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    Clinical Trial Results:
    A phase 2, multicenter, open-label study to assess appropriate dosing and to evaluate safety of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in sequential, descending age groups of pediatric sickle cell disease patients with vaso-occlusive crisis

    Summary
    EudraCT number
    		 2017-001747-12
    Trial protocol
    		 GB   DE   ES   FR   BE   IT  
    Global end of trial date
    06 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 May 2025
    First version publication date
    17 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSEG101B2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03474965
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Nov 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To confirm and establish appropriate dosing of crizanlizumab in participants aged 2 to <18 years at the time of study entry (Part A and B) -To evaluate the safety of crizanlizumab in participants aged 2 to <18 years at the time of study entry (Parts A and B). Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    India: 2
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Lebanon: 11
    Country: Number of subjects enrolled
    Oman: 8
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Türkiye: 6
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    117
    EEA total number of subjects
    33
    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)
    67
    Adolescents (12-17 years)
    50
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 117 participants were enrolled in the trial in total.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Age 12 to <18 years, 5 mg/kg
    Arm description
    		 Age 12 to <18 years, 5 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    crizanlizumab
    Investigational medicinal product code
    SEG101
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SEG101 (crizanlizumab) 5 mg/kg i.v. administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4- week cycle

    Arm title
    		 Age 6 to <12 years, 5 mg/kg
    Arm description
    		 Age 6 to <12 years, 5 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    crizanlizumab
    Investigational medicinal product code
    SEG101
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SEG101 (crizanlizumab) 5 mg/kg or 8.5 mg/kg i.v. administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4- week cycle

    Arm title
    		 Age 6 to <12 years, 8.5 mg/kg
    Arm description
    		 Age 6 to <12 years, 8.5 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    crizanlizumab
    Investigational medicinal product code
    SEG101
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SEG101 (crizanlizumab) 8.5 mg/kg i.v. administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4- week cycle

    Arm title
    		 Age 2 to <6 years, 8.5 mg/kg
    Arm description
    		 Age 2 to <6 years, 8.5 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    crizanlizumab
    Investigational medicinal product code
    SEG101
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    SEG101 (crizanlizumab) 8.5 mg/kg i.v. administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4- week cycle

    Number of subjects in period 1
    		Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Started
    50
    13
    40
    14
    Completed
    33
    10
    29
    11
    Not completed
    17
    3
    11
    3
         Adverse event, serious fatal
    1
    -
    -
    -
         Participant Decision
    7
    -
    1
    -
         Physician decision
    3
    1
    2
    -
         Adverse event, non-fatal
    1
    -
    -
    1
         Pregnancy
    1
    -
    -
    -
         Guardian Decision
    4
    2
    7
    2
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age 12 to <18 years, 5 mg/kg
    Reporting group description
    		 Age 12 to <18 years, 5 mg/kg

    Reporting group title
    Age 6 to <12 years, 5 mg/kg
    Reporting group description
    		 Age 6 to <12 years, 5 mg/kg

    Reporting group title
    Age 6 to <12 years, 8.5 mg/kg
    Reporting group description
    		 Age 6 to <12 years, 8.5 mg/kg

    Reporting group title
    Age 2 to <6 years, 8.5 mg/kg
    Reporting group description
    		 Age 2 to <6 years, 8.5 mg/kg

    Reporting group values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg Total
    Number of subjects
    		 50 13 40 14 117
    Age Categorical
    Units: Participants
        <=18 years
    		 50 13 40 14 117
        Between 18 and 65 years
    		 0 0 0 0 0
        >=65 years
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 15.00 ( 1.921 ) 8.87 ( 1.745 ) 9.29 ( 1.614 ) 4.81 ( 0.868 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 29 5 17 5 56
        Male
    		 21 8 23 9 61
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 3 4 7
        Asian
    		 7 0 3 0 10
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 32 7 19 8 66
        White
    		 11 4 13 2 30
        More than one race
    		 0 2 2 0 4
        Unknown or Not Reported
    		 0 0 0 0 0
    Age, Customized
    Units: Subjects
        0 - <28 d
    		 0 0 0 0 0
        28 d - <2 y
    		 0 0 0 0 0
        2 y - <12 y
    		 0 13 40 14 67
        12 y - <18 y
    		 50 0 0 0 50

    End points

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    End points reporting groups
    Reporting group title
    Age 12 to <18 years, 5 mg/kg
    Reporting group description
    		 Age 12 to <18 years, 5 mg/kg

    Reporting group title
    Age 6 to <12 years, 5 mg/kg
    Reporting group description
    		 Age 6 to <12 years, 5 mg/kg

    Reporting group title
    Age 6 to <12 years, 8.5 mg/kg
    Reporting group description
    		 Age 6 to <12 years, 8.5 mg/kg

    Reporting group title
    Age 2 to <6 years, 8.5 mg/kg
    Reporting group description
    		 Age 2 to <6 years, 8.5 mg/kg

    Primary: Pharmacokinetics (PK): AUCd15 of crizanlizumab after first dose - Part A

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    End point title
    		 Pharmacokinetics (PK): AUCd15 of crizanlizumab after first dose - Part A [1]
    End point description
    The area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) following the first dose. AUCd15 was calculated based on serum concentrations of crizanlizumab.
    End point type
    Primary
    End point timeframe
    Week 1
    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: single arm study - statistical analyses is not applicable.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    10
    11
    13
    10
    Units: hr*ug/mL
        arithmetic mean (standard deviation)
    10500 ( 2290 )
    8180 ( 1620 )
    20600 ( 4530 )
    14400 ( 3990 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics (PK) - AUCtau for serum crizanlizumab after multiple doses - Part A - steady state

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    End point title
    		 Pharmacokinetics (PK) - AUCtau for serum crizanlizumab after multiple doses - Part A - steady state [2]
    End point description
    The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1).
    End point type
    Primary
    End point timeframe
    Week 15 - Steady state
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: single arm study - statistical analyses is not applicable.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    7
    6
    11
    12
    Units: hr*ug/mL
        arithmetic mean (standard deviation)
    15800 ( 2080 )
    14800 ( 3770 )
    35700 ( 8100 )
    22100 ( 6200 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics (PK) - Cmax for Crizanlizumab after first dose and multiple doses - Part A - steady state

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    End point title
    		 Pharmacokinetics (PK) - Cmax for Crizanlizumab after first dose and multiple doses - Part A - steady state [3]
    End point description
    The maximum (peak) observed, serum, drug concentration after single or multiple dose administration (mass x volume-1)
    End point type
    Primary
    End point timeframe
    Week 1 (after first dose) and Week 15 (steady state)
    Notes
    [3] - 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: single arm study - statistical analyses is not applicable.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    11
    11
    13
    12
    Units: ug/mL
    arithmetic mean (standard deviation)
        PK Single Dose (Week 1) (n=11,11,13,10)
    80.5 ( 17.7 )
    65.9 ( 11.3 )
    175 ( 36.0 )
    110 ( 37.3 )
        PK Multiple Dose - Week 15 (n=7,8,12,12)
    95.6 ( 26.6 )
    77.5 ( 19.0 )
    171 ( 35.3 )
    111 ( 27.4 )
    No statistical analyses for this end point

    Primary: Pharmacodynamics (PD) - P-selectin inhibition parameters for crizanlizumab after first dose - Part A - AUCd15

