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    Clinical Trial Results:
    A Phase II, multicenter, randomized, open label two arm study evaluating the effect of crizanlizumab + standard of care and standard of care alone on renal function in sickle cell disease patients ≥ 16 years with chronic kidney disease due to sickle cell nephropathy (STEADFAST) 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

    Summary
    EudraCT number
    		 2018-003608-38
    Trial protocol
    		 GB   GR   ES   FR   IT   NL   IE  
    Global end of trial date
    20 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2024
    First version publication date
    05 Apr 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CSEG101A2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04053764
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate descriptively the effect of crizanlizumab + standard of care and standard of care alone on albuminuria (albumin to creatinine ratio, ACR) decrease at 12 months, as assessed by the proportion of patients with ≥ 30% decrease in ACR at 12 months from baseline.
    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
    10 Dec 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Lebanon: 1
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Türkiye: 17
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    58
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    58
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled in 24 centers in 11 countries.

    Pre-assignment
    Screening details
    		 Patients were stratified at randomization based on CKD risk category (moderate risk or high/very high risk) and HU/HC use (Yes/No). At visit “Week 1 Day 1” all eligible patients were randomized via IRT to one of the treatment arms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Crizanlizumab + Standard of Care
    Arm description
    		 5 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HU/HC, ACE inhibitors, and/or ARBs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV as the drug insert for use

    Investigational medicinal product name
    Crizanlizumab
    Investigational medicinal product code
    SEG101
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg IV

    Arm title
    		 Standard of Care (SOC)
    Arm description
    		 Patients in the standard of care alone arm will continue to receive their usual standard of care treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    HU/HC, ACE inhibitors, and/or ARBs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV as the drug insert for use

    Number of subjects in period 1
    		Crizanlizumab + Standard of Care Standard of Care (SOC)
    Started
    30
    28
    Entered post-treatment f/u, discontinued
    7 [1]
    1 [2]
    Did not enter post-treatment follow-up
    3 [3]
    2 [4]
    Not Treated
    1 [5]
    0 [6]
    Completed
    20
    25
    Not completed
    10
    3
         Consent withdrawn by subject
    6
    2
         Physician decision
    2
    1
         Adverse event, non-fatal
    1
    -
         Pregnancy
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Numbers reported for these milestones are for informational purposes only.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Numbers reported for these milestones are for informational purposes only.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Numbers reported for these milestones are for informational purposes only.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Numbers reported for these milestones are for informational purposes only.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Numbers reported for these milestones are just for informational purposes
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Numbers reported for these milestones are for informational purposes only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Crizanlizumab + Standard of Care
    Reporting group description
    		 5 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 Patients in the standard of care alone arm will continue to receive their usual standard of care treatment.

    Reporting group values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC) Total
    Number of subjects
    		 30 28 58
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 28 58
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 41.8 ( 9.52 ) 41.1 ( 8.71 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 20 17 37
        Male
    		 10 11 21
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    		 15 15 30
        White
    		 15 12 27
        Multiple
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Crizanlizumab + Standard of Care
    Reporting group description
    		 5 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 Patients in the standard of care alone arm will continue to receive their usual standard of care treatment.

    Subject analysis set title
    All Patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All the participants enrolled in the trial.

    Subject analysis set title
    crizanlizumab + standard of care
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    5 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment.

    Primary: Percentage of participants with ≥ 30% decrease in albuminuria (ACR) at 12 months

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    End point title
    		 Percentage of participants with ≥ 30% decrease in albuminuria (ACR) at 12 months
    End point description
    The effect of SEG101 on clinical disease activity was measured by at least 30% decrease in Albumin to Creatinine Ratio (ACR) from baseline to month 12. A reduction from baseline indicates improvement in patients.
    End point type
    Primary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: participants
    10
    6
    Statistical analysis title
    		 Decrease in albuminuria at 12 months
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 7.14

