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    Clinical Trial Results:
    A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WITHOUT A RECENT HISTORY OF BLOOD TRANSFUSION

    Summary
    EudraCT number
    2017-003539-12
    Trial protocol
    AT   GB   DE   NO   ES   BE   NL   IT  
    Global end of trial date
    03 Dec 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2022
    First version publication date
    16 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC16216
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03347422
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND #: 128,190, STUDY NAME: Cadenza
    Sponsors
    Sponsor organisation name
    Sanofi-aventis Recherche & Développement
    Sponsor organisation address
    1, Avenue Pierre Brossolette, Chilly Mazarin, France, 91385
    Public contact
    Trial Transparency Team, Bioverativ, a Sanofi company, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Bioverativ, a Sanofi company, Contact-US@sanofi.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
    25 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of Part A was to determine whether sutimlimab administration results in a greater than or equal to (>=)1.5 grams per decilitre (g/dL) increase in hemoglobin (Hgb) level and avoidance of transfusion in subjects with primary cold agglutinin disease (CAD) without a recent history of blood transfusion. The purpose of Part B was to evaluate the long-term safety and tolerability of sutimlimab in subjects with primary CAD.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    42
    EEA total number of subjects
    25
    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)
    18
    From 65 to 84 years
    22
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 27 sites in 13 countries. Out of 66 screened subjects, a total of 42 subjects were enrolled and randomised from 17 March 2018 to 30 March 2020. This study consisted of 2 Parts: Part A and Part B.

    Pre-assignment
    Screening details
    Subjects were stratified based on baseline body weight to receive BIVV009 6.5 grams (g) (if <75 kg) or 7.5 g (if >=75 kg). As planned, data presented as: 1) Dose-wise (2 dose cohorts: BIVV009 6.5 g and BIVV009 7.5 g) for safety endpoints and adverse events (AEs). 2) combined population (BIVV009 at any dose) for efficacy endpoints.

    Period 1
    Period 1 title
    Part A (26 Weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BIVV009
    Arm description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for subjects less than [<]75 kilograms [kg]) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.
    Arm type
    Experimental

    Investigational medicinal product name
    BIVV009
    Investigational medicinal product code
    Other name
    Sutimlimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received fixed doses of BIVV009 6.5 g or 7.5 g based on body weight, as IV infusion on Day 0 and Day 7 and every 14 days thereafter up to Week 25.

    Arm title
    Placebo
    Arm description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received fixed doses of placebo matched to BIVV009 (6.5 g or 7.5 g) as IV infusion on Day 0 and Day 7 and every 14 days thereafter up to Week 25.

    Number of subjects in period 1
    BIVV009 Placebo
    Started
    22
    20
    Completed
    19
    20
    Not completed
    3
    0
         Adverse event, non-fatal
    3
    -
    Period 2
    Period 2 title
    Part B (149 Weeks)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BIVV009/BIVV009
    Arm description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 6.5 g (for subjects <75 kg) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Subjects who completed Part A per protocol through the end of treatment visit (Week 26), received placebo on Week 26 and continued to receive BIVV009 6.5 or 7.5 g in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g). All subjects who completed Part A elected to continue in Part B.
    Arm type
    Experimental

    Investigational medicinal product name
    BIVV009
    Investigational medicinal product code
    Other name
    Sutimlimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with body weight <75 kg (for 6.5 g) and body weight >=75 kg (for 7.5 g) received placebo on Week 26 and continued to receive fixed doses of BIVV009 6.5 g or 7.5 g as IV infusion every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g).

    Arm title
    Placebo/BIVV009
    Arm description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Subjects who completed Part A per protocol through the end of treatment visit (Week 26) received BIVV009 6.5 (if <75 kg) or 7.5 g (if >=75 kg) in Part B, on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g). All subjects who completed Part A elected to continue in Part B.
    Arm type
    Experimental

    Investigational medicinal product name
    BIVV009
    Investigational medicinal product code
    Other name
    Sutimlimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with body weight <75 kg (for 6.5 g) and body weight >=75 kg (for 7.5 g) received fixed doses of BIVV009 6.5 g or 7.5 g as IV infusion on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g).

    Number of subjects in period 2
    BIVV009/BIVV009 Placebo/BIVV009
    Started
    19
    20
    Completed
    16
    16
    Not completed
    3
    4
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    -
    1
         Unspecified
    1
    -
         Lack of efficacy
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BIVV009
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for subjects less than [<]75 kilograms [kg]) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

    Reporting group title
    Placebo
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

    Reporting group values
    BIVV009 Placebo Total
    Number of subjects
    22 20 42
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.3 ± 10.9 68.2 ± 10.1 -
    Gender categorical
    Units: Subjects
        Female
    17 16 33
        Male
    5 4 9
    Race
    Units: Subjects
        Asian
    5 2 7
        White
    0 4 4
        Black or African American
    0 0 0
        American Indian or Alaska Native
    0 0 0
        Native Hawaiian or other Pacific Islander
    0 0 0
        More than one race
    0 0 0
        Unknown or Not Reported
    17 14 31

    End points

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    End points reporting groups
    Reporting group title
    BIVV009
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for subjects less than [<]75 kilograms [kg]) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

    Reporting group title
    Placebo
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.
    Reporting group title
    BIVV009/BIVV009
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 6.5 g (for subjects <75 kg) or 7.5 g dose (for subjects >=75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Subjects who completed Part A per protocol through the end of treatment visit (Week 26), received placebo on Week 26 and continued to receive BIVV009 6.5 or 7.5 g in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g). All subjects who completed Part A elected to continue in Part B.

    Reporting group title
    Placebo/BIVV009
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Subjects who completed Part A per protocol through the end of treatment visit (Week 26) received BIVV009 6.5 (if <75 kg) or 7.5 g (if >=75 kg) in Part B, on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g). All subjects who completed Part A elected to continue in Part B.

    Subject analysis set title
    Part B: BIVV009 6.5 g
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who completed Part A per protocol through the end of treatment visit (Week 26) were eligible to be enrolled in Part B where they were treated for up to an additional 149 weeks. Subjects who received placebo in Part A received BIVV009 6.5 g on Week 26, Week 27 and every 2 weeks thereafter; subjects who received BIVV009 6.5 g in Part A received placebo on Week 26, BIVV009 6.5 g on Week 27 and every 2 weeks thereafter for up to an additional 149 weeks.

    Subject analysis set title
    Part B: BIVV009 7.5 g
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who completed Part A per protocol through the end of treatment visit (Week 26) were eligible to be enrolled in Part B where they were treated for up to an additional 137 weeks. Subjects who received placebo in Part A received BIVV009 7.5 g on Week 26, Week 27 and every 2 weeks thereafter; subjects who received BIVV009 7.5 g in Part A received placebo on Week 26, BIVV009 7.5 g on Week 27 and every 2 weeks thereafter for up to an additional 137 weeks.

    Primary: Part A: Percentage of Subjects With Response to Treatment

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    End point title
    Part A: Percentage of Subjects With Response to Treatment
    End point description
    A subject was considered a responder: if he or she did not receive blood transfusion from Week 5 through Week 26 (end of treatment) and did not receive treatment for CAD beyond what was permitted per protocol. Additionally, subject’s hemoglobin (Hgb) level must have increased to >=1.5 g/dL from baseline (defined as last Hgb value before administration of first dose of study drug) at treatment assessment timepoint (defined as average of values from the Week 23, 25, and 26 visits). Percentage of responders was calculated together with 95% exact Clopper-Pearson confidence interval (CI). Analysed on Part A-full analysis set (FAS) which included all subjects who received at least 1 dose (including partial dose) of study drug (BIVV009 or placebo). Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either at 6.5 or 7.5 g] and placebo in Part A.
    End point type
    Primary
    End point timeframe
    From Week 5 through Week 26
    End point values
    BIVV009 Placebo
    Number of subjects analysed
    22
    20
    Units: percentage of subjects
        number (confidence interval 95%)
    72.7 (49.8 to 89.3)
    15.0 (3.2 to 37.9)
    Statistical analysis title
    BIVV009 versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints were reported and continued when primary endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    BIVV009 v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    15.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.88
         upper limit
    88.04
    Notes
    [1] - Stratified by baseline hemoglobin (< median versus >=median) and geographic region (Asia/Other, North America, and Europe).
    [2] - Threshold for significance was 0.05.

    Primary: Part B: Number of Subjects With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)

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    End point title
    Part B: Number of Subjects With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs) [3]
    End point description
    Adverse Event (AE): any untoward medical occurrence in a subject who received study drug and did not necessarily have to have a causal relationship with the treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. TEAEs: AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from first investigational medicinal product [IMP] administration in Part B to last IMP administration + 9 weeks follow-up period). Analysed on Part B safety analysis set (SAS) which included all subjects who received at least 1 dose (including partial dose) of study drug in Part B. Data for this endpoint was planned to be collected and analysed separately for each dose (BIVV009 6.5 g and 7.5 g).
    End point type
    Primary
    End point timeframe
    Part B, 6.5 g cohort: From first dose (Week 26) up to 149 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 184); Part B, 7.5 g cohort: From first dose (Week 26) up to 137 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 172)
    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: As the endpoint was descriptive in nature, no statistical analysis was provided.
    End point values
    Part B: BIVV009 6.5 g Part B: BIVV009 7.5 g
    Number of subjects analysed
    32
    7
    Units: subjects
        TEAEs
    29
    7
        TESAEs
    6
    1
    No statistical analyses for this end point

    Secondary: Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint

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    End point title
    Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
    End point description
    Mean change from baseline (Week 0) in Hemoglobin (Hgb) at the treatment assessment timepoint is reported in this endpoint. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Least squares (LS) mean and 95 % confidence interval (CI) was assessed by Mixed Model for Repeated Measures (MMRM) approach using heterogeneous Toeplitz (TOEPH) covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
    End point values
    BIVV009 Placebo
    Number of subjects analysed
    22
    20
    Units: gram per decilitre
        least squares mean (confidence interval 95%)
    2.66 (2.09 to 3.22)
    0.09 (-0.50 to 0.68)
    Statistical analysis title
    BIVV009 versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoint were reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    BIVV009 v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    Mixed model for repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    2.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.75
         upper limit
    3.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.408
    Notes
    [4] - Threshold of significance at 0.05 level.

