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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel-group study of the safety, tolerability, pharmacokinetics, and therapeutic efficacy of SAR441344 in adult patients with primary Sjögren’s syndrome (pSjS)

    Summary
    EudraCT number
    2020-000511-77
    Trial protocol
    DE   BE   HU  
    Global end of trial date
    09 Feb 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Feb 2025
    First version publication date
    21 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT16618
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04572841
    WHO universal trial number (UTN)
    U1111-1244-2266
    Sponsors
    Sponsor organisation name
    Sanofi Aventis Recherche & Développement
    Sponsor organisation address
    82 Avenue Raspail, Gentilly, France, 94250
    Public contact
    Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Aventis Recherche & Développement, 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
    04 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the therapeutic efficacy of 1 dose level of SAR441344 versus placebo over 12 weeks in adult participants with primary Sjögren’s syndrome (pSjS), assessed by the change of the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI).
    Protection of trial subjects
    Participants were fully informed of all pertinent aspects of clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trial, participants were provided with individual participant cards indicating the nature of the trial the participant 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
    12 Nov 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    84
    EEA total number of subjects
    26
    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)
    76
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 35 centers in 12 countries. A total of 234 participants were screened from 12 November 2020 to 10 August 2023, of which 150 were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.

    Pre-assignment
    Screening details
    A total of 84 participants were randomized in a ratio of 1:1 to either placebo or SAR441344 (frexalimab) arm. Randomization was stratified by Baseline EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score greater than or equal to (≥) 5 versus less than (<) 5.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received a single intravenous (IV) loading dose of placebo matched to SAR441344 on Day 1, followed by a subcutaneous (SC) dose of placebo matched to SAR441344 administered once every 2 weeks (q2w) at Weeks 2, 4, 6, 8 and 10.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Placebo matched to SAR441344 was administered via IV infusion on Day 1, followed by an SC injection administered q2w at Weeks 2, 4, 6, 8 and 10.

    Arm title
    SAR441344
    Arm description
    Participants received a single IV loading dose of SAR441344 1200 milligram (mg) on Day 1, followed by an SC dose of SAR441344 600 mg administered q2w at Weeks 2, 4, 6, 8 and 10.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR441344
    Investigational medicinal product code
    Other name
    Frexalimab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    SAR441344 1200 mg was administered via IV infusion on Day 1, followed by an SC injection of SAR441344 600 mg administered q2w at Weeks 2, 4, 6, 8 and 10.

    Number of subjects in period 1
    Placebo SAR441344
    Started
    42
    42
    Completed
    39
    40
    Not completed
    3
    2
         Consent withdrawn by subject
    2
    1
         Adverse event
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single intravenous (IV) loading dose of placebo matched to SAR441344 on Day 1, followed by a subcutaneous (SC) dose of placebo matched to SAR441344 administered once every 2 weeks (q2w) at Weeks 2, 4, 6, 8 and 10.

    Reporting group title
    SAR441344
    Reporting group description
    Participants received a single IV loading dose of SAR441344 1200 milligram (mg) on Day 1, followed by an SC dose of SAR441344 600 mg administered q2w at Weeks 2, 4, 6, 8 and 10.

    Reporting group values
    Placebo SAR441344 Total
    Number of subjects
    42 42 84
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    47.8 ( 12.9 ) 49.2 ( 11.1 ) -
    Sex: Female, Male
    Units: participants
        Female
    40 40 80
        Male
    2 2 4
    Race/Ethnicity, Customized
    Units: Subjects
        White
    34 28 62
        Black or African American
    1 4 5
        Asian
    5 4 9
        American Indian or Alaska Native
    1 6 7
        Missing/Not reported
    1 0 1
    EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) Score
    ESSDAI:validated and established outcome measurement for therapeutic efficacy in Sjögren’s syndrome, evaluating disease activity mainly on extra-glandular manifestations, and consisted of 12 organ-specific domains(constitutional,lymphadenopathy,glandular,articular,cutaneous,pulmonary, renal,muscular,peripheral and central nervous system,hematological,biological), scored based on organ-specific items in 3 to 4 different severity grades (0=no to 3=high). These scores were summed up in weighted way to summarize into total score ranging from 0-123. Higher scores=worse outcome.
    Units: score on a scale
        arithmetic mean (standard deviation)
    10.38 ( 3.64 ) 8.43 ( 3.88 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single intravenous (IV) loading dose of placebo matched to SAR441344 on Day 1, followed by a subcutaneous (SC) dose of placebo matched to SAR441344 administered once every 2 weeks (q2w) at Weeks 2, 4, 6, 8 and 10.