    Secondary: Change from baseline in albuminuria (ACR) at 3, 6, 9 and 12 months

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    End point title
    		 Change from baseline in albuminuria (ACR) at 3, 6, 9 and 12 months
    End point description
    The effect of SEG101 on clinical disease activity was measured was measured by the change in albuminuria (ACR) between baseline and month 3, baseline and month 6, baseline and month 9, baseline and month 12. A reduction from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline to 3, 6, 9, and 12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: mg/g
    arithmetic mean (standard deviation)
        Baseline (BL)
    597.0 ( 534.3 )
    499.0 ( 486.7 )
        Month 3 change from BL (n = 26, 27)
    -56.9 ( 362.8 )
    159.0 ( 809.9 )
        Month 6 change from BL (n = 23, 25)
    -98.5 ( 382.2 )
    -35.4 ( 384.4 )
        Month 9 change from BL (n = 23, 24)
    -12.3 ( 586.6 )
    95.2 ( 376.2 )
        Month 12 change from BL (n = 21, 24
    17.7 ( 620.7 )
    14.7 ( 307.1 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with ≥ 30% decrease in albuminuria (ACR) at 6 months

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    End point title
    		 Percentage of participants with ≥ 30% decrease in albuminuria (ACR) at 6 months
    End point description
    The effect of SEG101 on clinical disease activity was measured by at least 30% decrease in Albumin to Creatinine Ratio (ACR) from baseline to month 6. A reduction from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: Percentage of participants
        number (not applicable)
    30.0
    35.7
    Statistical analysis title
    		 Decrease in albuminuria at 6 months
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 2.31

    Secondary: Percentage of participants with Protein/creatinine ratio (PCR) improvement and stable PCR at 12 months

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    End point title
    		 Percentage of participants with Protein/creatinine ratio (PCR) improvement and stable PCR at 12 months
    End point description
    The effect of SEG101 on clinical disease activity was measured by counting patients who had Stable PCR: within ± 20% change from baseline to month 12. PCR improvement: ≥ 20% decrease in PCR from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: Percentage of participants
    number (not applicable)
        % of subjects with PCR improvement at 12 months
    33.3
    35.7
        % of subjects with stable PCR at 12 months
    16.7
    25.0
    Statistical analysis title
    		 PCR Improvement 2
    Statistical analysis description
    Stable PCR
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 3.2
    Statistical analysis title
    		 PCR Improvement
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 3.02

    Secondary: Percentage change in estimated glomerular filtration rate (eGFR)

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    End point title
    		 Percentage change in estimated glomerular filtration rate (eGFR)
    End point description
    The effect of SEG101 on clinical disease activity was measured by at least 30% decrease in Albumin to Creatinine Ratio (ACR) from baseline to month 6. The percentage change in eGFR was calculated as the post-baseline eGFR value minus the baseline eGFR divided by the eGFR at baseline. A reduction from baseline indicates improvement in participants.
    End point type
    Secondary
    End point timeframe
    Baseline to 3, 6, 9, and 12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: Percentage change in eGFR
    arithmetic mean (standard deviation)
        Baseline (BL) (n = 28, 28)
    107.9 ( 28.0 )
    102.5 ( 23.2 )
        Month 3 change from BL (n = 24, 26)
    -2.5 ( 8.9 )
    -0.5 ( 10.0 )
        Month 6 change from BL (n = 21, 25)
    -2.7 ( 5.5 )
    -7.3 ( 12.7 )
        Month 9 change from BL (n = 23,23)
    -0.2 ( 12.8 )
    -2.7 ( 8.7 )
        Month 12 change from BL (n =16, 24)
    -4.9 ( 14.1 )
    -6.3 ( 13.2 )
    Statistical analysis title
    		 eGFR
    Statistical analysis description
    From baseline to 3 months
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.53
         upper limit
    		 4.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.53
    Statistical analysis title
    		 eGFR 2
    Statistical analysis description
    From baseline to 6 months
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 11.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.32
    Statistical analysis title
    		 eGFR 3
    Statistical analysis description
    From baseline to 9 months
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.58
         upper limit
    		 11.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.77
    Statistical analysis title
    		 eGFR 4
    Statistical analysis description
    From baseline to 12 months
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 13.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.17

    Secondary: Slope of albumin to creatinine ratio (ACR) decline

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    End point title
    		 Slope of albumin to creatinine ratio (ACR) decline
    End point description
    The effect of SEG101 on clinical disease activity was measured by the slope of ACR between baseline and Month 12. A reduction from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    29
    28
    Units: ACR decline rate
        least squares mean (standard error)
    1.70 ( 8.655 )
    4.49 ( 8.159 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with progression of chronic kidney disease (CKD) at 12 months