    Secondary: Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint

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    End point title
    Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint
    End point description
    Mean change from baseline (Week 0) in total bilirubin at the treatment assessment timepoint is reported in this endpoint. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
    End point values
    BIVV009 Placebo
    Number of subjects analysed
    19
    20
    Units: micromoles per litre
        arithmetic mean (standard deviation)
    -22.881 ± 10.401
    -1.388 ± 13.901
    No statistical analyses for this end point

    Secondary: Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint

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    End point title
    Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint
    End point description
    FACIT-Fatigue scale consists of 13 questions assessed using a 5-point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added to obtain a total score. Total score ranged from 0 to 52, with higher score indicating more fatigue. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. LS mean and 95 % CI was assessed by MMRM approach using TOEPH covariance matrix with change from baseline (Week 0) as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
    End point values
    BIVV009 Placebo
    Number of subjects analysed
    22
    20
    Units: score on a scale
        least squares mean (confidence interval 95%)
    10.83 (7.45 to 14.22)
    1.91 (-1.65 to 5.46)
    Statistical analysis title
    BIVV009 versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoint were reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    BIVV009 v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    Mixed model for repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    8.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4
         upper limit
    13.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.45
    Notes
    [5] - Threshold of significance at 0.05 level.

    Secondary: Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint

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    End point title
    Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
    End point description
    Mean change from baseline (Week 0) in LDH at the treatment assessment timepoint is reported in this endpoint. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Baseline was defined as the last non-missing value prior to the first administration of study drug. Analysis was performed on Part A-FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
    End point values
    BIVV009 Placebo
    Number of subjects analysed
    19
    20
    Units: units per litre
        arithmetic mean (standard deviation)
    -150.833 ± 160.824
    7.600 ± 212.690
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Subjects With Solicited Symptomatic Anemia at Week 26

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    End point title
    Part A: Percentage of Subjects With Solicited Symptomatic Anemia at Week 26
    End point description
    Symptomatic anemia was defined as having following symptoms: i. Fatigue; ii. Weakness; iii. Shortness of breath; iv. Palpitations, fast heart beat; v. Light headedness and/or vi. Chest pain. Percentage of subjects with solicited symptomatic anemia symptoms was reported in this endpoint. Analysis was performed on Part A-FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]) and placebo in Part A.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    BIVV009 Placebo
    Number of subjects analysed
    19
    19
    Units: percentage of subjects
    number (not applicable)
        Fatigue
    31.6
    68.4
        Weakness
    5.3
    31.6
        Shortness of breath
    5.3
    36.8
        Palpitations
    0
    15.8
        Light headedness
    5.3
    15.8
        Chest pain
    0
    5.3
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points

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    End point title
    Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
    End point description
    Change from baseline (Week 0) in Hgb levels at each specified time points is reported in this endpoint. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. Early Termination (ET) visit/safety follow up (SFU) visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS which included all subjects who enrolled in Part B and received at least 1 dose (including partial dose) of study drug (BIVV009). Here, 'n' = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as space filler which denotes that standard deviation (SD) was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: grams per decilitre
    arithmetic mean (standard deviation)
        Week 27 (n=19,20)
    2.647 ± 1.348
    1.125 ± 1.545
        Week 29 (n=17,18)
    2.507 ± 1.669
    1.947 ± 1.467
        Week 31 (n=18,19)
    2.490 ± 1.550
    2.358 ± 1.471
        Week 33 (n=18,19)
    2.519 ± 1.520
    1.987 ± 2.054
        Week 35 (n=17,19)
    2.611 ± 1.522
    1.977 ± 2.010
        Week 37 (n=18,19)
    2.197 ± 1.461
    2.469 ± 1.550
        Week 39 (n=17,18)
    2.528 ± 1.607
    2.368 ± 1.835
        Week 41 (n=19,19)
    2.162 ± 1.636
    2.074 ± 1.825
        Week 43 (n=17,19)
    2.436 ± 1.103
    2.182 ± 1.643
        Week 45 (n=18,20)
    2.644 ± 1.688
    2.249 ± 1.858
        Week 47 (n=16,19)
    2.335 ± 1.108
    2.315 ± 2.129
        Week 49 (n=16,18)
    2.531 ± 1.280
    2.121 ± 1.883
        Week 51 (n=16,19)
    2.349 ± 1.260
    2.394 ± 1.870
        Week 53 (n=16,18)
    2.346 ± 1.182
    2.411 ± 1.786
        Week 55 (n=17,18)
    2.438 ± 1.396
    2.539 ± 1.403
        Week 57 (n=16,17)
    2.531 ± 1.446
    2.250 ± 1.774
        Week 59 (n=17,17)
    2.590 ± 1.397
    2.008 ± 2.615
        Week 61 (n=17,18)
    4.073 ± 6.761
    2.059 ± 1.911
        Week 63 (n=17,17)
    2.382 ± 1.546
    2.102 ± 1.780
        Week 65 (n=16,17)
    2.925 ± 1.447
    2.311 ± 1.986
        Week 67 (n=17,17)
    4.170 ± 6.509
    2.534 ± 2.036
        Week 69 (n=16,17)
    2.777 ± 1.411
    2.505 ± 2.093
        Week 71 (n=14,15)
    2.654 ± 1.495
    2.357 ± 1.758
        Week 73 (n=15,16)
    2.800 ± 2.132
    2.197 ± 1.989
        Week 75 (n=15,16)
    2.391 ± 1.700
    2.175 ± 2.151
        Week 77 (n=14,16)
    3.074 ± 2.088
    2.451 ± 1.878
        Week 79 (n=13,15)
    2.614 ± 1.874
    2.419 ± 2.247
        Week 81 (n=14,17)
    2.598 ± 1.801
    2.458 ± 1.579
        Week 83 (n=14,13)
    2.469 ± 1.777
    2.762 ± 1.539
        Week 85 (n=12,15)
    2.755 ± 1.942
    2.489 ± 1.375
        Week 87 (n=13,15)
    2.477 ± 1.779
    2.765 ± 1.605
        Week 89 (n=12,13)
    2.551 ± 1.835
    2.482 ± 2.004
        Week 91 (n=11,12)
    2.380 ± 2.084
    2.556 ± 1.538
        Week 93 (n=11,12)
    2.931 ± 2.386
    2.655 ± 2.033
        Week 95 (n=11,12)
    2.262 ± 2.014
    2.578 ± 1.970
        Week 97 (n=11,12)
    2.413 ± 2.262
    2.551 ± 1.544
        Week 99 (n=11,13)
    2.019 ± 1.799
    2.412 ± 1.822
        Week 101 (n=11,12)
    2.276 ± 1.986
    2.171 ± 1.852
        Week 103 (n=11,13)
    2.378 ± 2.342
    2.527 ± 1.807
        Week 105 (n=11,12)
    2.291 ± 1.719
    2.321 ± 1.805
        Week 107 (n=11,13)
    2.319 ± 1.511
    2.560 ± 1.858
        Week 109 (n=11,11)
    2.509 ± 1.772
    2.645 ± 1.608
        Week 111 (n=11,12)
    2.416 ± 1.908
    2.750 ± 1.707
        Week 113 (n=11,12)
    2.860 ± 1.832
    2.268 ± 1.497
        Week 115 (n=10,10)
    2.622 ± 1.986
    2.326 ± 1.809
        Week 117 (n=9,11)
    3.135 ± 1.598
    2.474 ± 1.808
        Week 119 (n=9,10)
    3.106 ± 1.493
    2.608 ± 2.045
        Week 121 (n=9,8)
    3.388 ± 1.616
    2.325 ± 2.223
        Week 123 (n=9,9)
    3.255 ± 1.346
    2.878 ± 2.667
        Week 125 (n=8,7)
    3.197 ± 1.366
    1.700 ± 2.684
        Week 127 (n=7,8)
    3.371 ± 1.551
    2.102 ± 3.211
        Week 129 (n=7,7)
    3.171 ± 1.566
    2.129 ± 2.739
        Week 131 (n=6,6)
    3.453 ± 1.823
    1.423 ± 3.184
        Week 133 (n=5,4)
    3.520 ± 1.707
    2.025 ± 1.167
        Week 135 (n=5,5)
    3.611 ± 1.458
    3.048 ± 1.620
        Week 137 (n=4,3)
    4.074 ± 2.392
    2.400 ± 1.808
        Week 139 (n=5,3)
    3.929 ± 1.889
    3.334 ± 2.669
        Week 141 (n=3,3)
    3.500 ± 0.656
    2.733 ± 1.674
        Week 143 (n=4,3)
    3.220 ± 1.064
    2.985 ± 1.904
        Week 145 (n=2,3)
    3.350 ± 0.636
    3.467 ± 2.108
        Week 147 (n=3,2)
    3.202 ± 0.591
    2.300 ± 0.566
        Week 149 (n=1,2)
    2.900 ± 99999
    2.550 ± 0.778
        Week 151 (n=2,1)
    2.961 ± 0.370
    3.000 ± 99999
        Week 153 (n=1,1)
    2.800 ± 99999
    2.800 ± 99999
        Week 155 (n=1,1)
    2.700 ± 99999
    3.600 ± 99999
        Week 157 (n=1,1)
    2.700 ± 99999
    3.000 ± 99999
        Week 159 (n=1,1)
    3.300 ± 99999
    2.300 ± 99999
        Week 161 (n=1,1)
    4.100 ± 99999
    2.400 ± 99999
        Week 163 (n=1,1)
    4.100 ± 99999
    2.600 ± 99999
        Week 165 (n=1,0)
    3.800 ± 99999
    9999 ± 99999
        Week 167 (n=1,0)
    4.700 ± 99999
    9999 ± 99999
        Week 169 (n=1,0)
    4.300 ± 99999
    9999 ± 99999
        Week 171 (n=1,0)
    4.200 ± 99999
    9999 ± 99999
        Week 173 (n=1,0)
    4.000 ± 99999
    9999 ± 99999
        Week 175 (n=1,0)
    2.500 ± 99999
    9999 ± 99999
        ET/SFU Visit (n=17,18)
    0.149 ± 2.073
    0.359 ± 1.872
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points