    Reporting group title
    SAR441344
    Reporting group description
    Participants received a single IV loading dose of SAR441344 1200 milligram (mg) on Day 1, followed by an SC dose of SAR441344 600 mg administered q2w at Weeks 2, 4, 6, 8 and 10.

    Primary: Change From Baseline to Week 12 in ESSDAI Score

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    End point title
    Change From Baseline to Week 12 in ESSDAI Score
    End point description
    ESSDAI:validated,established outcome measurement for therapeutic efficacy in Sjögren’s syndrome evaluating disease activity on extra-glandular manifestations.Score includes 12 organ-specific domains(constitutional,lymphadenopathy,glandular,articular,cutaneous,pulmonary,renal,muscular,peripheral and central nervous system,hematological,biological), scored based on organ-specific items in 3-4 severity grades(0=no to 3=high).Scores are summed up in weighted way(severity grades multiplied with weights 1-6) to summarize into total score(0-123).Higher scores=worse outcome.Negative change from baseline=improvement.Baseline=Day 1 assessment value.Efficacy population=all randomly assigned participants who received at least 1 complete dose of IMP with at least 1 post-IMP administration measurement with available Baseline assessment of ESSDAI.Least squares(LS) mean is calculated using mixed models for repeated measures (MMRM).Observed values after occurrence of intercurrent events are excluded.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to Week 12
    End point values
    Placebo SAR441344
    Number of subjects analysed
    36
    38
    Units: score on a scale
        least squares mean (standard error)
    -5.60 ( 0.60 )
    -5.29 ( 0.59 )
    Statistical analysis title
    Placebo Versus SAR441344
    Statistical analysis description
    Analysis was performed for change from baseline using a mixed model for repeated measures with visit, intervention group (SAR441344 and Placebo), and visit by intervention group interaction as fixed categorical effects, and participant specific baseline ESSDAI as continuous covariate.
    Comparison groups
    Placebo v SAR441344
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Least Square Mean Difference
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.39
         upper limit
    2.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85

    Secondary: Change From Baseline to Week 12 in European League Against Rheumatism (EULAR) Sjögren’s Syndrome Patient Reported Index (ESSPRI) Score

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    End point title
    Change From Baseline to Week 12 in European League Against Rheumatism (EULAR) Sjögren’s Syndrome Patient Reported Index (ESSPRI) Score
    End point description
    The ESSPRI is a validated and established outcome measurement, reported by participants, which rates the key disease manifestations: fatigue, dryness, and pain, based on a numeric scale ranging from 0 to 10, where 0 is defined as no symptoms and 10 as maximum imaginable complaints. The total score is the mean score of the 3 scales and ranges from 0 to 10. Higher scores indicates worse outcome. A negative change from baseline indicates improvement. Baseline is defined as Day 1 assessment value. LS mean is calculated using MMRM. Observed values after occurrence of intercurrent events are excluded. Efficacy population includes all randomly assigned participants who actually received at least 1 complete dose of IMP with at least 1 post-IMP administration measurement, with available Baseline assessment of the ESSDAI. Only participants with data collected for this endpoint are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 12
    End point values
    Placebo SAR441344
    Number of subjects analysed
    38
    38
    Units: score on a scale
        least squares mean (standard error)
    -2.21 ( 0.34 )
    -1.92 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 12 in Multidimensional Fatigue Inventory (MFI) General Fatigue Subscale and Other Subscales Score