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    End point title
    		 Percentage of participants with progression of chronic kidney disease (CKD) at 12 months
    End point description
    The effect of SEG101 on clinical disease activity was measured by percentage of participants with CKD progression between baseline and Month 12. A reduction from baseline indicates improvement in participants. CKD progression is defined as an increase in CKD progression category, a 25% or greater drop in eGFR from baseline or at least 50% increase in ACR for patients with severe (A3) albuminuria and a doubling of albumin levels in patients with moderate (A2) albuminuria.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: Percentage of participants
        number (not applicable)
    13.3
    32.1
    Statistical analysis title
    		 Progression of CKD
    Comparison groups
    Crizanlizumab + Standard of Care v Standard of Care (SOC)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 1.21

    Secondary: Slope of estimated glomerular filtration rate (eGFR) decline

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    End point title
    		 Slope of estimated glomerular filtration rate (eGFR) decline
    End point description
    The effect of SEG101 on clinical disease activity was measured by the slope of eGFR between baseline and Month 12. The calculation of eGFR is based on the chronic kidney disease epidemiology collaboration (CKD-EPI) (for patients ≥ 18) and Creatinine-based “Bedside Schwartz” (for patients < 18) equations. A reduction in drop rate from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    28
    28
    Units: eGFR decline rate
        least squares mean (standard error)
    -0.1 ( 0.18 )
    -0.4 ( 0.16 )
    No statistical analyses for this end point

    Secondary: Shift table for Chronic kidney disease (CKD) progression

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    End point title
    		 Shift table for Chronic kidney disease (CKD) progression
    End point description
    The effect of SEG101 on clinical disease activity was measured by percentage of participants with CKD progression between baseline and Month 12. A reduction from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline and month 12
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC) All Patients
    Number of subjects analysed
    30
    28
    58
    Units: Percentage of participants
    number (not applicable)
        Cat 0 at baseline (BL)
    3.3
    14.3
    8.6
        Cat 0 at baseline to Cat 2 at Worst post-BL
    100.0
    75.0
    80.0
        Cat 0 at baseline to Cat 3 at Worst post-BL
    0
    25.0
    20.0
        Cat 0 at baseline to Cat 4 at Worst post-BL
    0
    0
    0
        Cat 0 at baseline to Missing at Worst post-BL
    0
    0
    0
        Cat 1 at baseline
    36.7
    53.6
    44.8
        Cat 1 at baseline to Cat 2 at Worst post-BL
    36.4
    40.0
    38.5
        Cat 1 at baseline to Cat 3 at Worst post-BL
    45.5
    53.3
    50.0
        Cat 1 at baseline to Cat 4 at Worst post-BL
    0
    6.7
    3.8
        Cat 1 at baseline to Missing at Worst post-BL
    18.2
    0
    7.7
        Cat 2 at baseline
    43.3
    28.6
    36.2
        Cat 2 at baseline to Cat 2 at Worst post-BL
    15.4
    12.5
    14.3
        Cat 2 at baseline to Cat 3 at Worst post-BL
    69.2
    75.5
    71.4
        Cat 2 at baseline to Cat 4 at Worst post-BL
    7.7
    12.5
    9.5
        Cat 2 at baseline to Missing at Worst post-BL
    7.7
    0
    4.8
        Cat 3 at baseline
    6.7
    3.6
    5.2
        Cat 3 at baseline to Cat 2 at Worst post-BL
    0
    0
    0
        Cat 3 at baseline to Cat 3 at Worst post-BL
    50.0
    0
    33.3
        Cat 3 at baseline to Cat 4 at Worst post-BL
    50.0
    100.0
    66.7
        Cat 3 at BL to Missing at Worst post-BL
    0
    0
    0
        Cat 4 at baseline
    0
    0
    0
        Cat 4 at baseline to Cat 2 at Worst post-BL
    0
    0
    0
        Cat 4 at baseline to Cat 3 at Worst post-BL
    0
    0
    0
        Cat 4 at baseline to Cat 4 at Worst post-BL
    0
    0
    0
        Cat 4 at baseline to Missing at Worst post-BL
    0
    0
    0
        Cat Missing at baseline
    10.0
    0
    5.2
        Cat Missing baseline to Cat 2 at Worst post-BL
    0
    0
    0
        Cat Missing baseline to Cat 3 at Worst post-BL
    0
    0
    0
        Cat Missing baseline to Cat 4 at Worst post-BL
    0
    0
    0
        Cat Missing baseline to Missing at Worst post-BL
    100.0
    0
    100.0
    No statistical analyses for this end point