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    End point title
    Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points
    End point description
    Change from baseline (Week 0) in total bilirubin levels at each specified time point is reported in this endpoint. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    17
    18
    Units: micromoles per litre
    arithmetic mean (standard deviation)
        Week 27 (n=17,18)
    -22.965 ± 9.899
    -18.761 ± 13.353
        Week 29 (n=16,18)
    -20.119 ± 12.170
    -19.889 ± 14.500
        Week 31 (n=16,17)
    -21.675 ± 11.025
    -22.153 ± 14.962
        Week 33 (n=15,16)
    -19.860 ± 11.527
    -24.263 ± 15.169
        Week 35 (n=15,16)
    -20.540 ± 10.557
    -21.888 ± 13.930
        Week 37 (n=16,15)
    -21.350 ± 13.234
    -22.527 ± 16.315
        Week 39 (n=15,15)
    -23.493 ± 11.425
    -21.173 ± 15.901
        Week 41 (n=16,16)
    -18.694 ± 12.189
    -21.138 ± 16.150
        Week 43 (n=15,16)
    -20.593 ± 11.449
    -21.544 ± 16.603
        Week 45 (n=16,18)
    -18.556 ± 11.213
    -20.156 ± 16.757
        Week 47 (n=14,18)
    -20.400 ± 9.803
    -20.250 ± 15.536
        Week 49 (n=14,17)
    -21.450 ± 10.271
    -21.024 ± 13.630
        Week 51 (n=14,16)
    -19.686 ± 11.072
    -19.444 ± 15.942
        Week 53 (n=15,17)
    -19.107 ± 11.267
    -20.335 ± 17.126
        Week 55 (n=13,16)
    -19.354 ± 12.209
    -23.481 ± 12.300
        Week 57 (n=13,15)
    -21.708 ± 10.467
    -18.953 ± 15.825
        Week 59 (n=14,15)
    -19.979 ± 9.706
    -19.820 ± 16.209
        Week 61 (n=13,15)
    -18.254 ± 10.541
    -21.073 ± 17.457
        Week 63 (n=15,15)
    -21.587 ± 9.680
    -21.753 ± 16.663
        Week 65 (n=14,14)
    -20.400 ± 9.866
    -20.950 ± 19.833
        Week 67 (n=15,14)
    -22.680 ± 10.317
    -20.150 ± 20.250
        Week 69 (n=14,15)
    -21.279 ± 9.423
    -17.827 ± 22.194
        Week 71 (n=12,13)
    -19.008 ± 8.255
    -20.585 ± 21.125
        Week 73 (n=12,15)
    -23.058 ± 7.766
    -20.080 ± 17.803
        Week 75 (n=12,14)
    -21.492 ± 7.453
    -20.771 ± 20.261
        Week 77 (n=12,14)
    -23.267 ± 8.972
    -19.814 ± 19.337
        Week 79 (n=12,15)
    -21.125 ± 12.701
    -21.027 ± 19.830
        Week 81 (n=11,13)
    -19.255 ± 9.478
    -22.331 ± 20.117
        Week 83 (n=12,11)
    -16.567 ± 12.565
    -25.091 ± 13.838
        Week 85 (n=11,13)
    -18.045 ± 12.183
    -23.292 ± 12.976
        Week 87 (n=10,11)
    -19.990 ± 12.043
    -21.473 ± 14.444
        Week 89 (n=10,11)
    -17.790 ± 11.036
    -24.782 ± 13.390
        Week 91 (n=9,11)
    -16.944 ± 13.476
    -23.091 ± 14.949
        Week 93 (n=9,10)
    -18.300 ± 11.132
    -24.970 ± 13.852
        Week 95 (n=8,11)
    -18.613 ± 12.265
    -23.564 ± 11.122
        Week 97 (n=9,9)
    -18.656 ± 11.462
    -26.122 ± 11.870
        Week 99 (n=9,11)
    -17.389 ± 10.932
    -23.700 ± 12.919
        Week 101 (n=9,10)
    -18.411 ± 10.175
    -25.940 ± 12.309
        Week 103 (n=9,11)
    -18.178 ± 11.156
    -22.655 ± 11.308
        Week 105 (n=9,10)
    -19.422 ± 8.444
    -26.920 ± 10.996
        Week 107 (n=9,11)
    -18.100 ± 9.955
    -23.018 ± 12.755
        Week 109 (n=9,9)
    -18.456 ± 10.606
    -25.422 ± 14.100
        Week 111 (n=9,10)
    -19.767 ± 9.992
    -24.380 ± 12.298
        Week 113 (n=9,10)
    -19.389 ± 9.192
    -23.940 ± 15.514
        Week 115 (n=9,9)
    -19.622 ± 8.194
    -21.533 ± 14.215
        Week 117 (n=8,8)
    -22.088 ± 10.247
    -22.225 ± 15.256
        Week 119 (n=8,8)
    -20.038 ± 8.529
    -22.713 ± 14.859
        Week 121 (n=8,6)
    -22.063 ± 7.215
    -21.183 ± 10.750
        Week 123 (n=8,7)
    -21.438 ± 8.058
    -22.029 ± 12.421
        Week 125 (n=7,5)
    -20.657 ± 8.889
    -19.560 ± 12.997
        Week 127 (n=6,6)
    -20.550 ± 9.782
    -21.433 ± 15.850
        Week 129 (n=6,5)
    -22.883 ± 11.291
    -19.020 ± 11.749
        Week 131 (n=5,5)
    -19.420 ± 12.936
    -23.100 ± 15.797
        Week 133 (n=4,4)
    -27.600 ± 7.477
    -17.450 ± 16.917
        Week 135 (n=4,5)
    -29.500 ± 7.816
    -21.900 ± 19.552
        Week 137 (n=3,2)
    -28.833 ± 8.615
    -11.650 ± 18.173
        Week 139 (n=4,3)
    -25.800 ± 9.081
    -24.733 ± 17.470
        Week 141 (n=2,3)
    -34.400 ± 2.404
    -13.833 ± 16.669
        Week 143 (n=3,3)
    -26.967 ± 9.235
    -20.033 ± 22.861
        Week 145 (n=2,3)
    -32.900 ± 3.677
    -18.100 ± 27.217
        Week 147 (n=3,2)
    -29.300 ± 7.418
    -3.300 ± 34.083
        Week 149 (n=1,2)
    -31.700 ± 99999
    -7.300 ± 28.284
        Week 151 (n=2,1)
    -21.500 ± 0.566
    0.300 ± 99999
        Week 153 (n=1,1)
    -30.800 ± 99999
    -11.400 ± 99999
        Week 155 (n=1,1)
    -35.300 ± 99999
    0.700 ± 99999
        Week 157 (n=1,1)
    -32.400 ± 99999
    -0.100 ± 99999
        Week 159 (n=1,1)
    -32.500 ± 99999
    4.700 ± 99999
        Week 161 (n=1,1)
    -36.800 ± 99999
    5.500 ± 99999
        Week 163 (n=1,1)
    -37.100 ± 99999
    13.000 ± 99999
        Week 165 (n=1,0)
    -36.300 ± 99999
    9999 ± 99999
        Week 167 (n=1,0)
    -34.300 ± 99999
    9999 ± 99999
        Week 169 (n=1,0)
    -32.700 ± 99999
    9999 ± 99999
        Week 171 (n=1,0)
    -33.100 ± 99999
    9999 ± 99999
        Week 173 (n=1,0)
    -32.100 ± 99999
    9999 ± 99999
        Week 175 (n=1,0)
    -28.400 ± 99999
    9999 ± 99999
        ET/SFU Visit (n=17,17)
    1.976 ± 9.444
    1.165 ± 18.773
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points