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    End point title
    		 Pharmacodynamics (PD) - P-selectin inhibition parameters for crizanlizumab after first dose - Part A - AUCd15 [4]
    End point description
    The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) following the first dose. AUCd15 was calculated based on P-selectin inhibition curves.
    End point type
    Primary
    End point timeframe
    Week 1
    Notes
    [4] - 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: single arm study - statistical analyses is not applicable.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    11
    12
    13
    0 [5]
    Units: hr*{Percent} inhibition P-selectin
        arithmetic mean (standard deviation)
    33700 ( 2440 )
    34400 ( 3660 )
    33200 ( 3410 )
    ( )
    Notes
    [5] - insufficient samples
    No statistical analyses for this end point

    Primary: Pharmacodynamics (PD) - P-selectin inhibition parameters for crizanlizumab - Part A - AUCtau after multiple dose - steady state

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    End point title
    		 Pharmacodynamics (PD) - P-selectin inhibition parameters for crizanlizumab - Part A - AUCtau after multiple dose - steady state [6]
    End point description
    The AUC of %inhibition calculated to the end of a dosing interval (tau) after multiple dose. AUCtau was calculated based on P-selectin inhibition curves.
    End point type
    Primary
    End point timeframe
    Week 15 - Steady state
    Notes
    [6] - 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: single arm study - statistical analyses is not applicable.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    6
    7
    11
    10
    Units: hr*{Percent} inhibition P-selectin
        arithmetic mean (standard deviation)
    66700 ( 9560 )
    64800 ( 3550 )
    68600 ( 9210 )
    66300 ( 5710 )
    No statistical analyses for this end point

    Primary: Frequency of any adverse events (AEs) as a measure of safety and tolerability

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    End point title
    		 Frequency of any adverse events (AEs) as a measure of safety and tolerability [7]
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject
    End point type
    Primary
    End point timeframe
    Adverse events are reported from the first dose of study treatment until end of study treatment Week 103 plus 105 days post-treatment follow-up, up to a maximum timeframe of approximately 2 years and 3.25 months.
    Notes
    [7] - 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: single arm study - statistical analyses is not applicable.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: Participants
        Adverse events (AEs)
    47
    13
    38
    14
        AEs -Treatment-related
    16
    5
    14
    4
        Serious Adverse events (SAEs)
    18
    9
    20
    12
        SAEs -Treatment-related
    1
    1
    2
    1
        Fatal SAEs
    1
    0
    0
    0
        Fatal SAEs-Treatment-related
    0
    0
    0
    0
        AEs leading to dose interruption/reduction
    17
    6
    10
    7
        AEs requiring additional therapy
    45
    13
    37
    14
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit in clinic / Emergency Room (ER) / hospital

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit in clinic / Emergency Room (ER) / hospital
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. The baseline annualized rate of VOC was defined as the number of VOCs leading to healthcare visit occurring within the last 12 months prior to screening until first dose. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B)
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1 and Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: VOC events per year
    median (full range (min-max))
        Baseline annualized (annual.) rate of VOC
    3.00 (1.0 to 26.0)
    1.00 (0.0 to 6.0)
    2.00 (1.0 to 13.0)
    1.00 (1.0 to 5.0)
        Annualized rate of VOC on treatment (up to Year 2)
    1.80 (0.0 to 14.5)
    0.79 (0.0 to 10.4)
    1.48 (0.0 to 8.7)
    1.22 (0.0 to 5.3)
        Annual. rate of VOC on trt. Year 1 (n=42,11,35,12)
    2.00 (0.0 to 14.0)
    0.00 (0.0 to 4.0)
    1.00 (0.0 to 6.0)
    0.00 (0.0 to 3.0)
        Annual. rate of VOC on trt. Year 2 (n=32,10,27,10)
    2.00 (0.0 to 8.0)
    0.00 (0.0 to 5.0)
    1.00 (0.0 to 9.0)
    2.00 (0.0 to 4.0)
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient)

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient)
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B)
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    19
    2
    10
    2
    Units: rate
        median (full range (min-max))
    0.94 (0.5 to 3.9)
    2.71 (0.5 to 4.9)
    0.49 (0.49 to 3.0)
    0.73 (0.5 to 1.0)
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - uncomplicated pain crisis

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - uncomplicated pain crisis
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Uncomplicated pain crisis is defined as an acute episode of pain with no known cause for pain other than a vaso-occlusive event; and requiring treatment with a parenteral or oral opioids or other parenteral analgesic; but is NOT classified as an acute chest syndrome, hepatic sequestration, splenic sequestration or priapism. The end of an uncomplicated pain crisis will be considered the resolution of acute pain, such that residual pain (or absence of any pain) is considered to be chronic, and the current pain medication regimen is considered to be for this chronic pain.
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    12
    38
    14
    Units: rate
        median (full range (min-max))
    1.79 (0.0 to 14.5)
    0.98 (0.0 to 10.4)
    1.47 (0.0 to 8.7)
    0.97 (0.0 to 5.3)
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - acute chest syndrome

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - acute chest syndrome
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Acute Chest Syndrome (ACS) is defined on the basis of the finding of a new pulmonary infiltrate involving at least one complete lung segment that was consistent with alveolar consolidation, but excluding atelectasis (as indicated by chest X-ray). At least one of the following additional signs or symptoms needs to be present as well: chest pain, a temperature of more than 38.5°C, tachypnea, wheezing or cough. ACS will be considered resolved when the patient is no longer hospitalized (unless for reason other than the ACS episode) and none of the additional signs or symptoms above are present (unless for reason other than the ACS).
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    18
    4
    15
    6
    Units: rate
        median (full range (min-max))
    0.49 (0.0 to 3.7)
    0.64 (0.0 to 1.5)
    0.49 (0.0 to 1.0)
    0.49 (0.0 to 1.9)
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient) - hepatic sequestration

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient) - hepatic sequestration
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Hepatic sequestration is defined on the basis of findings of right upper quadrant pain, an enlarged liver, and an acute decrease in hemoglobin concentration (e.g. a decrease in hemoglobin of ~ 2 g/dL). Acute hepatic sequestration will be considered resolved when right upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has been stable for 24 hrs. There were no patients with VOC events of hepatic sequestration treated at home. Therefore, there were no observations which met the report criteria.
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: VOC events per year
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - splenic sequestration

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - splenic sequestration
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Splenic sequestration if defined on the basis of findings of left upper quadrant pain, an enlarged spleen, and an acute decrease in hemoglobin concentration (e.g., a decrease in hemoglobin of ~ 2 g/dL). Acute splenic sequestration will be considered resolved when left upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has been stable for 24 hrs.
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    3
    1
    1
    0 [8]
    Units: rate
        median (full range (min-max))
    0.00 (0.0 to 0.5)
    0.00 (0.0 to 0.0)
    0.00 (0.0 to 0.0)
    ( to )
    Notes
    [8] - There were no participants with VOC)events leading to healthcare visit - splenic sequestration
    No statistical analyses for this end point

    Secondary: Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - priapism

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    End point title
    		 Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit - priapism
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This annualized rate of VOC was calculated by multiplying the number of VOCs by 365 and dividing by the number of days in the observation period. (Parts A and B) Priapism is defined as an unwanted or painful penile erection lasting at least 30 minutes. The end of an acute priapism event will be when the unwanted erection has resolved for at least 2 hours.
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    0 [9]
    1
    1
    0 [10]
    Units: rate
        median (full range (min-max))
    ( to )
    0.49 (0.49 to 0.49)
    0.00 (0.0 to 0.0)
    ( to )
    Notes
    [9] - There were no participants with VOC events leading to healthcare visit - priapism
    [10] - There were no participants with VOC events leading to healthcare visit - priapism
    No statistical analyses for this end point