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    End point title
    Change From Baseline to Week 12 in Multidimensional Fatigue Inventory (MFI) General Fatigue Subscale and Other Subscales Score
    End point description
    MFI is validated,20 item self-report instrument to evaluate fatigue by investigating subscales: general fatigue,physical fatigue,mental fatigue,reduced motivation,reduced activity. Each subscale consists of 4 items that are scored from 1 (yes, this is true) to 5 (no, this is not true) on which participants indicate how listed statements applied to their current fatigue situation. Item scores are summed to create individual subscale score (4-20).Higher score=higher degree of fatigue.Negative change from baseline=improvement.Baseline=Day 1 assessment value.LS mean is calculated using ANCOVA. Observed values after occurrence of intercurrent events are excluded.Efficacy population=all randomly assigned participants who received at least 1 complete dose of IMP with at least 1 post-IMP administration measurement, with available Baseline assessment of ESSDAI. Only participants with data collected for this endpoint are reported. n=number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 12
    End point values
    Placebo SAR441344
    Number of subjects analysed
    38
    38
    Units: score on a scale
    least squares mean (standard error)
        General Fatigue Scale Score (n=38, 38)
    0.37 ( 0.30 )
    -0.18 ( 0.30 )
        Mental Fatigue Scale Score (n=38, 38)
    0.26 ( 0.36 )
    0.37 ( 0.36 )
        Physical Fatigue Scale Score (n=38, 38)
    0.27 ( 0.36 )
    -0.30 ( 0.36 )
        Reduced Activity Scale Score (n=37, 38)
    0.22 ( 0.31 )
    0.29 ( 0.31 )
        Reduced Motivation Scale Score (n=37, 38)
    0.30 ( 0.30 )
    0.26 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Mean Plasma Concentration of SAR441344

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    End point title
    Mean Plasma Concentration of SAR441344 [1]
    End point description
    Blood samples were collected for the measurement of plasma concentrations of SAR441344. Pharmacokinetic (PK) population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    At end of infusion and 4 hours post-infusion on Day 1; pre-dose at Weeks 2, 4, 6, 8, 10, and at Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    39
    Units: microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Day 1 (end of infusion) (n=21)
    466.10 ( 93.86 )
        Day 1 (4 hours post-infusion) (n=36)
    427.22 ( 102.07 )
        Week 2 (pre-dose) (n=39)
    139.98 ( 28.30 )
        Week 4 (pre-dose) (n=39)
    132.91 ( 36.21 )
        Week 6 (pre-dose) (n=38)
    135.18 ( 46.39 )
        Week 8 (pre-dose) (n=38)
    141.34 ( 44.85 )
        Week 10 (pre-dose) (n=38)
    142.25 ( 48.80 )
        Week 12 (n=36)
    151.59 ( 56.49 )
    No statistical analyses for this end point

    Secondary: Median Plasma Concentration of SAR441344

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    End point title
    Median Plasma Concentration of SAR441344 [2]
    End point description
    Blood samples were collected for the measurement of plasma concentrations of SAR441344. PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    At end of infusion and 4 hours post-infusion on Day 1; pre-dose at Weeks 2, 4, 6, 8, 10, and at Week 12
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    39
    Units: mcg/mL
    median (full range (min-max))
        Day 1 (end of infusion) (n=21)
    479.06 (302.4 to 652.2)
        Day 1 (4 hours post-infusion) (n=36)
    408.37 (253.1 to 623.6)
        Week 2 (pre-dose) (n=39)
    132.21 (98.3 to 203.1)
        Week 4 (pre-dose) (n=39)
    133.01 (45.6 to 236.5)
        Week 6 (pre-dose) (n=38)
    127.32 (60.2 to 237.5)
        Week 8 (pre-dose) (n=38)
    135.10 (76.9 to 284.9)
        Week 10 (pre-dose) (n=38)
    134.39 (58.0 to 268.1)
        Week 12 (n=36)
    148.11 (64.4 to 306.2)
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of SAR441344

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    End point title
    Maximum Plasma Concentration (Cmax) of SAR441344 [3]
    End point description
    Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. Cmax was assessed by a Bayesian approach using the population PK model. PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected for this outcome measure are reported.
    End point type
    Secondary
    End point timeframe
    After the last SC dose on Week 10 up to 336 hours post-dose
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    38
    Units: mcg/mL
        arithmetic mean (standard deviation)
    190 ( 54.5 )
    No statistical analyses for this end point

    Secondary: Terminal Half-life (t1/2z) of SAR441344

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    End point title
    Terminal Half-life (t1/2z) of SAR441344 [4]
    End point description
    Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. t1/2z was assessed by a Bayesian approach using the population PK model. PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population.
    End point type
    Secondary
    End point timeframe
    Week 10 to Week 12
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    42
    Units: hours
        median (full range (min-max))
    662 (374 to 997)
    No statistical analyses for this end point

    Secondary: Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344

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    End point title
    Area Under the Curve Over the Dosing Interval (AUC0-tau) of SAR441344 [5]
    End point description
    Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. AUC0-tau was assessed by a Bayesian approach using the population PK model. PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected for this outcome measure are reported.
    End point type
    Secondary
    End point timeframe
    After the last SC dose on Week 10 up to 336 hours post-dose
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    38
    Units: microgram*hour per milliliter (mcg*h/mL)
        arithmetic mean (standard deviation)
    57900 ( 18000 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration (tmax) of SAR441344

