / 378 (8.73%)
    15 / 387 (3.88%)
         occurrences all number
    50
    17
    Pain in extremity
         subjects affected / exposed
    23 / 378 (6.08%)
    15 / 387 (3.88%)
         occurrences all number
    31
    15
    Musculoskeletal pain
         subjects affected / exposed
    19 / 378 (5.03%)
    7 / 387 (1.81%)
         occurrences all number
    28
    10
    Infections and infestations
    Coronavirus infection
         subjects affected / exposed
    49 / 378 (12.96%)
    47 / 387 (12.14%)
         occurrences all number
    49
    50
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    53 / 378 (14.02%)
    13 / 387 (3.36%)
         occurrences all number
    75
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2021
    • Added DMFS by BICR as a secondary objective of the study and associated data analysis. • Elevated time to disease progression after the next line of treatment from an exploratory objective to a secondary objective of the study. • Clarified the definition for end of study. • Clarified that patients ≥ 12 years of age at the time of signing the informed consent are eligible to participate in the study, except where local regulations, countries and/or institutional policies do not allow for patients < 18 years of age (adolescents) to participate. • Modified inclusion criterion 11.c to indicate women should use “effective methods” of contraception. • Modified exclusion criterion 19 to extract Criterion 19b for TIA/CVA to its own exclusion criterion 20. • Added a new section for measures of treatment compliance. • Specified the EORTC QLQ-C30 and EQ-5D-5L to be administered before any other study-related procedures, with the EORTC QLQ-C30 assessed before the EQ-5D-5L. • Removed medical resource utilization and healthcare economics from study assessments. • Clarified PK and immunogenicity blood samples should be drawn from a site other than the infusion site (ie, contralateral arm) on days of infusion and clarified the sample analysis methodologies. • Added blood samples to be collected for exploratory biomarker analysis to characterize TIA events and clarified blood samples should be collected as close as possible to the new CVA or TIA event. • Reorganized monitoring and management of bempegaldesleukin-induced eosinophilia; updated language characterizing eosinophilia in patients receiving bempegaldesleukin; added language to describe isolated cases of hypereosinophilic syndrome and drug reaction with eosinophilia. • Other changes.

    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.
    Not applicable
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