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    End point title
    Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points
    End point description
    FACIT-Fatigue scale consists of 13 questions assessed using a 5-point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question were added to obtain a total score. The Total score ranged from 0 to 52, with higher score indicating more fatigue. Baseline (Week 0) was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable due to only one subject being available for analysis and "9999 & 99999" denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 39 (n=18,18)
    11.048 ± 12.333
    7.958 ± 12.003
        Week 51 (n=15,16)
    10.080 ± 11.506
    6.354 ± 9.680
        Week 63 (n=16,16)
    10.672 ± 13.225
    8.499 ± 11.146
        Week 75 (n=13,14)
    9.861 ± 12.953
    10.304 ± 9.722
        Week 87 (n=13,15)
    11.015 ± 13.972
    8.483 ± 11.323
        Week 99 (n=11,13)
    12.109 ± 14.786
    8.788 ± 10.985
        Week 111 (n=11,12)
    11.563 ± 13.411
    10.688 ± 11.768
        Week 123 (n=9,9)
    10.806 ± 13.736
    6.583 ± 16.613
        Week 135 (n=5,5)
    16.683 ± 18.953
    12.650 ± 15.243
        Week 147 (n=2,2)
    9.208 ± 1.120
    0.500 ± 2.121
        Week 159 (n=1,1)
    20.000 ± 99999
    10.000 ± 99999
        Week 171 (n=1,0)
    15.000 ± 99999
    9999 ± 99999
        ET/SFU Visit (n=19,18)
    -1.257 ± 10.399
    -1.551 ± 12.840
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points

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    End point title
    Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points
    End point description
    SF-12: 12 item-questionnaire contained 12 items, categorised into 8 domains (subscales) of functioning and well-being: physical functioning, role-physical, role emotional, mental health, bodily pain, general health, vitality and social functioning, with each domain score ranged from 0 (poor health) to 100 (better health). Higher scores = good health condition. The 8 domains were further summarised into 2 summary scores, PCS and MCS that ranged from 0 (poor health) to 100 (better health). Higher scores = better HRQOL. Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184). Part B-FAS. Here, 'n' = subjects with available data. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., either 6.5 g or 7.5 g). '99999'=1 subject thus SD was not estimable & '99999' & '9999' = no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 39-PCS (n=18,18)
    4.814 ± 8.830
    6.745 ± 11.255
        Week 39-MCS (n=18,18)
    8.543 ± 9.155
    1.151 ± 11.591
        Week 51-PCS (n=14,16)
    5.320 ± 6.913
    5.654 ± 8.527
        Week 51-MCS (n=14,16)
    8.461 ± 6.754
    1.704 ± 8.813
        Week 63-PCS (n=16,16)
    5.840 ± 6.916
    6.216 ± 9.514
        Week 63-MCS (n=16,16)
    8.117 ± 9.955
    1.722 ± 10.175
        Week 75-PCS (n=12,15)
    5.723 ± 7.563
    7.661 ± 10.418
        Week 75-MCS (n=12,15)
    7.932 ± 9.279
    3.519 ± 7.891
        Week 87-PCS (n=12,15)
    5.226 ± 8.196
    8.778 ± 12.405
        Week 87-MCS (n=12,15)
    6.058 ± 10.981
    2.219 ± 9.111
        Week 99-PCS (n=10,13)
    3.945 ± 7.463
    8.262 ± 12.534
        Week 99-MCS (n=10,13)
    7.136 ± 11.850
    4.682 ± 7.698
        Week 111-PCS (n=10,12)
    4.800 ± 7.985
    8.080 ± 12.302
        Week 111-MCS (n=10,12)
    8.705 ± 7.777
    4.411 ± 10.249
        Week 123-PCS (n=9,9)
    4.147 ± 7.110
    7.973 ± 13.200
        Week 123-MCS (n=9,9)
    8.650 ± 8.323
    -2.538 ± 13.136
        Week 135-PCS (n=5,4)
    6.660 ± 9.096
    6.070 ± 13.819
        Week 135-MCS (n=5,4)
    8.860 ± 9.817
    2.790 ± 6.170
        Week 147-PCS (n=2,2)
    -1.655 ± 3.769
    -3.740 ± 1.824
        Week 147-MCS (n=2,2)
    11.220 ± 6.095
    -1.110 ± 0.679
        Week 159-PCS (n=1,1)
    5.620 ± 99999
    -10.410 ± 99999
        Week 159-MCS (n=1,1)
    16.400 ± 99999
    9.590 ± 99999
        Week 171-PCS (n=1,0)
    11.980 ± 99999
    9999 ± 99999
        Week 171-MCS (n=1,0)
    0.250 ± 99999
    9999 ± 99999
        ET/SFU Visit-PCS (n=18,18)
    -3.478 ± 10.875
    -0.429 ± 10.922
        ET/SFU Visit-MCS (n=18,18)
    1.835 ± 11.882
    -2.137 ± 10.148
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points

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    End point title
    Part B: Change From Baseline in 5-level European Quality of Life 5- Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Each Specified Time Points
    End point description
    EQ-5D-5L included 2 components: health state utility index (descriptive system) & Visual Analog Scale (VAS). EQ-5D descriptive system comprises 5 dimensions:mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response option: no, slight, moderate, severe & extreme problems measured with Likert scale. EQ-5D-5L responses converted into single index utility score between 0 to 1. Higher score=better health. EQ-5D-5L VAS rated subject’s current health state on scale from 0(worst imaginable health) to 100 (best imaginable health). Baseline(Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184). Part B FAS. Data was planned to be collected & analysed for combined population of BIVV009(6.5g or 7.5g). 'n'=subjects with available data. '99999'=only 1 subject SD was not estimable and 9999 and 99999=no subject available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 39 - Index score (n=17,18)
    0.020 ± 0.165
    0.054 ± 0.135
        Week 51 - Index score (n=15,16)
    0.075 ± 0.173
    -0.008 ± 0.197
        Week 63 - Index score (n=16,16)
    0.060 ± 0.214
    0.015 ± 0.157
        Week 75 - Index score (n=13,15)
    -0.004 ± 0.144
    0.063 ± 0.152
        Week 87 - Index score (n=13,15)
    -0.034 ± 0.240
    0.059 ± 0.158
        Week 99 - Index score (n=11,13)
    -0.058 ± 0.216
    0.058 ± 0.146
        Week 111 - Index score (n=11,12)
    -0.033 ± 0.205
    0.050 ± 0.194
        Week 123- Index score (n=9,9)
    -0.020 ± 0.235
    0.031 ± 0.221
        Week 135- Index score (n=5,5)
    0.008 ± 0.351
    0.094 ± 0.245
        Week 147- Index score (n=2,2)
    0.054 ± 0.037
    -0.087 ± 0.222
        Week 159- Index score (n=1,1)
    0.174 ± 99999
    0.087 ± 99999
        Week 171- Index score (n=1,0)
    0.053 ± 99999
    -9999 ± 99999
        ET/SFU - Index score (n=19,18)
    -0.108 ± 0.238
    -0.077 ± 0.169
        Week 39 - VAS score (n=17,18)
    20.647 ± 16.871
    12.000 ± 17.146
        Week 51 - VAS score (n=15,16)
    14.800 ± 27.589
    9.125 ± 21.112
        Week 63 - VAS score (n=15,16)
    19.867 ± 21.603
    14.375 ± 15.573
        Week 75 - VAS score (n=13,15)
    16.846 ± 22.120
    18.933 ± 20.243
        Week 87 - VAS score (n=13,15)
    14.077 ± 25.221
    16.867 ± 17.912
        Week 99 - VAS score (n=11,13)
    19.364 ± 20.796
    18.385 ± 20.706
        Week 111 - VAS score (n=11,12)
    18.273 ± 19.463
    22.833 ± 20.621
        Week 123- VAS score (n=9,9)
    21.667 ± 18.371
    18.000 ± 30.389
        Week 135- VAS score (n=5,5)
    26.000 ± 20.433
    23.400 ± 27.574
        Week 147- VAS score (n=2,2)
    17.500 ± 17.678
    3.500 ± 26.163
        Week 159- VAS score (n=1,1)
    40.000 ± 99999
    27.000 ± 99999
        Week 171- VAS score (n=1,0)
    35.000 ± 99999
    -9999 ± 99999
        ET/SFU - VAS score (n=19,18)
    1.526 ± 17.976
    -2.056 ± 14.957
    No statistical analyses for this end point

    Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points

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    End point title
    Part B: Number of Subjects With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points
    End point description
    The PGIS is a self-reported scale. The PGIS is a 1-item questionnaire designed to assess subject’s impression of disease severity using a 5-point scale ranging from 1 to 5, where 1=none, 2=mild, 3=moderate, 4=severe, 5=very severe. Higher scores indicated greater severity. Analysis was performed on Part B-FAS population. Here, ‘n’ = subjects with available data for each specified category. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, n=0 denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    At Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: subjects
        Week 39 - None (n=17,17)
    7
    5
        Week 39 - Mild (n=17,17)
    8
    7
        Week 39 - Moderate (n=17,17)
    1
    5
        Week 39 - Severe (n=17,17)
    1
    0
        Week 39 - Very Severe (n=17,17)
    0
    0
        Week 51 - None (n=15,16)
    5
    4
        Week 51 - Mild (n=15,16)
    8
    7
        Week 51 - Moderate (n=15,16)
    2
    5
        Week 51 - Severe (n=15,16)
    0
    0
        Week 51 - Very Severe (n=15,16)
    0
    0
        Week 63 - None (n=17,16)
    6
    4
        Week 63 - Mild (n=17,16)
    8
    7
        Week 63 - Moderate (n=17,16)
    3
    5
        Week 63 - Severe (n=17,16)
    0
    0
        Week 63 - Very Severe (n=17,16)
    0
    0
        Week 75 - None (n=13,15)
    5
    6
        Week 75 - Mild (n=13,15)
    6
    6
        Week 75 - Moderate (n=13,15)
    2
    3
        Week 75 - Severe (n=13,15)
    0
    0
        Week 75 - Very Severe (n=13,15)
    0
    0
        Week 87 - None (n=13,15)
    6
    7
        Week 87 - Mild (n=13,15)
    5
    4
        Week 87 - Moderate (n=13,15)
    1
    3
        Week 87 - Severe (n=13,15)
    1
    1
        Week 87 - Very Severe (n=13,15)
    0
    0
        Week 99 - None (n=11,13)
    5
    8
        Week 99 - Mild (n=11,13)
    5
    3
        Week 99 - Moderate (n=11,13)
    1
    2
        Week 99 - Severe (n=11,13)
    0
    0
        Week 99 - Very Severe (n=11,13)
    0
    0
        Week 111 - None (n=11,12)
    5
    7
        Week 111 - Mild (n=11,12)
    4
    3
        Week 111 - Moderate (n=11,12)
    2
    2
        Week 111 - Severe (n=11,12)
    0
    0
        Week 111 - Very Severe (n=11,12)
    0
    0
        Week 123 - None (n=9,9)
    2
    5
        Week 123 - Mild (n=9,9)
    6
    2
        Week 123 - Moderate (n=9,9)
    1
    2
        Week 123 - Severe (n=9,9)
    0
    0
        Week 123 - Very Severe (n=9,9)
    0
    0
        Week 135 - None (n=5,5)
    0
    2
        Week 135 - Mild (n=5,5)
    3
    1
        Week 135 - Moderate (n=5,5)
    2
    2
        Week 135 - Severe (n=5,5)
    0
    0
        Week 135 - Very Severe (n=5,5)
    0
    0
        Week 147 - None (n=2,2)
    0
    1
        Week 147 - Mild (n=2,2)
    1
    0
        Week 147 - Moderate (n=2,2)
    1
    1
        Week 147 - Severe (n=2,2)
    0
    0
        Week 147 - Very Severe (n=2,2)
    0
    0
        Week 159 - None (n=1,1)
    0
    0
        Week 159 - Mild (n=1,1)
    0
    0
        Week 159 - Moderate (n=1,1)
    1
    1
        Week 159 - Severe (n=1,1)
    0
    0
        Week 159 - Very Severe (n=1,1)
    0
    0
        Week 171 - None (n=1,0)
    0
    0
        Week 171 - Mild (n=1,0)
    1
    0
        Week 171 - Moderate (n=1,0)
    0
    0
        Week 171 - Severe (n=1,0)
    0
    0
        Week 171 - Very Severe (n=1,0)
    0
    0
        ET/SFU - None (n=19,18)
    2
    4
        ET/SFU - Mild (n=19,18)
    5
    3
        ET/SFU - Moderate (n=19,18)
    7
    5
        ET/SFU - Severe (n=19,18)
    3
    5
        ET/SFU - Very Severe (n=19,18)
    2
    1
    No statistical analyses for this end point

    Secondary: Part B: Number of Subjects With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points

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    End point title
    Part B: Number of Subjects With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points
    End point description
    PGIC is a self-administered questionnaire to evaluate the improvement or worsening compared to the start of the study. PGIC was assessed on a 7-point Likert scale ranged from 1 (greatly improved) to 7 (greatly worsened). Categories were defined based on the PGIC scores as follows: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worsen. Higher scores indicated greater severity. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysis was performed on Part B-FAS. Here, 'n' =subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, n=0 denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    At Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: subjects
        Week 39 - Very much improved (n=17,16)
    4
    3
        Week 39 - Much improved (n=17,16)
    8
    6
        Week 39 - Minimally improved (n=17,16)
    2
    6
        Week 39 - No Change (n=17,16)
    2
    1
        Week 39 - Minimally worse (n=17,16)
    1
    0
        Week 39 - Much worse (n=17,16)
    0
    0
        Week 39 - Very much worse (n=17,16)
    0
    0
        Week 51 - Very much improved (n=15,16)
    5
    3
        Week 51 - Much improved (n=15,16)
    3
    6
        Week 51 - Minimally improved (n=15,16)
    2
    4
        Week 51 - No Change (n=15,16)
    5
    2
        Week 51 - Minimally worse (n=15,16)
    0
    0
        Week 51 - Much worse (n=15,16)
    0
    1
        Week 51 - Very much worse (n=15,16)
    0
    0
        Week 63 - Very much improved (n=17,16)
    5
    3
        Week 63 - Much improved (n=17,16)
    8
    4
        Week 63 - Minimally improved (n=17,16)
    0
    5
        Week 63 - No change (n=17,16)
    4
    3
        Week 63 - Minimally worse (n=17,16)
    0
    0
        Week 63 - Much worse (n=17,16)
    0
    1
        Week 63 - Very much worse (n=17,16)
    0
    0
        Week 75 - Very much improved (n=13,15)
    6
    6
        Week 75 - Much improved (n=13,15)
    2
    3
        Week 75 - Minimally improved (n=13,15)
    1
    5
        Week 75 - No Change (n=13,15)
    4
    1
        Week 75 - Minimally worse (n=13,15)
    0
    0
        Week 75 - Much worse (n=13,15)
    0
    0
        Week 75 - Very much worse (n=13,15)
    0
    0
        Week 87 - Very much improved (n=13,15)
    7
    7
        Week 87 - Much improved (n=13,15)
    0
    3
        Week 87 - Minimally improved (n=13,15)
    2
    1
        Week 87 - No Change (n=13,15)
    2
    3
        Week 87 - Minimally worse (n=13,15)
    1
    1
        Week 87 - Much worse (n=13,15)
    1
    0
        Week 87 - Very much worse (n=13,15)
    0
    0
        Week 99 - Very much improved (n=11,13)
    3
    8
        Week 99 - Much improved (n=11,13)
    3
    2
        Week 99 - Minimally improved (n=11,13)
    1
    3
        Week 99 - No change (n=11,13)
    3
    0
        Week 99 - Minimally worse (n=11,13)
    1
    0
        Week 99 - Much worse (n=11,13)
    0
    0
        Week 99 - Very much worse (n=11,13)
    0
    0
        Week 111 - Very much improved (n=11,12)
    3
    6
        Week 111 - Much improved (n=11,12)
    5
    4
        Week 111 - Minimally improved (n=11,12)
    1
    1
        Week 111 - No Change (n=11,12)
    2
    1
        Week 111 - Minimally worse (n=11,12)
    0
    0
        Week 111 - Much worse (n=11,12)
    0
    0
        Week 111 - Very much worse (n=11,12)
    0
    0
        Week 123 - Very much improved (n=9,9)
    3
    4
        Week 123 - Much improved (n=9,9)
    3
    3
        Week 123 - Minimally improved (n=9,9)
    2
    1
        Week 123 - No Change (n=9,9)
    1
    1
        Week 123 - Minimally worse (n=9,9)
    0
    0
        Week 123 - Much worse (n=9,9)
    0
    0
        Week 123 - Very much worse (n=9,9)
    0
    0
        Week 135 - Very much improved (n=5,5)
    2
    2
        Week 135 - Much improved (n=5,5)
    2
    1
        Week 135 - Minimally improved (n=5,5)
    0
    1
        Week 135 - No Change (n=5,5)
    0
    1
        Week 135 - Minimally worse (n=5,5)
    1
    0
        Week 135 - Much worse (n=5,5)
    0
    0
        Week 135 - Very much worse (n=5,5)
    0
    0
        Week 147 - Very much improved (n=2,2)
    1
    0
        Week 147 - Much improved (n=2,2)
    0
    1
        Week 147 - Minimally improved (n=2,2)
    0
    1
        Week 147 - No Change (n=2,2)
    1
    0
        Week 147 - Minimally worse (n=2,2)
    0
    0
        Week 147 - Much worse (n=2,2)
    0
    0
        Week 147 - Very much worse (n=2,2)
    0
    0
        Week 159 - Very much improved (n=1,1)
    1
    0
        Week 159 - Much improved (n=1,1)
    0
    0
        Week 159 - Minimally improved (n=1,1)
    0
    1
        Week 159 - No Change (n=1,1)
    0
    0
        Week 159 - Minimally worse (n=1,1)
    0
    0
        Week 159 - Much worse (n=1,1)
    0
    0
        Week 159 - Very much worse (n=1,1)
    0
    0
        Week 171- Very much improved (n=1,0)
    1
    0
        Week 171- Much improved (n=1,0)
    0
    0
        Week 171- Minimally improved (n=1,0)
    0
    0
        Week 171- No Change (n=1,0)
    0
    0
        Week 171- Minimally worse (n=1,0)
    0
    0
        Week 171- Much worse (n=1,0)
    0
    0
        Week 171- Very much worse (n=1,0)
    0
    0
        ET/SFU Visit- Very much improved (n=19,18)
    3
    3
        ET/SFU Visit- Much improved (n=19,18)
    5
    6
        ET/SFU Visit- Minimally improved (n=19,18)
    4
    1
        ET/SFU Visit- No Change (n=19,18)
    3
    3
        ET/SFU Visit- Minimally worse (n=19,18)
    1
    2
        ET/SFU Visit- Much worse (n=19,18)
    3
    3
        ET/SFU Visit- Very much worse (n=19,18)
    0
    0
    No statistical analyses for this end point

