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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Ravulizumab in Complement-Inhibitor-Naïve Adult Patients With Generalized Myasthenia Gravis

    Summary
    EudraCT number
    		 2018-003243-39
    Trial protocol
    		 DE   AT   NL   DK   ES   FR   CZ   GB   PT   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 May 2024
    First version publication date
    03 Jun 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALXN1210-MG-306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03920293
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Inc.
    Sponsor organisation address
    100 College Street, New Haven, CT, United States, 06510
    Public contact
    Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 7 87148158, clinicaltrials.eu@alexion.com
    Scientific contact
    Alexion Europe SAS European Clinical Trial Information, Alexion Pharmaceuticals Inc., +33 7 87148158, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    Interim
    Date of interim/final analysis
    30 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study is to evaluate the safety and efficacy of ravulizumab for the treatment of participants with generalized myasthenia gravis (gMG).
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: • Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines • Applicable International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines • Applicable laws and regulations
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United States: 74
    Worldwide total number of subjects
    175
    EEA total number of subjects
    60
    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)
    115
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1 to either the ravulizumab or placebo group during the Randomized-Controlled Period. Following the placebo-controlled part of the study, participants were transitioned to the ongoing Open-Label Extension Period to receive treatment with ravulizumab.

    Period 1
    Period 1 title
    Randomized-Controlled Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ravulizumab
    Arm description
    		 Participants received a weight-based single loading dose (2400 to 3000 milligrams [mg]) of ravulizumab intravenously (IV) on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 once every 8 weeks (q8w), during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210 Ultomiris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received ravulizumab at prespecified dose and timepoints.

    Arm title
    		 Placebo
    Arm description
    		 Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received placebo at prespecified dose and timepoints.

    Number of subjects in period 1
    		Ravulizumab Placebo
    Started
    86
    89
    Received at Least 1 Dose of Study Drug
    86
    89
    Completed
    79
    83
    Not completed
    7
    6
         Adverse event, serious fatal
    2
    -
         Consent withdrawn by subject
    2
    1
         Physician decision
    1
    2
         Adverse event, non-fatal
    -
    2
         Sponsor Decision
    -
    1
         Protocol deviation
    1
    -
         Noncompliance
    1
    -
    Period 2
    Period 2 title
    Open- Label Extension Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ravulizumab to Ravulizumab
    Arm description
    		 Participants received a weight-based single loading dose (2400 to 3000 milligrams [mg]) of ravulizumab intravenously (IV) on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 once every 8 weeks (q8w), during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ravulizumab
    Investigational medicinal product code
    Other name
    ALXN1210 Ultomiris
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received ravulizumab at prespecified dose and timepoints.

    Arm title
    		 Placebo to Ravulizumab
    Arm description
    		 Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received placebo at prespecified dose and timepoints.

    Number of subjects in period 2 [1]
    		Ravulizumab to Ravulizumab Placebo to Ravulizumab
    Started
    78
    83
    Completed
    60
    63
    Not completed
    18
    20
         Consent withdrawn by subject
    7
    9
         Physician decision
    5
    3
         Subjects transitioned to other t/t by Investigator
    3
    5
         Death
    3
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 participant in the Ravulizumab group withdrew from the study and did not enter the open label extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ravulizumab
    Reporting group description
    		 Participants received a weight-based single loading dose (2400 to 3000 milligrams [mg]) of ravulizumab intravenously (IV) on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 once every 8 weeks (q8w), during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Reporting group values
    		 Ravulizumab Placebo Total
    Number of subjects
    		 86 89 175
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.0 ( 13.82 ) 53.3 ( 16.05 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 44 45 89
        Male
    		 42 44 86
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 5 7
        Not Hispanic or Latino
    		 79 78 157
        Unknown or Not Reported
    		 5 6 11
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 15 16 31
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 4 6
        White
    		 67 61 128
        Other
    		 0 1 1
        Unknown or Not Reported
    		 2 6 8