    Secondary: Annualized rate of hospitalizations and Emergency Room (ER) visits (VOC-related)

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    End point title
    		 Annualized rate of hospitalizations and Emergency Room (ER) visits (VOC-related)
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. This rate was calculated by multiplying the number of hospitalizations and ER visits (VOC-related) by 365 and dividing by the number of days in the observation period. Units would be something like: hospitalizations and ER visits per year. (Parts A and B)
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: rate
    median (full range (min-max))
        Up to Year 2
    1.78 (0.0 to 13.5)
    0.50 (0.0 to 10.4)
    1.01 (0.0 to 9.6)
    0.74 (0.0 to 5.3)
        Year 1 (n=42,11,35,12)
    2.00 (0.0 to 14.0)
    0.00 (0.0 to 5.0)
    1.00 (0.0 to 6.0)
    0.00 (0.0 to 3.0)
        Year 2 (n=32,10,27,10)
    2.00 (0.0 to 9.0)
    0.00 (0.0 to 5.0)
    1.00 (0.0 to 10.0)
    1.00 (0.0 to 3.0)
    No statistical analyses for this end point

    Secondary: Annualized rate of hospitalizations and Emergency Room (ER) visits (total)

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    End point title
    		 Annualized rate of hospitalizations and Emergency Room (ER) visits (total)
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. The baseline annualized rate of VOC was defined as the number of VOCs leading to healthcare visit occurring within the last 12 months prior to screening until first dose. This rate was calculated by multiplying the number of hospitalizations and ER visits (VOC-related) by 365 and dividing by the number of days in the observation period. Units would be something like: hospitalizations and ER visits per year. (Parts A and B)
    End point type
    Secondary
    End point timeframe
    Up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: rate
    median (full range (min-max))
        Up to Year 2
    2.68 (0.0 to 15.5)
    1.46 (0.0 to 11.4)
    1.59 (0.0 to 11.7)
    1.74 (0.0 to 7.7)
        Year 1 (n=42,11,35,12)
    2.00 (0.0 to 16.0)
    1.00 (0.0 to 5.0)
    2.00 (0.0 to 7.0)
    2.00 (0.0 to 8.0)
        Year 2 (n=32,10,27,10)
    2.50 (0.0 to 10.0)
    1.00 (0.0 to 8.0)
    1.00 (0.0 to 10.0)
    2.00 (0.0 to 4.0)
    No statistical analyses for this end point

    Secondary: Annualized days of Emergency Room (ER) / hospitalization (both overall and VOC-related)

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    End point title
    		 Annualized days of Emergency Room (ER) / hospitalization (both overall and VOC-related)
    End point description
    VOC is defined as pain crises as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration. The baseline annualized rate of VOC was defined as the number of VOCs leading to healthcare visit occurring within the last 12 months prior to screening until first dose. This rate was calculated by multiplying the number of days of ER/hospitalizations (both overall and VOC-related) by 365 and dividing by the number of days in the observation period. (Parts A and B)
    End point type
    Secondary
    End point timeframe
    Years 1 and 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: Days per year
    median (full range (min-max))
        On treatment - VOC related (up to Year 2)
    6.74 (0.0 to 87.0)
    0.98 (0.0 to 59.2)
    5.36 (0.0 to 40.0)
    2.20 (0.0 to 42.7)
        On treatment - Total (up to Year 2)
    12.37 (0.0 to 87.0)
    5.41 (0.0 to 59.2)
    9.03 (0.0 to 57.5)
    10.48 (0.0 to 42.7)
        Year 1 - VOC related (n=42,11,12, 12)
    7.00 (0.0 to 60.3)
    0.00 (0.0 to 23.0)
    5.00 (0.0 to 37.0)
    0.00 (0.0 to 29.0)
        Year 1 - Total (n=42,11,12, 12)
    7.00 (0.0 to 60.3)
    2.00 (0.0 to 24.0)
    11.00 (0.0 to 37.0)
    6.50 (0.0 to 34.0)
        Year 2 - VOC related (n=32,10,11, 10)
    10.50 (0.0 to 71.0)
    0.00 (0.0 to 48.0)
    2.00 (0.0 to 40.0)
    3.00 (0.0 to 19.0)
        Year 2 - Total (n=32,10,11, 10)
    13.00 (0.0 to 71.0)
    2.00 (0.0 to 64.0)
    3.00 (0.0 to 40.0)
    10.50 (0.0 to 37.0)
    No statistical analyses for this end point

    Secondary: Annualized rate of dactylitis events

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    End point title
    		 Annualized rate of dactylitis events
    End point description
    Dactylitis, also known as 'hand-foot syndrome', is a complication of acute vaso-occlusive disease characterized by pain and edema of the digits as well as the dorsum of the hands or feet, or both simultaneously, often accompanied by increased local temperature and erythema. There were no patients with dactylitis events. Therefore, there were no observations which met the report criteria.
    End point type
    Secondary
    End point timeframe
    On Treatment, up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: dactylitis events per year
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in hemoglobin

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    End point title
    		 Absolute change from baseline in hemoglobin
    End point description
    Hemoglobin is a protein that carries oxygen through the body. It attaches to red blood cells, delivers oxygen throughout the body, and transports carbon dioxide back to the lungs. In sickle cell disease, red blood cells are crescent or sickle-shaped due to a genetic mutation, and those sickled red blood cells can clog blood flow, causing debilitating pain and even organ damage.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 27, Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    39
    9
    36
    11
    Units: g/L
    arithmetic mean (standard deviation)
        Week 27
    -1.26 ( 11.472 )
    2.33 ( 6.856 )
    -0.33 ( 7.015 )
    1.55 ( 9.905 )
        End Of Treatment / Year 2 (n=24,6,11,2)
    -5.38 ( 11.088 )
    2.33 ( 7.941 )
    -1.18 ( 11.677 )
    15.00 ( 1.414 )
    No statistical analyses for this end point

    Secondary: Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab

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    End point title
    		 Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab
    End point description
    Anti-drug antibodies (ADA) are antibodies elicited from therapeutics and they are used to measure immunogenicity.
    End point type
    Secondary
    End point timeframe
    up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    39
    14
    Units: Participants
        Baseline - Negative
    50
    13
    39
    14
        Baseline - Positive
    0
    0
    0
    0
        Baseline - Missing
    0
    0
    1
    0
        Post-baseline - Any positive
    0
    1
    1
    0
        Post-baseline - only last sample positive
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Notable on-treatment findings from the Electrocardiogram (ECG) assessments