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    End point title
    Time to Maximum Plasma Concentration (tmax) of SAR441344 [6]
    End point description
    Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. tmax was assessed by a Bayesian approach using the population PK model. PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected for this outcome measure are reported.
    End point type
    Secondary
    End point timeframe
    After the last SC dose on Week 10 up to 336 hours post-dose
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    38
    Units: hours
        median (full range (min-max))
    89.1 (76.8 to 139)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESI)

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    End point title
    Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESI)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of IMP, whether or not considered related to the IMP. TEAEs: AEs that occurred, worsened, or became serious during the TEAE period (time from the first IMP administration up to Week 24). Serious adverse events (SAE): Any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or was a congenital anomaly/birth defect. An AESI: an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    From first dose of IMP (Day 1) up to end of follow-up period (Week 24)
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        Any TEAE
    26
    29
        Any TESAE
    1
    1
        Any AESI
    5
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Discontinuation and Withdrawals due to TEAEs

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    End point title
    Number of Participants With Treatment Discontinuation and Withdrawals due to TEAEs
    End point description
    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of IMP, whether or not considered related to the IMP. TEAEs were AEs that occurred, worsened, or became serious during the TEAE period (time from the first IMP administration up to Week 24). Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    From first dose of IMP (Day 1) up to end of follow-up period (Week 24)
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        Treatment discontinuation due to TEAEs
    4
    4
        Treatment withdrawal due to TEAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Increase in Pain Intensity Compared to Pre-dose Pain Intensity at Injection Site by Verbal Descriptor Scale (VDS)

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    End point title
    Number of Participants With Increase in Pain Intensity Compared to Pre-dose Pain Intensity at Injection Site by Verbal Descriptor Scale (VDS)
    End point description
    For measurement of local tolerability, participants had a self-evaluation using VDS before IMP administration, after completion of IMP administration, and 2 hours post-administration. Participants were asked to report sensations at injection site and rated pain severity as following grading: 0= no pain; 1= mild pain; 2= moderate pain, 3= severe pain, 4= very severe. Positive change in VDS score indicated higher pain severity compared to pre-dose pain. Numerical change provides number of grades the pain got worse (positive change) or improved (negative change). Total number of participants with pain intensity increase (change in VDS score of greater than or equal to 1) compared to pre-dose pain intensity are reported. Safety population included all randomized participants exposed to IMP (regardless of amount of treatment administered). Only participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 24 hours prior IMP dosing), post-dose (up to 15 minutes after dosing) and 2 hours post-dose at Weeks 2, 4, 6, 8 and 10
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    40
    Units: participants
        Week 2: Post-dose versus (vs) pre-dose(n=42,40)
    7
    7
        Week 2: 2 hours post-dose vs pre-dose (n=42,40)
    5
    8
        Week 4: Post-dose vs pre-dose (n=39,40)
    12
    8
        Week 4: 2 hours post-dose vs pre-dose (n=39,40)
    5
    6
        Week 6: Post-dose vs pre-dose (n=41,38)
    13
    10
        Week 6: 2 hours post-dose vs pre-dose (n=41,38)
    3
    3
        Week 8: Post-dose vs pre-dose (n=39,38)
    7
    11
        Week 8: 2 hours post-dose vs pre-dose (n=39,38)
    3
    1
        Week 10: Post-dose vs pre-dose (n=37,38)
    7
    10
        Week 10: 2 hours post-dose vs pre-dose (n=37,38)
    5
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With AEs Related to Local Tolerability Findings

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    End point title
    Number of Participants With AEs Related to Local Tolerability Findings
    End point description
    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of IMP, whether or not considered related to the IMP. Local tolerability at injection site was assessed following IMP injection and findings at the site of injection such as injection site erythema, injection site reaction, and injection site pain were recorded. Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 10
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        Injection site erythema
    1
    3
        Injection site reaction
    2
    0
        Injection site pain
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Vital Signs