    End points

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    End points reporting groups
    Reporting group title
    Ravulizumab
    Reporting group description
    		 Participants received a weight-based single loading dose (2400 to 3000 milligrams [mg]) of ravulizumab intravenously (IV) on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 once every 8 weeks (q8w), during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.
    Reporting group title
    Ravulizumab to Ravulizumab
    Reporting group description
    		 Participants received a weight-based single loading dose (2400 to 3000 milligrams [mg]) of ravulizumab intravenously (IV) on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 once every 8 weeks (q8w), during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Reporting group title
    Placebo to Ravulizumab
    Reporting group description
    		 Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Primary: Change From Baseline In Myasthenia Gravis-Activities Of Daily Living (MG-ADL) Total Score At Week 26

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    End point title
    		 Change From Baseline In Myasthenia Gravis-Activities Of Daily Living (MG-ADL) Total Score At Week 26
    End point description
    MG-ADL: 8-point questionnaire focusing on relevant symptoms/functional performance of activities of daily living in participants with MG. The 8 items of MGADL questionnaire derived from symptom-based components of original 13-item QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response was graded 0 (normal)-3 (most severe). Range of total MG-ADL score: 0-24. Decrease in score indicated improvement. Estimates based on MMRM that included treatment group, stratification factor region, and MG-ADL total score at baseline, study visit, and study visit by treatment group interaction. Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Ravulizumab Placebo
    Number of subjects analysed
    86
    89
    Units: units on a scale
        least squares mean (standard error)
    -3.1 ( 0.38 )
    -1.4 ( 0.37 )
    Statistical analysis title
    		 Ravulizumab versus Placebo
    Comparison groups
    Ravulizumab v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0009 [1]
    Method
    		 MMRM
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.49
    Notes
    [1] - Statistical significance was tested at α=0.05.

    Secondary: Change From Baseline In The Quantitative Myasthenia Gravis (QMG) Total Score At Week 26

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    End point title
    		 Change From Baseline In The Quantitative Myasthenia Gravis (QMG) Total Score At Week 26
    End point description
    The QMG scoring system consisted of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0 to 39. The QMG scoring system was considered to be an objective evaluation of therapy for MG and was based on quantitative testing of sentinel muscle groups. A decrease in score indicated improvement. Estimates were based on MMRM that included treatment group, stratification factor region, and QMG total score at baseline, study visit, and study visit by treatment group interaction. Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Ravulizumab Placebo
    Number of subjects analysed
    86
    89
    Units: units on a scale
        least squares mean (standard error)
    -2.8 ( 0.46 )
    -0.8 ( 0.45 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In the Revised 15 Component Myasthenia Gravis Quality of Life (MG-QOL15r) At Week 26

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    End point title
    		 Change From Baseline In the Revised 15 Component Myasthenia Gravis Quality of Life (MG-QOL15r) At Week 26
    End point description
    The revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QOL15r) is a health-related QoL evaluative instrument specific to participants with MG. MG-QOL15r was designed to provide information about participants’ perception of impairment and disability, determine the degree to which disease manifestations are tolerated, and to be administered and interpreted easily. Each item was graded on a scale of 0 to 2, with 2 being the most severe. The range of MG-QOL15r score is 0 to 30. Higher scores indicated greater extent of and dissatisfaction with MG-related dysfunction. Estimates are based on MMRM that included treatment group, stratification factor region and MG-QOL15r score at baseline, study visit and study visit by treatment group interaction. Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Ravulizumab Placebo
    Number of subjects analysed
    86
    89
    Units: score on a scale
        least squares mean (standard error)
    -3.3 ( 0.71 )
    -1.6 ( 0.70 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Quantitative Myasthenia Gravis (QMG) Total Score Reduction of at Least 5 Points At Week 26

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    End point title
    		 Percentage of Participants With a Quantitative Myasthenia Gravis (QMG) Total Score Reduction of at Least 5 Points At Week 26
    End point description
    The QMG scoring system consisted of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0 to 39. A decrease in score indicated improvement. Percentage of participants with a ≥5-point reduction in the QMG total score are reported. Estimates were based on a generalized linear mixed model (GLMM) that included treatment group, stratification factor region and QMG total score at baseline, study visit and study visit by treatment group interaction. Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Ravulizumab Placebo
    Number of subjects analysed
    86
    89
    Units: percentage of participants
        number (confidence interval 95%)
    30.0 (19.2 to 43.5)
    11.3 (5.6 to 21.5)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Neurological Quality of Life (Neuro-QoL) Fatigue Score at Week 26