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    End point title
    		 Notable on-treatment findings from the Electrocardiogram (ECG) assessments
    End point description
    QTcF = QT interval corrected by Fridericia’s formula QTcB = Corrected QT interval Bazett's Formula QT = QT interval PR = PR interval QRS = QRS interval RR = RR interval HR = heart rate In = increase De = decrease
    End point type
    Secondary
    End point timeframe
    Baseline, up to Year 2
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    49
    13
    40
    13
    Units: Participants
        QTcF (ms)-In >30 to <=60 ms (n=49,13,37,12)
    1
    1
    2
    1
        QTcF (ms)- In >60 ms (n=49,13,37,12)
    0
    0
    0
    0
        QTcF (ms)- New >450 to <=480 ms (n=49,13,40,13)
    3
    0
    0
    0
        QTcF (ms)- New >480 to <=500 ms (n=49,13,40,13)
    0
    0
    1
    0
        QTcF (ms)-New >500 ms (n=49,13,40,13)
    0
    0
    0
    0
        QTcB (ms)-In >30 to <=60 ms (n=49,13,37,12)
    12
    3
    7
    1
        QTcB (ms)-In >60 ms (n=49,13,37,12)
    0
    0
    0
    0
        QTcB (ms)-New >450 to <=480 ms (n=40,12,35,13)
    10
    2
    14
    6
        QTcB (ms)-New >480 to <=500 ms (n=49,13,40,13)
    3
    0
    1
    0
        QTcB (ms)-New >500 ms (n=49,13,40,13)
    0
    0
    0
    0
        QT (ms)-In >30 to <=60 ms (n=49,13,37,12)
    13
    5
    17
    3
        QT (ms)-In >60 ms (n=49,13,37,12)
    2
    0
    2
    0
        QT (ms)-New >450 to <=480 ms (n=49,13,40,13)
    0
    0
    0
    0
        QT (ms)-New >480 to <=500 ms (n=49,13,40,13)
    0
    0
    0
    0
        QT (ms)-New >500 ms (n=49,13,40,13)
    0
    0
    0
    0
        PR (ms)-In >25% and PR >200 ms (n=48,13,37,12)
    0
    0
    0
    0
        PR (ms)-New PR >200 ms (n=48,13,40,13)
    2
    0
    0
    0
        QRS (ms)- In >25% and QRS >120 ms (n=49,13,37,12)
    0
    0
    0
    0
        QRS (ms)-New QRS >120 ms (n=49,13,40,13)
    0
    0
    0
    0
        RR (ms)-In >25% and RR >1200 ms (n=49,13,37,12)
    1
    0
    0
    0
        RR (ms)-De >25% and RR <600 ms (n=49,12,34,7)
    0
    1
    2
    0
        HR (bpm)-In >25% and HR >100 bpm (n=49,12,34,7)
    1
    1
    3
    0
        HR (bpm)-De >25% and HR <50 bpm (n=49,13,37,12)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Growth and sexual maturation assessments (Tanner stage) - abnormalities - for female participants at risk of delayed puberty at start date of study treatment

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    End point title
    		 Growth and sexual maturation assessments (Tanner stage) - abnormalities - for female participants at risk of delayed puberty at start date of study treatment
    End point description
    As assessed per Tanner criteria. The number of Participants Analyzed row refer to participants who have not started puberty and have not had delayed puberty prior to start date of study treatment. Delayed puberty in females is defined as failure to attain Tanner Stage 2 (for both breast development and pubic hair) by age 13, or absence of menarche by age 15 or within 5 years of attainment of Tanner Stage 2.
    End point type
    Secondary
    End point timeframe
    Week 51
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    0 [11]
    3
    12
    5
    Units: Participants
        Delayed puberty = yes
    0
    0
    0
        Delayed puberty = no
    0
    0
    0
        unknown / NA - pt not yet in puberty age range
    3
    12
    5
    Notes
    [11] - Participants had already started puberty prior to study enrolment.
    No statistical analyses for this end point

    Secondary: Growth and sexual maturation assessments (Tanner stage) - abnormalities - for male participants at risk of delayed puberty at start date of study treatment

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    End point title
    		 Growth and sexual maturation assessments (Tanner stage) - abnormalities - for male participants at risk of delayed puberty at start date of study treatment
    End point description
    As assessed per Tanner criteria. The number of Participants Analyzed row refer to participants who have not started puberty and have not had delayed puberty prior to start date of study treatment. Delayed puberty in males is defined as failure to attain Tanner Stage 2 (for both genitalia and pubic hair) by age 14.
    End point type
    Secondary
    End point timeframe
    Week 51
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    4
    7
    18
    9
    Units: Participants
        Delayed puberty = yes
    0
    0
    0
    0
        Delayed puberty = no
    4
    0
    0
    0
        unknown / NA - pt not yet in puberty age range
    0
    7
    18
    9
    No statistical analyses for this end point

    Secondary: PK pre-dose concentrations of crizanlizumab prior to each study drug dose - Part A

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    End point title
    		 PK pre-dose concentrations of crizanlizumab prior to each study drug dose - Part A
    End point description
    End point type
    Secondary
    End point timeframe
    Week 3, Week 7, Week 11, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 (Day 1, 0 hr (pre-dose))
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    11
    12
    13
    12
    Units: µg/mL
    arithmetic mean (standard deviation)
        Week 3 Day 1, 0 hr (pre-dose) (n=11,12,13,10)
    16.8 ( 4.40 )
    14.1 ( 5.61 )
    30.1 ( 6.17 )
    19.8 ( 5.62 )
        Week 7 Day 1, 0 hr (pre-dose) (n=9,12,12,12)
    10.7 ( 3.30 )
    8.70 ( 5.32 )
    22.1 ( 8.09 )
    13.4 ( 3.21 )
        Week 11 Day 1, 0 hr (pre-dose) (n=9,11,12,11)
    10.2 ( 4.92 )
    6.02 ( 4.43 )
    20.1 ( 9.36 )
    11.0 ( 3.80 )
        Week 15 Day 1, 0 hr (pre-dose) (n=7,9,11,12)
    9.42 ( 6.47 )
    8.45 ( 2.93 )
    20.4 ( 7.22 )
    10.3 ( 5.84 )
        Week 19 Day 1, 0 hr (pre-dose) (n=6,9,12,11)
    6.77 ( 4.53 )
    7.75 ( 4.92 )
    18.8 ( 5.28 )
    10.2 ( 5.93 )
        Week 23 Day 1, 0 hr (pre-dose) (n=9,12,12,10)
    6.17 ( 3.92 )
    7.15 ( 5.23 )
    20.0 ( 6.74 )
    10.6 ( 5.24 )
        Week 27 Day 1, 0 hr (pre-dose) (n=9,10,12,10)
    8.05 ( 5.32 )
    7.70 ( 5.93 )
    22.4 ( 8.71 )
    11.8 ( 9.30 )
        Week 31 Day 1, 0 hr (pre-dose) (n=6,10,11,10)
    9.46 ( 4.34 )
    8.57 ( 6.17 )
    19.3 ( 6.36 )
    9.68 ( 8.29 )
        Week 35 Day 1, 0 hr (pre-dose) (n=5,11,10,9)
    12.0 ( 6.04 )
    6.88 ( 3.04 )
    17.9 ( 8.03 )
    8.43 ( 6.78 )
        Week 39 Day 1, 0 hr (pre-dose) (n=7,11,10,11)
    4.93 ( 3.00 )
    7.04 ( 5.75 )
    19.9 ( 5.21 )
    12.8 ( 7.98 )
        Week 43 Day 1, 0 hr (pre-dose) (n=8,10,11,8)
    9.23 ( 4.73 )
    7.45 ( 5.66 )
    18.0 ( 8.07 )
    12.8 ( 4.95 )
        Week 47 Day 1, 0 hr (pre-dose) (n=8,8,10,10)
    7.32 ( 3.84 )
    10.4 ( 7.29 )
    14.6 ( 8.22 )
    10.5 ( 9.26 )
        Week 51 Day 1, 0 hr (pre-dose) (n=5,9,10,8)
    9.78 ( 6.61 )
    9.44 ( 8.22 )
    12.8 ( 10.6 )
    10.3 ( 3.21 )
    No statistical analyses for this end point

    Secondary: PK pre-dose concentrations of crizanlizumab prior to each study drug dose - Parts A and B