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    End point title
    Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Vital Signs
    End point description
    PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Sitting systolic blood pressure (SSBP) less than or equal to (≤)95 millimeters of mercury (mmHg) and decrease from baseline ≥20 mmHg; ≥160 mmHg and increase from baseline ≥20 mmHg; Sitting diastolic blood pressure (SDBP) ≤45 mmHg and decrease from baseline ≥10 mmHg, ≥110 mmHg and increase from baseline ≥10 mmHg; Sitting heart rate (HR) ≤50 beats per minute (bpm) and decrease from baseline ≥20 bpm, ≥120 bpm and increase from baseline ≥20 bpm; Weight ≥5% decrease from baseline, ≥5% increase from baseline. Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        SSBP: ≤95 mmHg; decrease from baseline ≥20 mmHg
    2
    2
        SSBP: ≥160mmHg; increase from baseline ≥20mmHg
    0
    0
        SDBP: ≤45 mmHg; decrease from baseline ≥10 mmHg
    0
    0
        SDBP: ≥110 mmHg; increase from baseline ≥10 mmHg
    0
    0
        Sitting HR: ≤50bpm; decrease from baseline ≥20bpm
    1
    0
        Sitting HR: ≥120bpm; increase from baseline ≥20bpm
    0
    0
        Weight: ≥5% decrease from baseline
    6
    3
        Weight: ≥5% increase from baseline
    2
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With PCSA in Electrocardiogram

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    End point title
    Number of Participants With PCSA in Electrocardiogram
    End point description
    PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: HR <50 bpm, <40 bpm, >90 bpm, >90 bpm and increase from baseline ≥20 bpm, >100 bpm; PR interval, aggregate >200 milliseconds (msec), >200 msec and increase from baseline ≥25%, >220 msec, >220 msec and increase from baseline ≥25%, >240 msec, >240 msec and increase from baseline ≥25%; QRS duration, aggregate >110 msec, >110 msec and increase from baseline ≥25%, >120 msec, >120 msec and increase from baseline ≥25%; QT interval, aggregate >500 msec; corrected QT (QTc) correction method unspecified (CMU) >450 msec, >480 msec, increase from baseline [30-60] msec, increase from baseline >60 msec. Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered). IFB= increase from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        HR: <50 bpm
    2
    1
        HR: <40 bpm
    0
    0
        HR: >90 bpm
    3
    1
        HR: >90 bpm; IFB ≥20 bpm
    1
    0
        HR: >100 bpm
    0
    0
        PR interval, aggregate: >200 msec
    4
    2
        PR interval, aggregate: >200 msec; IFB ≥25%
    1
    0
        PR interval, aggregate: >220 msec
    1
    0
        PR interval, aggregate: >220 msec; IFB ≥25%
    0
    0
        PR interval, aggregate: >240 msec
    1
    0
        PR interval, aggregate: >240 msec; IFB ≥25%
    0
    0
        QRS duration, aggregate: >110 msec
    2
    0
        QRS duration, aggregate: >110 msec; IFB ≥25%
    0
    0
        QRS duration, aggregate: >120 msec
    1
    0
        QRS duration, aggregate: >120 msec; IFB ≥25%
    0
    0
        QT interval, aggregate: >500 msec
    0
    0
        QTc CMU: >450 msec
    5
    2
        QTc CMU: >480 msec
    0
    0
        QTc CMU: IFB [30-60] msec
    3
    7
        QTc CMU: IFB >60 msec
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With PCSA in Hematology Parameters

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    End point title
    Number of Participants With PCSA in Hematology Parameters
    End point description
    PCSA values were defined as abnormal values considered medically important by Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by Sponsor. Criteria for PCSA: Hemoglobin (Hb) ≤115 grams per liter (g/L) (Male [M]) or ≤95 g/L (Female [F]), ≥185 g/L (M) or ≥165 g/L (F), decrease from baseline ≥20 g/L; Hematocrit ≤0.37 volume per volume (v/v) (M) or ≤0.32 v/v (F), ≥0.55 v/v (M) or ≥0.5 v/v (F); Erythrocytes (red blood cells [RBC]) ≥6 x 10^12 per liter (/L); Platelets <100 x 10^9/L, ≥700 x 10^9/L; Leukocytes (white blood cells [WBC]) <3 x 10^9/L (Non-Black[NB]) or <2 x 10^9/L (Black[B]), ≥16 x 10^9/L; Neutrophils <1.5 x 10^9/L (NB) or <1 x 10^9/L (B); Lymphocytes >4 x 10^9/L, <0.5 x 10^9L; Monocytes >0.7 x 10^9/L; Basophils >0.1 x 10^9/L; Eosinophils >0.5 x 10^9/L or >upper limit of normal(ULN) (if ULN ≥0.5 x 10^9/L). Safety population included all randomized participants exposed to the IMP (regardless of amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        Hb: ≤115 g/L (M); ≤95 g/L (F)
    0
    1
        Hb: ≥185 g/L (M); ≥165 g/L (F)
    0
    1
        Hb: Decrease from baseline ≥20 g/L
    2
    2
        Hematocrit: ≤0.37 v/v (M); ≤0.32 v/v (F)
    5
    3
        Hematocrit: ≥0.55 v/v (M); ≥0.5 v/v (F)
    0
    1
        RBC: ≥6 x 10^12/L
    0
    1
        Platelets: <100 x 10^9/L
    0
    0
        Platelets: ≥700 x 10^9/L
    0
    0
        WBC: <3 x 10^9/L (NB); <2 x 10^9/L (B)
    8
    5
        WBC: ≥16 x 10^9/L
    0
    0
        Neutrophils: <1.5 x 10^9/L (NB); <1 x 10^9/L (B)
    7
    7
        Lymphocytes: >4 x 10^9/L
    0
    1
        Lymphocytes: <0.5 x 10^9L
    2
    0
        Monocytes: >0.7 x 10^9/L
    1
    2
        Basophils: >0.1 x 10^9/L
    0
    8
        Eosinophils: >0.5 x 10^9/L or >ULN
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With PCSA in Clinical Chemistry Parameters