    Secondary: Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points

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    End point title
    Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
    End point description
    Mean change from baseline (Week 0) in LDH levels at each specified time points is reported in this endpoint. Baseline was defined as last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Analysed on Part B-FAS. Here, 'n' = subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: units per litre
    arithmetic mean (standard deviation)
        Week 27 (n=19,20)
    -151.000 ± 184.640
    0.650 ± 208.051
        Week 29 (n=18,19)
    -115.944 ± 226.913
    11.000 ± 222.383
        Week 31 (n=18,17)
    -85.111 ± 247.506
    38.882 ± 211.386
        Week 33 (n=17,16)
    -66.176 ± 324.145
    4.813 ± 203.939
        Week 35 (n=18,16)
    -64.667 ± 261.431
    -19.313 ± 142.989
        Week 37 (n=16,17)
    4.438 ± 398.843
    25.765 ± 219.679
        Week 39 (n=16,16)
    -88.500 ± 271.941
    27.313 ± 210.705
        Week 41 (n=18,17)
    23.778 ± 342.195
    -6.000 ± 173.810
        Week 43 (n=17,17)
    -22.118 ± 310.381
    -21.706 ± 181.668
        Week 45 (n=17,18)
    26.529 ± 329.717
    -13.500 ± 190.460
        Week 47 (n=15,18)
    -22.600 ± 302.511
    -24.944 ± 153.580
        Week 49 (n=16,18)
    -29.250 ± 289.392
    15.722 ± 193.630
        Week 51 (n=16,18)
    -12.563 ± 290.489
    -9.556 ± 155.646
        Week 53 (n=16,17)
    -16.938 ± 299.788
    12.529 ± 206.642
        Week 55 (n=14,16)
    -89.500 ± 219.634
    -11.250 ± 177.647
        Week 57 (n=15,16)
    -78.200 ± 285.140
    64.188 ± 266.395
        Week 59 (n=16,17)
    -84.438 ± 220.376
    31.647 ± 226.128
        Week 61 (n=17,17)
    -74.353 ± 215.414
    20.588 ± 263.984
        Week 63 (n=17,17)
    -98.235 ± 185.259
    38.059 ± 325.329
        Week 65 (n=16,15)
    -97.438 ± 212.335
    -16.467 ± 246.765
        Week 67 (n=17,15)
    -127.824 ± 192.148
    29.667 ± 269.918
        Week 69 (n=16,16)
    -113.625 ± 197.270
    36.563 ± 303.550
        Week 71 (n=13,15)
    -101.692 ± 320.348
    4.067 ± 307.924
        Week 73 (n=14,16)
    -174.500 ± 177.153
    7.063 ± 245.723
        Week 75 (n=14,15)
    -157.429 ± 184.525
    7.067 ± 285.183
        Week 77 (n=14,15)
    -142.857 ± 199.169
    -24.867 ± 291.754
        Week 79 (n=13,16)
    -98.077 ± 271.632
    -20.063 ± 265.761
        Week 81 (n=13,15)
    -127.846 ± 233.663
    7.200 ± 219.952
        Week 83 (n=13,11)
    -59.000 ± 346.917
    8.818 ± 250.068
        Week 85 (n=13,15)
    -72.000 ± 350.021
    28.400 ± 282.626
        Week 87 (n=13,13)
    -101.385 ± 285.590
    83.385 ± 288.731
        Week 89 (n=12,12)
    -78.667 ± 351.059
    10.833 ± 323.647
        Week 91 (n=9,13)
    -143.000 ± 273.540
    0.846 ± 288.451
        Week 93 (n=10,11)
    -133.500 ± 254.332
    10.818 ± 268.308
        Week 95 (n=11,13)
    -59.364 ± 368.708
    18.231 ± 241.354
        Week 97 (n=11,10)
    -53.364 ± 343.820
    -38.500 ± 188.403
        Week 99 (n=11,12)
    -80.909 ± 312.405
    -12.917 ± 183.844
        Week 101 (n=11,11)
    -90.273 ± 293.680
    -17.182 ± 249.134
        Week 103 (n=11,13)
    -50.273 ± 331.072
    5.692 ± 211.233
        Week 105 (n=11,12)
    -96.455 ± 276.907
    -34.250 ± 147.738
        Week 107 (n=11,13)
    -28.091 ± 354.244
    20.769 ± 222.772
        Week 109 (n=11,11)
    -50.727 ± 335.078
    -2.000 ± 243.243
        Week 111 (n=10,12)
    -83.000 ± 303.258
    -5.583 ± 219.850
        Week 113 (n=10,12)
    -80.700 ± 319.283
    0.667 ± 294.904
        Week 115 (n=10,10)
    -109.500 ± 256.395
    44.700 ± 295.946
        Week 117 (n=9,10)
    -140.444 ± 280.944
    12.700 ± 254.786
        Week 119 (n=9,10)
    -149.556 ± 237.771
    -26.500 ± 274.168
        Week 121 (n=9,8)
    -195.778 ± 225.978
    -42.375 ± 211.840
        Week 123 (n=9,9)
    -185.000 ± 231.489
    22.222 ± 278.037
        Week 125 (n=7,7)
    -99.429 ± 285.513
    -85.143 ± 265.374
        Week 127 (n=7,8)
    -154.714 ± 231.922
    -28.875 ± 312.483
        Week 129 (n=7,7)
    -136.429 ± 234.954
    -18.571 ± 354.584
        Week 131 (n=6,6)
    -120.833 ± 300.454
    -2.000 ± 270.245
        Week 133 (n=5,4)
    -179.000 ± 298.811
    -47.500 ± 367.639
        Week 135 (n=5,5)
    -211.800 ± 265.438
    58.000 ± 449.233
        Week 137 (n=4,2)
    -252.500 ± 264.591
    46.500 ± 768.625
        Week 139 (n=5,3)
    -181.800 ± 284.966
    -48.667 ± 373.339
        Week 141 (n=3,3)
    -259.667 ± 362.136
    30.667 ± 372.889
        Week 143 (n=4,2)
    -160.250 ± 357.021
    -7.500 ± 21.920
        Week 145 (n=2,2)
    -340.500 ± 458.912
    290.000 ± 562.857
        Week 147 (n=3,2)
    -248.667 ± 355.136
    311.000 ± 547.301
        Week 149 (n=1,2)
    -78.000 ± 99999
    116.000 ± 175.362
        Week 151 (n=2,1)
    58.000 ± 32.527
    295.000 ± 99999
        Week 153 (n=1,1)
    7.000 ± 99999
    75.000 ± 99999
        Week 155 (n=1,0)
    -50.000 ± 99999
    9999 ± 99999
        Week 157 (n=1,1)
    -50.000 ± 99999
    369.000 ± 99999
        Week 159 (n=1,1)
    -155.000 ± 99999
    365.000 ± 99999
        Week 161 (n=1,0)
    -175.000 ± 99999
    9999 ± 99999
        Week 163 (n=1,1)
    -149.000 ± 99999
    782.000 ± 99999
        Week 165 (n=1,0)
    -155.000 ± 99999
    9999 ± 99999
        Week 167 (n=1,0)
    -162.000 ± 99999
    9999 ± 99999
        Week 169 (n=1,0)
    -180.000 ± 99999
    9999 ± 99999
        Week 171 (n=1,0)
    -167.000 ± 99999
    9999 ± 99999
        Week 173 (n=1,0)
    -171.000 ± 99999
    9999 ± 99999
        Week 175 (n=1,0)
    -121.000 ± 99999
    9999 ± 99999
        ET/SFU Visit (n=16,17)
    -2.500 ± 195.967
    -11.706 ± 206.321
    No statistical analyses for this end point

    Secondary: Part B: Number of Blood Transfusions Per Subject

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    End point title
    Part B: Number of Blood Transfusions Per Subject
    End point description
    A subject was to receive a transfusion if his or her Hgb level met either of the following criteria: Hgb was <9 g/dL and the subject had symptoms of anemia or Hgb was <7 g/dL and the subject was asymptomatic. Analysis was performed on Part B-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]).
    End point type
    Secondary
    End point timeframe
    From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: blood transfusions per subject
        arithmetic mean (standard deviation)
    0.4 ± 0.8
    0.3 ± 0.4
    No statistical analyses for this end point