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    End point title
    		 PK pre-dose concentrations of crizanlizumab prior to each study drug dose - Parts A and B
    End point description
    End point type
    Secondary
    End point timeframe
    Week 3, Week 7, Week 11, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 (0 hr (pre-dose))
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    45
    12
    36
    13
    Units: µg/mL
    arithmetic mean (standard deviation)
        Week 3 Day 1, 0 hr (pre-dose) (n=45,12,36,11)
    16.6 ( 4.40 )
    14.1 ( 5.61 )
    23.6 ( 7.54 )
    20.0 ( 5.37 )
        Week 7 Day 1, 0 hr (pre-dose) (n=44,12,35,13)
    10.3 ( 5.49 )
    8.70 ( 5.32 )
    16.3 ( 7.50 )
    14.4 ( 4.57 )
        Week 11 Day 1, 0 hr (pre-dose)(n=45,11,33,11)
    9.18 ( 5.57 )
    6.02 ( 4.43 )
    15.3 ( 7.78 )
    11.0 ( 3.80 )
        Week 15 Day 1, 0 hr (pre-dose) (n=39,9,33,12)
    8.65 ( 5.73 )
    8.45 ( 2.93 )
    16.7 ( 7.34 )
    10.3 ( 5.84 )
        Week 19 Day 1, 0 hr (pre-dose) (n=38,9,35,11)
    8.13 ( 5.65 )
    7.75 ( 4.92 )
    17.5 ( 5.93 )
    10.2 ( 5.93 )
        Week 23 Day 1, 0 hr (pre-dose) (n=43,12,35,10)
    7.09 ( 4.45 )
    7.15 ( 5.23 )
    16.6 ( 6.90 )
    10.6 ( 5.24 )
        Week 27 Day 1, 0 hr (pre-dose) (n=40,10,34,10)
    7.07 ( 4.26 )
    7.70 ( 5.93 )
    16.5 ( 8.45 )
    11.8 ( 9.30 )
        Week 31 Day 1, 0 hr (pre-dose) (n=39,10,35,10)
    7.30 ( 4.80 )
    8.57 ( 6.17 )
    16.1 ( 7.57 )
    9.68 ( 8.29 )
        Week 35 Day 1, 0 hr (pre-dose) (n=35,11,32,10)
    8.96 ( 4.94 )
    6.88 ( 3.04 )
    13.6 ( 7.75 )
    10.0 ( 8.11 )
        Week 39 Day 1, 0 hr (pre-dose) (n=38,11,35,12)
    7.69 ( 5.46 )
    7.04 ( 5.75 )
    14.2 ( 7.79 )
    13.4 ( 7.89 )
        Week 43 Day 1, 0 hr (pre-dose) (n=35,10,34,9)
    8.68 ( 4.50 )
    7.45 ( 5.66 )
    14.8 ( 6.94 )
    13.6 ( 5.15 )
        Week 47 Day 1, 0 hr (pre-dose)
    8.99 ( 5.76 )
    10.4 ( 7.29 )
    13.8 ( 6.80 )
    10.5 ( 9.26 )
        Week 51 Day 1, 0 hr (pre-dose)
    8.48 ( 5.48 )
    9.44 ( 8.22 )
    13.4 ( 7.90 )
    11.6 ( 4.90 )
    No statistical analyses for this end point

    Secondary: Percent P-selectin inhibition of crizanlizumab prior to dosing - Part A

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    End point title
    		 Percent P-selectin inhibition of crizanlizumab prior to dosing - Part A
    End point description
    A PD marker of crizanlizumab is the ex vivo P-selectin inhibition measured by a surface plasmon resonance assay using human serum samples. Crizanlizumab in serum samples binds to spiked Psel-Ig (P-selectin coupled to Ig) and inhibits its binding to a PSGL1 peptide.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 7, 11,15, 19, 23, 27, 31, 35, 39, 43,47,51 (Day 1, 0 hr (pre-dose))
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    11
    12
    13
    10
    Units: % inhibition P-selectin
    arithmetic mean (standard deviation)
        Week 3 Day 1, 0 hr (pre-dose) (n=11,12,13,9)
    100 ( 0.0924 )
    97.9 ( 2.97 )
    99.1 ( 1.41 )
    98.6 ( 2.54 )
        Week 7 Day 1, 0 hr (pre-dose) (n=9,11,12,10)
    99.0 ( 1.61 )
    94.2 ( 12.2 )
    98.5 ( 3.48 )
    98.9 ( 1.91 )
        Week 11 Day 1, 0 hr (pre-dose) (n=9,9,12,9)
    97.7 ( 4.56 )
    80.8 ( 32.4 )
    98.5 ( 2.93 )
    98.4 ( 2.50 )
        Week 15 Day 1, 0 hr (pre-dose) (n=6,8,11,10)
    96.6 ( 8.04 )
    99.8 ( 0.422 )
    99.2 ( 1.86 )
    91.7 ( 19.8 )
        Week 19 Day 1, 0 hr (pre-dose) (n=6,9,12,10)
    88.6 ( 20.6 )
    83.5 ( 34.8 )
    99.2 ( 1.54 )
    96.7 ( 5.51 )
        Week 23 Day 1, 0 hr (pre-dose) (n=9,10,11,9)
    83.8 ( 28.9 )
    91.2 ( 14.0 )
    99.5 ( 1.24 )
    92.2 ( 15.7 )
        Week 27 Day 1, 0 hr (pre-dose) (n=9,9,11,8)
    88.0 ( 25.0 )
    90.8 ( 20.4 )
    99.4 ( 1.36 )
    85.4 ( 19.1 )
        Week 31 Day 1, 0 hr (pre-dose) (n=6,9,9,9)
    97.8 ( 2.83 )
    88.9 ( 21.0 )
    99.6 ( 1.30 )
    75.5 ( 37.9 )
        Week 35 Day 1, 0 hr (pre-dose) (n=5,10,8,9)
    97.2 ( 6.04 )
    92.3 ( 10.6 )
    97.9 ( 3.81 )
    67.4 ( 42.1 )
        Week 39 Day 1, 0 hr (pre-dose) (n=7,7,8,9)
    80.8 ( 28.0 )
    88.6 ( 25.3 )
    99.1 ( 2.01 )
    87.6 ( 19.2 )
        Week 43 Day 1, 0 hr (pre-dose) (n=8,3,9,6)
    96.7 ( 4.19 )
    99.0 ( 1.67 )
    98.8 ( 2.14 )
    98.8 ( 2.37 )
        Week 47 Day 1, 0 hr (pre-dose) (n=8,2,8,8)
    87.1 ( 30.5 )
    98.8 ( 1.77 )
    98.1 ( 3.73 )
    69.8 ( 44.0 )
        Week 51 Day 1, 0 hr (pre-dose) (n=5,3,8,7)
    80.9 ( 34.0 )
    95.4 ( 4.24 )
    98.9 ( 1.86 )
    92.1 ( 13.0 )
    No statistical analyses for this end point

    Secondary: Percent P-selectin inhibition of crizanlizumab prior to dosing - Part A and B