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    End point title
    		 Change from Baseline in Neurological Quality of Life (Neuro-QoL) Fatigue Score at Week 26
    End point description
    The Neuro-QOL Fatigue is a reliable and validated brief 19-item survey of fatigue, completed by the participant. Each items was rated on a scale of 1 to 5, with 5 being the most severe. The range of total score is 19 to 95. Higher scores indicated greater fatigue and greater impact of MG on activities. Estimates were based on MMRM that included treatment group, stratification factor region and Neuro-QoL Fatigue score at baseline, study visit, and study visit by treatment group interaction. Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Ravulizumab Placebo
    Number of subjects analysed
    86
    89
    Units: units on a scale
        least squares mean (standard error)
    -7.0 ( 1.92 )
    -4.8 ( 1.87 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction of at Least 3 Points At Week 26

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    End point title
    		 Percentage of Participants with a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction of at Least 3 Points At Week 26
    End point description
    MG-ADL is an 8-point questionnaire that focused on relevant symptoms and functional performance of activities of daily living in participants with MG. The 8 items of the MGADL questionnaire derived from symptom-based components of the original 13-item QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response was graded 0 (normal)-3 (most severe). Range of total MG-ADL score was 0-24. A decrease in score indicated improvement. Percentage of participants with a ≥3-point reduction in the MG-ADL total score are reported. Estimates based on a GLMM that included treatment group, stratification factor region and MG-ADL total score at baseline, study visit and study visit by treatment group interaction. Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Ravulizumab Placebo
    Number of subjects analysed
    86
    89
    Units: percentage of participants
        number (confidence interval 95%)
    56.7 (44.3 to 68.3)
    34.1 (23.8 to 46.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) up to 2 years
    Adverse event reporting additional description
    Treatment-emergent adverse events were reported for 26-week randomized-controlled period and open-label extension period separately.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Randomized-Controlled Period: Ravulizumab
    Reporting group description
    		 Participants received a weight-based single loading dose (2400 to 3000 mg) of ravulizumab IV on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 q8w during the 26-week Randomized-Controlled Period of the study. Following the placebo-controlled part of the study, participants were transitioned to the ongoing Open-Label Extension Period to receive treatment with ravulizumab.

    Reporting group title
    Open-Label Extension Period: Placebo to Ravulizumab
    Reporting group description
    		 After the randomized-controlled part of the study, participants in the placebo group were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Reporting group title
    Randomized-Controlled Period: Placebo
    Reporting group description
    		 Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. Following the placebo-controlled part of the study, participants were transitioned to the ongoing Open-Label Extension Period to receive treatment with ravulizumab.

    Reporting group title
    Open-Label Extension Period: Ravulizumab to Ravulizumab
    Reporting group description
    		 After the randomized-controlled part of the study, participants in the ravulizumab group were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years.