    Secondary: Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points

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    End point title
    Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points
    End point description
    Change from baseline (Week 0) in haptoglobin values at each specified time points is reported in this endpoint. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Haptoglobin values <0.2 were imputed as 0.2. Analysis was performed on Part B-FAS. Here, 'n' =subjects with available data for each specified category. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either at 6.5 g or 7.5 g]). Here, '99999' is used as a space filler and denotes that SD was not estimable since only one subject was available for analysis and "9999 & 99999" denotes no subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: grams per litre
    arithmetic mean (standard deviation)
        Week 27 (n=19,19)
    0.219 ± 0.380
    0.082 ± 0.197
        Week 29 (n=18,20)
    0.240 ± 0.317
    0.182 ± 0.482
        Week 31 (n=19,20)
    0.183 ± 0.311
    0.256 ± 0.516
        Week 33 (n=19,17)
    0.212 ± 0.423
    0.229 ± 0.379
        Week 35 (n=18,19)
    0.207 ± 0.355
    0.151 ± 0.280
        Week 37 (n=18,18)
    0.232 ± 0.419
    0.187 ± 0.291
        Week 39 (n=16,16)
    0.213 ± 0.330
    0.165 ± 0.295
        Week 41 (n=19,18)
    0.119 ± 0.238
    0.082 ± 0.168
        Week 43 (n=18,18)
    0.100 ± 0.224
    0.161 ± 0.234
        Week 45 (n=18,20)
    0.114 ± 0.205
    0.189 ± 0.275
        Week 47 (n=15,20)
    0.135 ± 0.243
    0.255 ± 0.416
        Week 49 (n=16,18)
    0.139 ± 0.205
    0.172 ± 0.345
        Week 51 (n=15,17)
    0.083 ± 0.197
    0.207 ± 0.369
        Week 53 (n=16,19)
    0.045 ± 0.137
    0.122 ± 0.296
        Week 55 (n=17,18)
    0.149 ± 0.251
    0.179 ± 0.343
        Week 57 (n=16,17)
    0.158 ± 0.234
    0.158 ± 0.362
        Week 59 (n=17,17)
    0.132 ± 0.229
    0.131 ± 0.306
        Week 61 (n=17,18)
    0.153 ± 0.286
    0.184 ± 0.350
        Week 63 (n=17,17)
    0.202 ± 0.265
    0.177 ± 0.357
        Week 65 (n=16,16)
    0.101 ± 0.232
    0.198 ± 0.384
        Week 67 (n=17,16)
    0.178 ± 0.241
    0.162 ± 0.363
        Week 69 (n=16,17)
    0.168 ± 0.255
    0.169 ± 0.348
        Week 71 (n=14,15)
    0.220 ± 0.288
    0.236 ± 0.388
        Week 73 (n=14,16)
    0.261 ± 0.335
    0.174 ± 0.348
        Week 75 (n=15,16)
    0.275 ± 0.321
    0.197 ± 0.362
        Week 77 (n=14,16)
    0.249 ± 0.374
    0.232 ± 0.398
        Week 79 (n=14,16)
    0.299 ± 0.419
    0.290 ± 0.464
        Week 81 (n=13,16)
    0.438 ± 0.463
    0.207 ± 0.421
        Week 83 (n=14,13)
    0.297 ± 0.379
    0.233 ± 0.394
        Week 85 (n=13,15)
    0.374 ± 0.374
    0.266 ± 0.426
        Week 87 (n=12,13)
    0.334 ± 0.409
    0.344 ± 0.471
        Week 89 (n=12,13)
    0.348 ± 0.482
    0.198 ± 0.351
        Week 91 (n=11,12)
    0.313 ± 0.449
    0.279 ± 0.449
        Week 93 (n=11,12)
    0.262 ± 0.383
    0.178 ± 0.373
        Week 95 (n=11,13)
    0.263 ± 0.495
    0.198 ± 0.414
        Week 97 (n=11,12)
    0.245 ± 0.306
    0.210 ± 0.407
        Week 99 (n=11,13)
    0.266 ± 0.351
    0.213 ± 0.370
        Week 101 (n=11,12)
    0.289 ± 0.289
    0.207 ± 0.417
        Week 103 (n=11,13)
    0.219 ± 0.291
    0.212 ± 0.389
        Week 105 (n=11,12)
    0.216 ± 0.291
    0.174 ± 0.399
        Week 107 (n=11,13)
    0.182 ± 0.273
    0.245 ± 0.459
        Week 109 (n=10,11)
    0.207 ± 0.311
    0.254 ± 0.507
        Week 111 (n=11,12)
    0.282 ± 0.556
    0.263 ± 0.459
        Week 113 (n=11,12)
    0.248 ± 0.366
    0.335 ± 0.614
        Week 115 (n=10,11)
    0.324 ± 0.413
    0.165 ± 0.432
        Week 117 (n=9,10)
    0.450 ± 0.492
    0.181 ± 0.489
        Week 119 (n=9,10)
    0.348 ± 0.400
    0.187 ± 0.404
        Week 121 (n=9,8)
    0.459 ± 0.414
    0.174 ± 0.479
        Week 123 (n=9,9)
    0.350 ± 0.375
    0.192 ± 0.512
        Week 125 (n=8,7)
    0.303 ± 0.425
    0.114 ± 0.298
        Week 127 (n=7,8)
    0.309 ± 0.401
    0.220 ± 0.420
        Week 129 (n=7,7)
    0.393 ± 0.506
    0.191 ± 0.506
        Week 131 (n=6,5)
    0.480 ± 0.529
    0.222 ± 0.430
        Week 133 (n=5,4)
    0.342 ± 0.469
    0.125 ± 0.155
        Week 135 (n=5,5)
    0.454 ± 0.643
    0.280 ± 0.425
        Week 137 (n=4,3)
    0.545 ± 0.631
    0.070 ± 0.121
        Week 139 (n=5,3)
    0.494 ± 0.676
    0.293 ± 0.508
        Week 141 (n=3,2)
    0.667 ± 0.583
    0.025 ± 0.035
        Week 143 (n=4,3)
    0.513 ± 0.604
    0.270 ± 0.292
        Week 145 (n=2,3)
    0.580 ± 0.820
    0.130 ± 0.141
        Week 147 (n=3,2)
    0.400 ± 0.592
    0.195 ± 0.276
        Week 149 (n=1,2)
    0.000 ± 99999
    0.000 ± 0.000
        Week 151 (n=2,1)
    0.000 ± 0.000
    0.000 ± 99999
        Week 153 (n=1,1)
    0.000 ± 99999
    0.000 ± 99999
        Week 155 (n=1,1)
    0.000 ± 99999
    0.000 ± 99999
        Week 157 (n=1,1)
    0.000 ± 99999
    0.000 ± 99999
        Week 159 (n=1,1)
    0.000 ± 99999
    0.000 ± 99999
        Week 161 (n=1,1)
    0.180 ± 99999
    0.000 ± 99999
        Week 163 (n=1,1)
    0.000 ± 99999
    0.000 ± 99999
        Week 165 (n=1,0)
    0.000 ± 99999
    9999 ± 99999
        Week 167 (n=1,0)
    0.000 ± 99999
    9999 ± 99999
        Week 169 (n=1,0)
    0.000 ± 99999
    99999 ± 99999
        Week 171 (n=1,0)
    0.000 ± 99999
    9999 ± 99999
        Week 173 (n=1,0)
    0.000 ± 99999
    9999 ± 99999
        Week 175 (n=1,0)
    0.000 ± 99999
    9999 ± 99999
        ET/SFU Visit (n=19,18)
    0.055 ± 0.200
    0.181 ± 0.426
    No statistical analyses for this end point

    Secondary: Part B: Number of Healthcare Visits by Type

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    End point title
    Part B: Number of Healthcare Visits by Type
    End point description
    In this endpoint, number of healthcare visits which included non-study healthcare resource utilisation visit (consisted mainly of extra visits to the office of the study doctor, visit to a generalist doctor or visit to a specialist doctor), hospitalisation visit and visit to hospital emergency is reported. Analysis was performed on Part B-FAS. Data for this endpoint was planned to be collected and analysed for combined population of BIVV009 (i.e., all subjects who received BIVV009 [either 6.5 g or 7.5 g]).
    End point type
    Secondary
    End point timeframe
    From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
    End point values
    BIVV009/BIVV009 Placebo/BIVV009
    Number of subjects analysed
    19
    20
    Units: visits
    number (not applicable)
        Non-study healthcare resource utilisation visits
    13
    12
        Hospitalisation
    3
    1
        Visit to a hospital emergency room
    1
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part A:first dose (Day 0) up to Week 25; Part B 6.5 g cohort:first dose (Week 26) up to 149 weeks of treatment+9 weeks of follow-up (up to Week 184); Part B, 7.5 g cohort:first dose (Week 26) up to 137 weeks of treatment+9 weeks follow up (up to Week 172)
    Adverse event reporting additional description
    Reported AEs and SAEs including fatal AEs were TEAEs that developed/worsened or became serious during on-treatment period. Analysis was performed on SAS.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Part A: BIVV009 6.5 g
    Reporting group description
    Subjects with primary CAD and body weight <75 kg and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 6.5 g on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

    Reporting group title
    Part A: BIVV009 7.5 g
    Reporting group description
    Subjects with primary CAD and body weight >=75 kg and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of BIVV009 7.5 g on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

    Reporting group title
    Part A: Placebo
    Reporting group description
    Subjects with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25.

    Reporting group title
    Part B: BIVV009 6.5 g
    Reporting group description
    Subjects who completed Part A per protocol through the end of treatment visit (Week 26) were eligible to be enrolled in Part B where they were treated for up to an additional 149 weeks. Subjects who received placebo in Part A received BIVV009 6.5 g on Week 26, Week 27 and every 2 weeks thereafter; subjects who received BIVV009 6.5 g in Part A received placebo on Week 26, BIVV009 6.5 g on Week 27 and every 2 weeks thereafter for up to an additional 149 weeks.

    Reporting group title
    Part B: BIVV009 7.5 g
    Reporting group description
    Subjects who completed Part A per protocol through the end of treatment visit (Week 26) were eligible to be enrolled in Part B where they were treated for up to an additional 137 weeks. Subjects who received placebo in Part A received BIVV009 7.5 g on Week 26, Week 27 and every 2 weeks thereafter; subjects who received BIVV009 7.5 g in Part A received placebo on Week 26, BIVV009 7.5 g on Week 27 and every 2 weeks thereafter for up to an additional 137 weeks.