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    End point title
    		 Percent P-selectin inhibition of crizanlizumab prior to dosing - Part A and B
    End point description
    A PD marker of crizanlizumab is the ex vivo P-selectin inhibition measured by a surface plasmon resonance assay using human serum samples. Crizanlizumab in serum samples binds to spiked Psel-Ig (P-selectin coupled to Ig) and inhibits its binding to a PSGL1 peptide.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 7, 11,15, 19, 23, 27, 31, 35, 39, 43,47,51 (Day 1, 0 hr (pre-dose))
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    42
    12
    36
    12
    Units: % inhibition P-selectin
    arithmetic mean (standard deviation)
        Week 3 Day 1, 0 hr (pre-dose) (n=42,12,36,11)
    99.3 ( 2.14 )
    97.9 ( 2.97 )
    98.3 ( 3.74 )
    97.6 ( 3.71 )
        Week 7 Day 1, 0 hr (pre-dose) (n=41,12,35,12)
    93.7 ( 17.0 )
    94.6 ( 11.7 )
    97.1 ( 7.36 )
    97.3 ( 5.92 )
        Week 11 Day 1, 0 hr (pre-dose) (n=41,10,33,10)
    92.7 ( 17.8 )
    82.3 ( 30.9 )
    97.5 ( 6.08 )
    98.3 ( 2.39 )
        Week 15 Day 1, 0 hr (pre-dose) (n=39,9,33,11)
    92.6 ( 18.9 )
    98.9 ( 2.90 )
    96.8 ( 8.46 )
    92.5 ( 19.0 )
        Week 19 Day 1, 0 hr (pre-dose) (n=36,9,35,10)
    92.4 ( 12.3 )
    83.5 ( 34.8 )
    96.8 ( 7.36 )
    96.7 ( 5.51 )
        Week 23 Day 1, 0 hr (pre-dose) (n=42,11,34,9)
    86.5 ( 26.3 )
    92.0 ( 13.5 )
    94.2 ( 17.6 )
    92.2 ( 15.7 )
        Week 27 Day 1, 0 hr (pre-dose) (n=37,10,33,9)
    87.6 ( 26.1 )
    91.6 ( 19.4 )
    95.4 ( 10.4 )
    87.0 ( 18.5 )
        Week 31 Day 1, 0 hr (pre-dose) (n=36,10,32,9)
    90.9 ( 18.7 )
    89.1 ( 19.8 )
    97.3 ( 7.02 )
    75.5 ( 37.9 )
        Week 35 Day 1, 0 hr (pre-dose) (n=32,11,29,10)
    93.1 ( 18.0 )
    92.8 ( 10.3 )
    92.7 ( 16.4 )
    70.6 ( 41.0 )
        Week 39 Day 1, 0 hr (pre-dose) (n=33,8,33,11)
    85.4 ( 23.6 )
    89.7 ( 23.6 )
    92.7 ( 18.7 )
    89.8 ( 17.9 )
        Week 43 Day 1, 0 hr (pre-dose) (n=31,3,32,8)
    93.1 ( 15.4 )
    99.0 ( 1.67 )
    95.3 ( 11.0 )
    99.1 ( 2.08 )
        Week 47 Day 1, 0 hr (pre-dose) (n=28,2,32,9)
    91.7 ( 17.7 )
    98.8 ( 1.77 )
    95.8 ( 7.45 )
    73.1 ( 42.4 )
        Week 51 Day 1, 0 hr (pre-dose) (n=27,3,26,9)
    86.4 ( 25.8 )
    95.4 ( 4.24 )
    92.5 ( 19.3 )
    93.8 ( 11.8 )
    No statistical analyses for this end point

    Secondary: Adverse events by preferred term related to study treatment

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    End point title
    		 Adverse events by preferred term related to study treatment
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject
    End point type
    Secondary
    End point timeframe
    Adverse events are reported from the first dose of study treatment until end of study treatment Week 103 plus 105 days post-treatment follow-up, up to a maximum timeframe of approximately 2 years and 3.25 months.
    End point values
    		 Age 12 to <18 years, 5 mg/kg Age 6 to <12 years, 5 mg/kg Age 6 to <12 years, 8.5 mg/kg Age 2 to <6 years, 8.5 mg/kg
    Number of subjects analysed
    50
    13
    40
    14
    Units: Participants
        Number of participants with at least one event
    16
    5
    14
    4
        Infusion related reaction
    5
    2
    3
    1
        Back pain
    3
    0
    4
    2
        Nausea
    3
    0
    1
    0
        Pain in extremity
    2
    0
    2
    0
        Sickle cell anaemia with crisis
    0
    0
    2
    1
        Arthralgia
    0
    1
    1
    0
        Conjunctivitis
    1
    1
    0
    0
        Dizziness
    2
    0
    0
    0
        Headache
    1
    0
    1
    0
        Infusion site pain
    1
    0
    1
    0
        Myalgia
    1
    1
    0
    0
        Neutropenia
    0
    0
    1
    1
        Pain
    1
    1
    0
    0
        Vomiting
    2
    0
    0
    0
        Abdominal pain
    0
    1
    0
    0
        Agitation
    1
    0
    0
    0
        Alopecia
    0
    0
    1
    0
        Anaemia
    0
    0
    1
    0
        Asthenia
    0
    0
    1
    0
        Blood bilirubin increased
    1
    0
    0
    0
        Blood creatine phosphokinase increased
    1
    0
    0
    0
        Dyspnoea
    0
    1
    0
    0
        Fatigue
    1
    0
    0
    0
        Hot flush
    1
    0
    0
    0
        Hypersensitivity
    0
    0
    1
    0
        Malaise
    0
    1
    0
    0
        Muscle fatigue
    1
    0
    0
    0
        Neck pain
    1
    0
    0
    0
        Paraesthesia
    0
    0
    1
    0
        Pruritus
    0
    1
    0
    0
        Pyrexia
    0
    1
    0
    0
        Sacral pain
    0
    0
    1
    0
        Spinal pain
    0
    0
    1
    0
        Vascular access complication
    0
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from the first dose of study treatment until end of study treatment Week 103 plus 105 days post-treatment follow-up, up to a maximum timeframe of approximately 2 years and 3.25 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fi eld “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Age 12 to < 18 years,@5 mg/kg
    Reporting group description
    		 Age 12 to < 18 years,@5 mg/kg

    Reporting group title
    Age 6 to < 12 years,@5 mg/kg
    Reporting group description
    		 Age 6 to < 12 years,@5 mg/kg

    Reporting group title
    All@Participants
    Reporting group description
    		 All@Participants

    Reporting group title
    Age 2 to < 6 years,@8.5 mg/kg
    Reporting group description
    		 Age 2 to < 6 years,@8.5 mg/kg

    Reporting group title
    Age 6 to < 12 years,@8.5 mg/kg
    Reporting group description
    		 Age 6 to < 12 years,@8.5 mg/kg