    Serious adverse events
    		 Randomized-Controlled Period: Ravulizumab Open-Label Extension Period: Placebo to Ravulizumab Randomized-Controlled Period: Placebo Open-Label Extension Period: Ravulizumab to Ravulizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 86 (23.26%)
    32 / 83 (38.55%)
    14 / 89 (15.73%)
    24 / 78 (30.77%)
         number of deaths (all causes)
    2
    3
    0
    3
         number of deaths resulting from adverse events
    2
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ureteral neoplasm
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic cystadenoma
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Vein rupture
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion-related reaction
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Myasthenia gravis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    3 / 89 (3.37%)
    4 / 78 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Granuloma skin
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nodal osteoarthritis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 86 (0.00%)
    9 / 83 (10.84%)
    0 / 89 (0.00%)
    11 / 78 (14.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 15
    0 / 0
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    0 / 89 (0.00%)
    6 / 78 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 86 (0.00%)
    10 / 83 (12.05%)
    0 / 89 (0.00%)
    6 / 78 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 83 (2.41%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    1 / 89 (1.12%)
    4 / 78 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    2 / 89 (2.25%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neisseria infection
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gonococcal infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    1 / 89 (1.12%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized-Controlled Period: Ravulizumab Open-Label Extension Period: Placebo to Ravulizumab Randomized-Controlled Period: Placebo Open-Label Extension Period: Ravulizumab to Ravulizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 86 (89.53%)
    79 / 83 (95.18%)
    75 / 89 (84.27%)
    77 / 78 (98.72%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 86 (0.00%)
    10 / 83 (12.05%)
    0 / 89 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    11
    0
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    3 / 78 (3.85%)
         occurrences all number
    0
    7
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 86 (9.30%)
    6 / 83 (7.23%)
    3 / 89 (3.37%)
    4 / 78 (5.13%)
         occurrences all number
    9
    10
    3
    5
    Headache
         subjects affected / exposed
    16 / 86 (18.60%)
    17 / 83 (20.48%)
    23 / 89 (25.84%)
    12 / 78 (15.38%)
         occurrences all number
    19
    21
    27
    19
    Myasthenia gravis
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 83 (3.61%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    3
    0
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 86 (6.98%)
    1 / 83 (1.20%)
    6 / 89 (6.74%)
    0 / 78 (0.00%)
         occurrences all number
    7
    1
    6
    0
    Pyrexia
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 83 (2.41%)
    5 / 89 (5.62%)
    0 / 78 (0.00%)
         occurrences all number
    1
    2
    6
    0
    General physical health deterioration
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    0
    0
    1
    Death
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 83 (0.00%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 86 (5.81%)
    4 / 83 (4.82%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    6
    5
    0
    4
    Diarrhoea
         subjects affected / exposed
    13 / 86 (15.12%)
    10 / 83 (12.05%)
    11 / 89 (12.36%)
    6 / 78 (7.69%)
         occurrences all number
    14
    12
    15
    6
    Nausea
         subjects affected / exposed
    9 / 86 (10.47%)
    9 / 83 (10.84%)
    9 / 89 (10.11%)
    7 / 78 (8.97%)
         occurrences all number
    12
    18
    10
    8
    Vomiting
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    1 / 78 (1.28%)
         occurrences all number
    0
    5
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    0 / 78 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 86 (0.00%)
    6 / 83 (7.23%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    6
    0
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 83 (1.20%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    1
    0
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 86 (0.00%)
    7 / 83 (8.43%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    8
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 86 (6.98%)
    9 / 83 (10.84%)
    7 / 89 (7.87%)
    11 / 78 (14.10%)
         occurrences all number
    8
    15
    8
    14
    Back pain
         subjects affected / exposed
    7 / 86 (8.14%)
    10 / 83 (12.05%)
    5 / 89 (5.62%)
    6 / 78 (7.69%)
         occurrences all number
    7
    10
    5
    6
    Myalgia
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    5
    0
    5
    Pain in extremity
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 83 (2.41%)
    0 / 89 (0.00%)
    6 / 78 (7.69%)
         occurrences all number
    0
    2
    0
    8
    Muscle spasms
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 83 (6.02%)
    0 / 89 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    5
    0
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 86 (5.81%)
    26 / 83 (31.33%)
    3 / 89 (3.37%)
    30 / 78 (38.46%)
         occurrences all number
    5
    28
    3
    32
    Urinary tract infection
         subjects affected / exposed
    5 / 86 (5.81%)
    8 / 83 (9.64%)
    4 / 89 (4.49%)
    7 / 78 (8.97%)
         occurrences all number
    7
    13
    5
    9
    Nasopharyngitis
         subjects affected / exposed
    3 / 86 (3.49%)
    11 / 83 (13.25%)
    5 / 89 (5.62%)
    8 / 78 (10.26%)
         occurrences all number
    3
    18
    7
    10
    Bronchitis
         subjects affected / exposed
    0 / 86 (0.00%)
    4 / 83 (4.82%)
    0 / 89 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    0
    4
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 86 (0.00%)
    9 / 83 (10.84%)
    0 / 89 (0.00%)
    2 / 78 (2.56%)
         occurrences all number
    0
    9
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2018
    The purpose of this amendment was to change duration of safety follow-up after last dose; add additional details on assessments, align pregnancy and clinical laboratory testing frequency with infusions; change supplemental dosing recommendations and sample collection when rescue therapy is provided; and update adverse event and pregnancy/contraception language.
    25 Oct 2019
    The purpose of this amendment was to revise secondary and exploratory endpoints, to decrease burden to participants by reduction in assessment and visit frequency, to provide additional guidance for supplemental dosing, and to clarify minor operational aspects of the protocol.

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

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

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