    Serious adverse events
    Part A: BIVV009 6.5 g Part A: BIVV009 7.5 g Part A: Placebo Part B: BIVV009 6.5 g Part B: BIVV009 7.5 g
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    6 / 32 (18.75%)
    1 / 7 (14.29%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Investigations
    Blood Immunoglobulin M Increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous Cell Carcinoma Of Lung
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Hip Fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle Strain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Polycystic Liver Disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Raynaud's Phenomenon
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Venous Sinus Thrombosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Febrile Infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         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
    Part A: BIVV009 6.5 g Part A: BIVV009 7.5 g Part A: Placebo Part B: BIVV009 6.5 g Part B: BIVV009 7.5 g
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 17 (94.12%)
    5 / 5 (100.00%)
    3 / 20 (15.00%)
    28 / 32 (87.50%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Melanocytic Naevus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vascular disorders
    Cyanosis
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    2 / 7 (28.57%)
         occurrences all number
    10
    0
    0
    2
    3
    Extremity Necrosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Flushing
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    3
    Haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    5 / 32 (15.63%)
    2 / 7 (28.57%)
         occurrences all number
    7
    1
    0
    7
    3
    Hypotension
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    1
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Poor Venous Access
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Raynaud's Phenomenon
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    0 / 7 (0.00%)
         occurrences all number
    4
    2
    0
    3
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    4 / 32 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    0
    6
    2
    Catheter Site Dryness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Chest Discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Chest Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Chills
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    7 / 32 (21.88%)
    5 / 7 (71.43%)
         occurrences all number
    1
    2
    0
    7
    10
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Influenza Like Illness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    0
    1
    Injection Site Erythema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Injection Site Pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Oedema Peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    2
    1
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    5 / 32 (15.63%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    6
    1
    Vaccination Site Erythema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vaccination Site Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    0
    2
    1
    Vaccination Site Rash
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    1
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Breast Calcifications
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Breast Cyst
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Cervical Dysplasia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 20 (5.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 5 (40.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    3 / 7 (42.86%)
         occurrences all number
    0
    2
    0
    2
    4
    Epistaxis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    Depressed Mood
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    4 / 32 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    2
    1
    0
    8
    0
    Product issues
    Device Kink
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    2
    Blood Immunoglobulin M Increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Blood Urine Present
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Transaminases Increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Face Injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    4 / 32 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    5
    3
    Fibula Fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infusion Related Reaction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Skin Laceration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Sunburn
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Tooth Fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    1
    1
    Vaccination Complication
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    1
    2
    Tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    0
    3
    2
    Headache
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    4 / 32 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    7
    1
    0
    9
    5
    Memory Impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Paraesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Parkinsonism
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Phantom Limb Syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 5 (40.00%)
    0 / 20 (0.00%)
    9 / 32 (28.13%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    0
    11
    3
    Blood Loss Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haemolysis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    4
    1
    Leukocytosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Eye disorders
    Visual Acuity Reduced
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    Angular Cheilitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Colitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    0
    3
    0
    Dental Caries
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    6 / 32 (18.75%)
    1 / 7 (14.29%)
         occurrences all number
    1
    4
    0
    13
    1
    Dyspepsia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Faeces Discoloured
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    0
    3
    2
    Odynophagia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Paraesthesia Oral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Tongue Ulceration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Cholelithiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dry Skin
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Erythema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Night Sweats
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Pruritus
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    2 / 7 (28.57%)
         occurrences all number
    3
    0
    0
    1
    2
    Rash
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Skin Discolouration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Skin Lesion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Toxic Skin Eruption
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haemoglobinuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    0
    3
    2
    Renal Cyst
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    1 / 20 (5.00%)
    6 / 32 (18.75%)
    2 / 7 (28.57%)
         occurrences all number
    2
    1
    1
    7
    2
    Back Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 20 (5.00%)
    2 / 32 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    2
    1
    Bone Swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Muscle Spasms
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Neck Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Pain In Extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    2
    1
    Pain In Jaw
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Anal Abscess
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    2
    2
    Diverticulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    3 / 32 (9.38%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    3
    1
    Herpes Zoster
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Mastoiditis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 5 (40.00%)
    0 / 20 (0.00%)
    5 / 32 (15.63%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    0
    9
    3
    Oral Candidiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Oral Herpes
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 20 (5.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    1
    Rhinitis
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    2 / 32 (6.25%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    0
    4
    1
    Sinusitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Skin Candida
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Staphylococcal Skin Infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Tooth Infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    4 / 32 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    5
    2
    Urinary Tract Infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Vulval Abscess
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 20 (0.00%)
    0 / 32 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    0
    1
    Iron Deficiency
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 20 (0.00%)
    1 / 32 (3.13%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2017
    Following changes were done: Incorporated a change in responsibility and obligations of the study sponsor; deleted exploratory efficacy end-point PGIS; changed timing of 12 lead electrocardiogram assessments.
    21 Mar 2018
    Following Changes were made: Consolidated all of changes in Amendments 1.1 to 1.6; added Phase 3 to title; updated background and study rationale; specified Part B length of study was 1 year and not approximately 1 year; End of Study/EOT visits were changed from 6 weeks to 9 weeks post last dose; number of subjects was changed from 40 subjects to approximately 40 subjects; added that subjects who received transfusion during Part A would be eligible for Part B; Inclusion criterion 5: Updated to include subjects with Gilbert’s Syndrome with bilirubin > upper limit of normal; inclusion criterion 6: added that subjects with ferritin values <lowe were not to be included and allowed concurrent treatment with iron supplementation if subject on a stable dose; Inclusion criterion 9: serogroup B meningococcus was added as a requirement; added inclusion criterion 10: subjects had to be willing to receive transfusion during study if they met study criteria for infusion; Inclusion criteria 12 and 13: post treatment birth control requirement increased from 6 to 9 weeks; Exclusion criterion 2: changed to exclude subjects with a blood transfusion within 6 months of screening or >1 transfusion within 12 months of screening; Exclusion criterion 4: Added that subjects with existing ANA could be adjudicated; Exclusion criterion 14 added: excluded subjects with hypersensitivity to sutimlimab or its components; original Appendix B (Vaccination Schedule) was removed and vaccination instructions were included within body of protocol; original Appendix C (Guidelines for Diagnosis and Treatment of Hypersensitivity Reactions and Anaphylaxis) was removed; healthcare resource utilisation survey was added to the assessments and description of the survey was added as an appendix; appendices were renumbered; For consistency across protocols, hemolytic “flare” was changed to hemolytic breakthrough; beginning on Day 0, urine pregnancy testing was changed to serum or urine pregnancy testing.
    19 Jul 2018
    Following changes were done: The study number was revised; PGIS was added per United States Food and Drug Administration request; a 25 milliliter (mL) vial (50 mg/mL) vial was added; inclusion criterion 9: added that previous vaccinations had to be documented records and serogroup B meningococcus vaccine requirement only applied where available (this was already included elsewhere in the protocol); corrected start date for the collection of pharmacokinetics and pharmacodynamics samples during Part B; sutimlimab background information of the study was revised for clarity and updated to mention Part E; added that subjects who received transfusion(s) during screening/observation period had to have their baseline visit at least 7 days after the transfusion; for subjects who had a transfusion, screening period could have been extended from 6 to 7 weeks; updated clinical experience section; the vaccination schedule from the country-specific protocol for Japan (Version 3.1) was added to the vaccination schedule for the other participating countries; windows were added for post-dose vital signs, ECGs, and PK/PD sampling time points; modified text to indicate sutimlimab would be supplied in larger volume and concentration.
    15 Oct 2019
    Following changes were done: Added home infusion in prespecified countries (US, Netherlands, Norway, France, Italy, Austria, Germany, Spain) in Part B, which was to be supported by a healthcare professional caregiver; added exploratory objective to describe the safety and subjects satisfaction with the convenience of home infusions with sutimlimab in a subset of subjects in Part B; added secondary objective to Part B to exploratory objective to evaluate immunogenicity of sutimlimab; added more time points for ADA sample collection and same objective added as an exploratory objective to Parts A and B; efficacy endpoint added to assess satisfaction with home infusion; safety endpoint added to assess AEs with home infusion; specified that predose PD back-up samples could be used to assess immunogenicity in subjects who consented to future use of sample; added time points for systemic lupus erythematosus panel sample collection during Part B. • Clarified PK/PD sampling schedules for Part B to match text description to assessment table • Corrected Appendix A to delete iron from chemistry panel • Added Appendix K which described country-specific requirements for home infusion substudy
    07 Jul 2020
    Following changes were done: Hypersensitivity or allergic reactions including anaphylaxis to IMP were added to reasons for study discontinuation; to match the statistical analysis plan, the intent-to-treat population was to be referred to as the Full Analysis Set; for home infusion substudy, removed requirements for cardiac resuscitation equipment during home infusion as the risk of emergency situations occurring during home infusions was minimized by enrolling subjects without a history of hypersensitivity reactions to IMP and assistance by personnel trained in basic life support was implemented; added that substudy is only open to subjects who have not or do not plan to receive undiluted infusions; introduced the option of infusion with undiluted solution of sutimlimab in a subset of subjects in Part B; added exploratory endpoint to describe safety of undiluted infusions in Part B; reworded primary endpoint (“responder”) definition for clarity, but definition was unchanged; clarified the order of post dose assessments so that assessments that may impact vital signs (eg, blood draws) occur after vital signs are measured.
    04 Nov 2020
    Following changes were done: “Post-infusion vital signs and” were added to the list of endpoints for the subjects receiving undiluted infusions; for the primary endpoint (responder status) analysis for Part A, Fisher’s Exact test was replaced by “Cochran-Mantel-Haenszel (CMH) test”; post infusion vital signs and” were added to the list of endpoints for the subjects receiving undiluted infusions; In Table 3, footnote “l” “added the follow text, “or for post-infusion vital signs in case of undiluted administration, after each undiluted infusion”; references to the study procedural manual were either removed or replaced by references to the applicable study manuals; references to the central laboratory were removed from the laboratory evaluation section; primary efficacy analysis method was changed from Fisher’s exact test to a stratified CMH test.

    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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