    Serious adverse events
    		 Age 12 to < 18 years,@5 mg/kg Age 6 to < 12 years,@5 mg/kg All@Participants Age 2 to < 6 years,@8.5 mg/kg Age 6 to < 12 years,@8.5 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 50 (36.00%)
    9 / 13 (69.23%)
    59 / 117 (50.43%)
    12 / 14 (85.71%)
    20 / 40 (50.00%)
         number of deaths (all causes)
    1
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Superficial vein thrombosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    6 / 117 (5.13%)
    3 / 14 (21.43%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 9
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 13 (15.38%)
    9 / 117 (7.69%)
    4 / 14 (28.57%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 10
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute chest syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Human rhinovirus test positive
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status migrainosus
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 13 (7.69%)
    9 / 117 (7.69%)
    1 / 14 (7.14%)
    5 / 40 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    1 / 11
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric lymphadenitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 13 (15.38%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    4 / 117 (3.42%)
    3 / 14 (21.43%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 4
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fasciitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 13 (0.00%)
    7 / 117 (5.98%)
    2 / 14 (14.29%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 9
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    9 / 117 (7.69%)
    3 / 14 (21.43%)
    4 / 40 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 11
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parvovirus B19 infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Thrombophlebitis septic
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Age 12 to < 18 years,@5 mg/kg Age 6 to < 12 years,@5 mg/kg All@Participants Age 2 to < 6 years,@8.5 mg/kg Age 6 to < 12 years,@8.5 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 50 (92.00%)
    13 / 13 (100.00%)
    108 / 117 (92.31%)
    13 / 14 (92.86%)
    36 / 40 (90.00%)
    Vascular disorders
    Pallor
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 13 (0.00%)
    4 / 117 (3.42%)
    2 / 14 (14.29%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    6
    3
    0
    Phlebitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 13 (0.00%)
    5 / 117 (4.27%)
    1 / 14 (7.14%)
    2 / 40 (5.00%)
         occurrences all number
    3
    0
    6
    1
    2
    Hyperthermia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    4 / 117 (3.42%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    5
    0
    6
    0
    1
    Device related thrombosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Chest pain
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 13 (15.38%)
    10 / 117 (8.55%)
    1 / 14 (7.14%)
    4 / 40 (10.00%)
         occurrences all number
    3
    2
    12
    1
    6
    Malaise
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    12 / 50 (24.00%)
    5 / 13 (38.46%)
    38 / 117 (32.48%)
    5 / 14 (35.71%)
    16 / 40 (40.00%)
         occurrences all number
    18
    9
    62
    7
    28
    Pain
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 13 (23.08%)
    11 / 117 (9.40%)
    2 / 14 (14.29%)
    4 / 40 (10.00%)
         occurrences all number
    4
    4
    16
    2
    6
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    2 / 14 (14.29%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Asthma exercise induced
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Cough
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 13 (15.38%)
    21 / 117 (17.95%)
    5 / 14 (35.71%)
    9 / 40 (22.50%)
         occurrences all number
    7
    2
    35
    13
    13
    Pleural effusion
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 13 (7.69%)
    6 / 117 (5.13%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    5
    2
    10
    0
    3
    Nasal congestion
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 13 (7.69%)
    6 / 117 (5.13%)
    0 / 14 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    4
    1
    9
    0
    4
    Hypoxia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    7
    1
    0
    Epistaxis
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 13 (23.08%)
    8 / 117 (6.84%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    4
    3
    9
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    1
    3
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    3
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 13 (7.69%)
    10 / 117 (8.55%)
    2 / 14 (14.29%)
    2 / 40 (5.00%)
         occurrences all number
    8
    1
    13
    2
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 13 (0.00%)
    5 / 117 (4.27%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    4
    0
    5
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    5
    0
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    8
    7
    1
    Blood bilirubin increased
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 13 (7.69%)
    5 / 117 (4.27%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    11
    3
    15
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    2
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    2 / 14 (14.29%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    4
    3
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 13 (7.69%)
    5 / 117 (4.27%)
    0 / 14 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    4
    1
    7
    0
    2
    Amylase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Anti factor Xa activity decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Arterial flow velocity increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 13 (15.38%)
    6 / 117 (5.13%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    5
    5
    11
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    5
    1
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    3
    0
    0
    SARS-CoV-2 test negative
         subjects affected / exposed
    12 / 50 (24.00%)
    3 / 13 (23.08%)
    15 / 117 (12.82%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    19
    10
    29
    0
    0
    Polymerase chain reaction negative
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Influenza virus test negative
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Influenza A virus test negative
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Epstein-Barr virus test positive
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Injury, poisoning and procedural complications
    Eye contusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Eye injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Femur fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 13 (15.38%)
    10 / 117 (8.55%)
    1 / 14 (7.14%)
    3 / 40 (7.50%)
         occurrences all number
    5
    3
    13
    1
    4
    Joint injury
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    2
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    3
    1
    2
    Nasal injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Penis injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Skeletal injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Vascular access complication
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Right ventricular enlargement
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 13 (7.69%)
    7 / 117 (5.98%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    7
    1
    9
    0
    1
    Headache
         subjects affected / exposed
    19 / 50 (38.00%)
    4 / 13 (30.77%)
    36 / 117 (30.77%)
    3 / 14 (21.43%)
    10 / 40 (25.00%)
         occurrences all number
    30
    4
    52
    4
    14
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    6 / 117 (5.13%)
    2 / 14 (14.29%)
    3 / 40 (7.50%)
         occurrences all number
    1
    0
    7
    2
    4
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    2
    1
    1
    Lymphocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    5
    4
    1
    Anaemia
         subjects affected / exposed
    8 / 50 (16.00%)
    1 / 13 (7.69%)
    16 / 117 (13.68%)
    3 / 14 (21.43%)
    4 / 40 (10.00%)
         occurrences all number
    8
    1
    24
    8
    7
    Thrombocytopenia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 13 (15.38%)
    4 / 117 (3.42%)
    0 / 14 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    4
    0
    2
    Thrombocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    6 / 117 (5.13%)
    2 / 14 (14.29%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    6
    2
    4
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    3
    0
    2
    Eye disorders
    Xerophthalmia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 50 (20.00%)
    5 / 13 (38.46%)
    28 / 117 (23.93%)
    1 / 14 (7.14%)
    12 / 40 (30.00%)
         occurrences all number
    14
    5
    34
    1
    14
    Abdominal pain upper
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    4 / 117 (3.42%)
    0 / 14 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    1
    0
    6
    0
    5
    Constipation
         subjects affected / exposed
    9 / 50 (18.00%)
    3 / 13 (23.08%)
    20 / 117 (17.09%)
    2 / 14 (14.29%)
    6 / 40 (15.00%)
         occurrences all number
    11
    4
    24
    2
    7
    Diarrhoea
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 13 (7.69%)
    13 / 117 (11.11%)
    2 / 14 (14.29%)
    5 / 40 (12.50%)
         occurrences all number
    6
    1
    16
    4
    5
    Vomiting
         subjects affected / exposed
    14 / 50 (28.00%)
    2 / 13 (15.38%)
    21 / 117 (17.95%)
    1 / 14 (7.14%)
    4 / 40 (10.00%)
         occurrences all number
    21
    3
    31
    2
    5
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Nausea
         subjects affected / exposed
    9 / 50 (18.00%)
    0 / 13 (0.00%)
    14 / 117 (11.97%)
    0 / 14 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    17
    0
    23
    0
    6
    Odynophagia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Gastritis
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 13 (7.69%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    1
    3
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    5 / 117 (4.27%)
    0 / 14 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    1
    1
    5
    0
    3
    Cholecystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Biliary colic
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Jaundice
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    4 / 117 (3.42%)
    0 / 14 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    1
    4
    0
    2
    Pruritus
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 13 (7.69%)
    5 / 117 (4.27%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    1
    6
    0
    0
    Nail dystrophy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    0
    5
    0
    0