    Secondary: Immunogenicity: Number of participants with anti-drug antibodies (ADA) to crizanlizumab

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    End point title
    		 Immunogenicity: Number of participants with anti-drug antibodies (ADA) to crizanlizumab [1]
    End point description
    The effect of SEG101 on clinical disease activity was measured by percentage of participants shifted to different worst post-baseline categories between baseline and Month 12. An increase in percentage shifting from higher category to lower category indicates improvement in patients. Baseline is defined as the last non-missing value prior to the first dose.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up period (at select time points), assessed up to approximately 1 year and 4 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK was assessed for only arm with experimental drug, not comparison drug.
    End point values
    		 Crizanlizumab + Standard of Care
    Number of subjects analysed
    29
    Units: Percentage of participants
    number (not applicable)
        Negative at baseline to Only last sample positive
    0
        Negative at baseline to Any positive
    3.4
        Negative at baseline to All positive
    0
        Negative at baseline to All Negative
    89.7
        Negative at baseline to All Missing
    6.9
    No statistical analyses for this end point

    Secondary: Annualized rate of visits to emergency room (ER) and hospitalizations

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    End point title
    		 Annualized rate of visits to emergency room (ER) and hospitalizations
    End point description
    The effect of SEG101 on clinical disease activity was measured by summarizing the annualized rate of visits to ER and hospitalizations between baseline and 1 year 4 months. Annualized rate of hospitalizations and ER visits due to VOC =(Number of ER/hospitalizations reported until End date x 365.25)/(End date-date of first dose of study treatment+1). A reduction from baseline indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up period (at select time points), assessed up to approximately 1 year and 4 months
    End point values
    		 Crizanlizumab + Standard of Care Standard of Care (SOC)
    Number of subjects analysed
    30
    28
    Units: rate/year
        arithmetic mean (standard deviation)
    0.6 ( 2.1 )
    1.1 ( 3.0 )
    No statistical analyses for this end point

    Secondary: Mean serum concentration (Ctrough) of crizanlizumab

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    End point title
    		 Mean serum concentration (Ctrough) of crizanlizumab
    End point description
    The effect of SEG101 on clinical disease activity was measured by checking the concentration of the Drug in serum at different time points. Crizanlizumab pre-dose/trough pharmacokinetic samples were taken at select time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 336 hours post-dose on Week 3 Day 1; pre-dose and 672 hours post dose on Week 11 Day 1, Week 23 Day 1 and Week 39 Day 1; and 672 hours post dose on Week 53 Day 1
    End point values
    		 crizanlizumab + standard of care
    Number of subjects analysed
    29
    Units: μg/mL
    arithmetic mean (standard deviation)
        Week 3 Day1: 0 hours pre-dose (n = 25)
    11.6 ( 2.66 )
        Week 3 Day1: 336 hours post-dose (n = 24)
    12.1 ( 2.38 )
        Week 11 Day1: 0 hours pre-dose (n = 24)
    4.78 ( 3.49 )
        Week 11 Day1: 672 hours post-dose (n = 23)
    5.67 ( 3.11 )
        Week 23 Day1: 0 hours pre-dose (n = 23)
    4.77 ( 2.82 )
        Week 23 Day1: 672 hours post-dose (n = 21)
    5.54 ( 2.21 )
        Week 39 Day1: 0 hours pre-dose (n = 20)
    5.55 ( 2.34 )
        Week 39 Day1: 672 hours post-dose (n = 17)
    5.16 ( 2.10 )
        Week 53 Day1: 672 hours post-dose (n = 16)
    15.2 ( 5.18 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment to 105 days after the last dose of study treatment with a median duration of exposure to crizanlizumab of 50.1 weeks.
    Adverse event reporting additional description
    An Adverse Event is any sign or symptom that occurs during the conduct of the trial and safety follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Crizanlizumab + Standard of Care
    Reporting group description
    		 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment

    Reporting group title
    Staandard of Care (SOC)
    Reporting group description
    		 Patients in the standard of care alone arm will continue to receive their usual standard of care treatment.