    Dysuria
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 13 (15.38%)
    5 / 117 (4.27%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    1
    2
    6
    1
    2
    Mobility decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Bone pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    3
    1
    1
    Bone infarction
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Back pain
         subjects affected / exposed
    11 / 50 (22.00%)
    2 / 13 (15.38%)
    26 / 117 (22.22%)
    4 / 14 (28.57%)
    9 / 40 (22.50%)
         occurrences all number
    31
    15
    80
    7
    27
    Arthralgia
         subjects affected / exposed
    11 / 50 (22.00%)
    1 / 13 (7.69%)
    20 / 117 (17.09%)
    1 / 14 (7.14%)
    7 / 40 (17.50%)
         occurrences all number
    17
    7
    38
    1
    13
    Myalgia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 13 (7.69%)
    6 / 117 (5.13%)
    0 / 14 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    8
    0
    2
    Neck pain
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 13 (0.00%)
    4 / 117 (3.42%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    4
    1
    1
    Spinal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    2
    0
    1
    Pain in extremity
         subjects affected / exposed
    11 / 50 (22.00%)
    3 / 13 (23.08%)
    27 / 117 (23.08%)
    3 / 14 (21.43%)
    10 / 40 (25.00%)
         occurrences all number
    21
    4
    53
    3
    25
    Osteonecrosis
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 13 (0.00%)
    7 / 117 (5.98%)
    0 / 14 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    4
    0
    7
    0
    3
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    5 / 117 (4.27%)
    3 / 14 (21.43%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    6
    4
    2
    Influenza
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 13 (15.38%)
    12 / 117 (10.26%)
    0 / 14 (0.00%)
    8 / 40 (20.00%)
         occurrences all number
    2
    2
    14
    0
    10
    Gastroenteritis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    6 / 117 (5.13%)
    0 / 14 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    3
    0
    6
    0
    3
    Conjunctivitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 13 (7.69%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    3
    1
    0
    COVID-19
         subjects affected / exposed
    11 / 50 (22.00%)
    1 / 13 (7.69%)
    18 / 117 (15.38%)
    2 / 14 (14.29%)
    4 / 40 (10.00%)
         occurrences all number
    14
    1
    21
    2
    4
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    2
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 13 (15.38%)
    5 / 117 (4.27%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    1
    2
    6
    2
    1
    Suspected COVID-19
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 13 (7.69%)
    4 / 117 (3.42%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    4
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 13 (15.38%)
    6 / 117 (5.13%)
    1 / 14 (7.14%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    6
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 50 (18.00%)
    1 / 13 (7.69%)
    16 / 117 (13.68%)
    4 / 14 (28.57%)
    2 / 40 (5.00%)
         occurrences all number
    11
    2
    25
    9
    3
    Urinary tract infection
         subjects affected / exposed
    6 / 50 (12.00%)
    1 / 13 (7.69%)
    11 / 117 (9.40%)
    3 / 14 (21.43%)
    1 / 40 (2.50%)
         occurrences all number
    9
    1
    14
    3
    1
    Rhinitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    3
    3
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    4 / 117 (3.42%)
    2 / 14 (14.29%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    4
    2
    1
    Pneumonia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    9 / 117 (7.69%)
    1 / 14 (7.14%)
    5 / 40 (12.50%)
         occurrences all number
    3
    0
    10
    1
    6
    Pharyngitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    1 / 117 (0.85%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    2 / 117 (1.71%)
    0 / 14 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    4
    0
    1
    Otitis media
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    3
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    4
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    1 / 14 (7.14%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    3
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 13 (0.00%)
    2 / 117 (1.71%)
    2 / 14 (14.29%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Iron deficiency
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 13 (7.69%)
    1 / 117 (0.85%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 13 (0.00%)
    3 / 117 (2.56%)
    0 / 14 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    3
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2018
    1. To update inclusion criteria: for participants receiving HU/HC: dose alterations of HU/HC performed during part A were not allowed to avoid any potential influence with the study treatment and PK results. Participants with active HIV were excluded as immunological effects of crizanlizumab were not sufficiently explored so far. 2. Addition of a DMC to be in charge of the review of the key safety and PK data review at each dosing confirmation in Part A including the recommendation to open the next age group and to open enrolment in Part B to ensure pediatric participant safety was monitored. 3. Pregnancy test was extended to all females of childbearing potential. 4. To update the declaration of Helsinki directive to fit to the last directive version (Art. 3 Par. 2 of the Directive 2005/28/EC).
    29 Jan 2020
    1. To update study objectives in order to - Modify the wording of the PK/PD endpoint for Part A to account for potential participants who had study treatment interruptions prior to Week 15, where multiple dose was defined as 3 consecutives doses (not including the loading dose at Week 3 Day 1) in the primary objective. - Change the wording “number of” to “annualized rate of” in the secondary objectives to account for participants who had not completed the full treatment period and standardize the outputs to one-year time-frame. This applied to all the secondary objectives to assess the long-term efficacy of crizanlizumab in 6 months to < 18-year-old participants at the time of study entry and to the RBC transfusions exploratory objective. - Include assessment of PK/PD at the time of transfusions as part of the exploratory objectives. 2. Risk benefit section has been updated to include information on immunogenicity and interference with automated platelets counts in line with the current version of the IB. 3. QTcF prolongation section had been removed, based on the current safety profile of crizanlizumab showing no QT liability as supported by absence of clinically relevant effect on QTc in SCD participants treated with crizanlizumab based on PK-QT analysis and assessment of safety as listed in the current IB.
    30 Mar 2021
    The primary purpose of this amendment was to update the requirement for a 105-days post-treatment follow-up visit for all participants. The intention of the 105-day post-treatment follow-up period was to capture any potential AEs including development of ADAs following discontinuation from study treatment, taking into account the half-life of the drug. This amendment clarified that participants continuing crizanlizumab after the EOT visit, via commercial supply or post-trial access (e.g. enrollment in a Novartis roll-over protocol to provide continued drug treatment) would not have to perform the 105-days post-treatment follow-up visit in this study.
    21 Jul 2021
    1. To update and clarify the criteria used for dose confirmation following single-dose analysis in Part A of each group. The decision was based on first dose PK results, key safety data, and Novartis’s assessment in conjunction with DMC recommendations. This amendment allowed evaluation of the newly defined dose in a new cohort of participants enrolled into Group 2 Part A (see study status above). 2. To include some language to address COVID-19-related changes to study conduct and allow some flexibility when needed. Recommendations for handling of study treatment in case of active or suspected COVID-19 infection were added. 3. To consider uptake of voxelotor within 30 days of screening or plan to start voxelotor during the course of the study as an exclusion criterion. A wash-out period of 30 days was required prior to screening to prevent impact on the results. 4. To modify guidance given to manage infusion-related reactions and corresponding dose interruption and re-initiation. Pre-medication prophylaxis against IRRs had been revised and was now allowed.
    31 Mar 2022
    The primary purpose of this amendment was to: • update the options of post-trial access for participants in this trial who continue to derive clinical benefit from the treatment based on the Investigator’s evaluation. The post-trial access language was revised to reflect the options available to participants to continue treatment after completion of the study. This may include access to Novartis investigational product in a rollover protocol or provision of the Novartis investigational product in a non-trial setting (known as post-study drug supply [PSDS]) when no further safety or efficacy data are required, or any other mechanism appropriate as per the country regulations. • update the risks and benefits of treatment with crizanlizumab to reflect the most recent available clinical data. • align with the requirements of EU Clinical Trial Regulation (EU CTR) to accommodate the transfer of the study under this regulation.
    14 Mar 2024
    The primary purpose of this protocol amendment was to amend the study plan by not extending it to the cohort of Group 3 Part B as Novartis no longer intended to enroll participants in Group 3 Part B (6 months to 6 years) of the trial. The rationale for cancelling the Group 3 Part B was to focus on age groups where the manifestation of Sickle Cell Disease (SCD) and the feasibility of intervention assessment were more suitable. The original study plan required at least 8 participants aged 2-<6 years to evaluate and determine the age-appropriate dose. Fourteen participants had already been enrolled in Group 3 Part A (participants 2 to <6 years), that were expected to provide sufficient data to study the PK parameters for this age group. Study of the youngest age group (6 months to < 24 months) had been withdrawn in its entirety due to the revocation of the conditional marketing authorization of crizanlizumab in the EU and UK. Therefore, Novartis decided not to study crizanlizumab for the reduction of VOCs in additional participants with SCD below the age of 6 years, as very young children with SCD are less likely to experience frequent vaso-occlusive crises (VOC) episodes compared to older children, adolescents, and adults.

    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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