    Reporting group title
    All Participants
    Reporting group description
    		 All Participants enrolled in the trial from whom safety was collected.

    Serious adverse events
    		 Crizanlizumab + Standard of Care Staandard of Care (SOC) All Participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
    4 / 57 (7.02%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Crizanlizumab + Standard of Care Staandard of Care (SOC) All Participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 29 (72.41%)
    19 / 28 (67.86%)
    40 / 57 (70.18%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 29 (20.69%)
    4 / 28 (14.29%)
    10 / 57 (17.54%)
         occurrences all number
    8
    5
    13
    Migraine
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    3 / 57 (5.26%)
         occurrences all number
    2
    2
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 28 (7.14%)
    5 / 57 (8.77%)
         occurrences all number
    6
    2
    8
    Fatigue
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 28 (10.71%)
    5 / 57 (8.77%)
         occurrences all number
    2
    4
    6
    Oedema peripheral
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 28 (10.71%)
    3 / 57 (5.26%)
         occurrences all number
    0
    3
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    2
    Constipation
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    3
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    3
    0
    3
    Vomiting
         subjects affected / exposed
    1 / 29 (3.45%)
    7 / 28 (25.00%)
    8 / 57 (14.04%)
         occurrences all number
    2
    8
    10
    Nausea
         subjects affected / exposed
    4 / 29 (13.79%)
    5 / 28 (17.86%)
    9 / 57 (15.79%)
         occurrences all number
    5
    6
    11
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    2 / 57 (3.51%)
         occurrences all number
    0
    2
    2
    Cough
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 28 (14.29%)
    6 / 57 (10.53%)
         occurrences all number
    2
    5
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
    4 / 57 (7.02%)
         occurrences all number
    7
    1
    8
    Dry skin
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    3
    0
    3
    Rash
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    3
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 28 (10.71%)
    8 / 57 (14.04%)
         occurrences all number
    7
    4
    11
    Back pain
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
    6 / 57 (10.53%)
         occurrences all number
    5
    3
    8
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    3
    0
    3
    Influenza
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 28 (14.29%)
    8 / 57 (14.04%)
         occurrences all number
    4
    4
    8
    COVID-19
         subjects affected / exposed
    7 / 29 (24.14%)
    4 / 28 (14.29%)
    11 / 57 (19.30%)
         occurrences all number
    11
    4
    15
    Pharyngitis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    3 / 57 (5.26%)
         occurrences all number
    3
    1
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    4
    0
    4
    Tooth infection
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 28 (0.00%)
    4 / 57 (7.02%)
         occurrences all number
    4
    0
    4
    Subcutaneous abscess
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    2 / 57 (3.51%)
         occurrences all number
    2
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2020
    At the time of this amendment, 1 patient was enrolled in the study. The reasons why this amendment was undertaken was to refine the data collection for the assessment of the primary and secondary efficacy endpoints, reduce confounding factors, strengthen the primary estimand framework by providing additional clarity regarding the handling of intercurrent events and clarifying the summary measure and providing additional clarity on the management of infusion related reactions.
    09 Mar 2021
    At the time of this amendment, 23 patients had been enrolled. The primary purpose of this amendment was to broaden the inclusion/exclusion criteria to allow for greater patient eligibility, modify study assessments, update sample collection requirements to reduce patient burden based on current clinical practice in the management of SCD-related CKD and amend the statistical power and sample size calculation.
    02 Dec 2021
    At the time of this amendment, only 47 out of planned 148 patients were randomized after almost two years. A decision was made to stop recruitment (screening) by 17-Nov-2021, and all eligible patients were expected to be enrolled by 15-Dec-2021. This decision was not triggered by any new and/or unexpected safety concerns. The ongoing patients continued in the study until discontinuation or completion. The primary purpose of this amendment was to adjust the sample size and planned statistical analyses. As a result of the reduced sample size and low statistical power, no formal hypothesis testing was conducted, and descriptive statistics with the 95% confidence intervals were provided instead.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd. com/CtrdWeb/home.nov for complete trial results
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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