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    End point title
    Number of Participants With PCSA in Clinical Chemistry Parameters
    End point description
    PCSA values:abnormal values considered medically important by Sponsor,according to predefined criteria/thresholds based on literature reviews;defined by Sponsor.Criteria for PCSA:Sodium≤129 millimoles per liter(mmol/L),≥160 mmol/L;Potassium<3 mmol/L,≥5.5 mmol/L;Glucose≤3.9 mmol/L and <lower limit of normal(LLN),≥11.1 mmol/L(unfasted);≥7 mmol/L(fasted); Creatine kinase(CK)>3 ULN,>10 ULN;Creatinine≥150 micromoles/L(adults),≥30% change from baseline,≥100% change from baseline;Creatinine clearance(CG)≥60-<90 milliliters per minute(mL/min)(mild decrease in glomerular filtration rate[GFR]),≥30-<60 mL/min(moderate decrease in GFR),≥15-<30 mL/min(severe decrease in GFR),<15 mL/min(end stage renal disease),Urea nitrogen≥17 mmol/L;Alkaline phosphatase(ALP)>1.5 ULN;Alanine aminotransferase(ALT)>3 ULN; ALT>3 ULN & bilirubin>2 ULN;Aspartate aminotransferase(AST)>3 ULN;Direct bilirubin>35% bilirubin & bilirubin>1.5 ULN;Total bilirubin>1.5 ULN,>2 ULN.Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        Sodium: ≤129 mmol/L
    0
    0
        Sodium: ≥160 mmol/L
    0
    0
        Potassium: <3 mmol/L
    0
    0
        Potassium: ≥5.5 mmol/L
    1
    0
        Glucose: ≤3.9 mmol/L and <LLN
    3
    5
        Glucose:≥11.1 mmol/L(unfasted); ≥7 mmol/L(fasted)
    3
    1
        CK: >3 ULN
    0
    1
        CK: >10 ULN
    0
    0
        Creatinine: ≥150 micromoles/L (Adults)
    0
    0
        Creatinine: ≥30% change from baseline
    1
    2
        Creatinine: ≥100% change from baseline
    0
    0
        CG: ≥60 - <90 mL/min
    24
    16
        CG: ≥30 - <60 mL/min
    3
    2
        CG: ≥15 - <30 mL/min
    0
    0
        CG: <15 mL/min
    0
    0
        Urea Nitrogen: ≥17 mmol/L
    0
    0
        ALP: >1.5 ULN
    0
    1
        ALT: >3 ULN
    0
    0
        ALT >3 ULN; Bilirubin >2 ULN
    0
    0
        AST: >3 ULN
    0
    0
        Direct Bilirubin>35% Bilirubin; Bilirubin>1.5 ULN
    0
    0
        Total Bilirubin: >1.5 ULN
    0
    1
        Total Bilirubin: >2 ULN
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With PCSA in Urinalysis Parameters

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    End point title
    Number of Participants With PCSA in Urinalysis Parameters
    End point description
    PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Potential of hydrogen (pH) ≤4.6 or ≥8. Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    Placebo SAR441344
    Number of subjects analysed
    42
    42
    Units: participants
        pH ≤4.6
    0
    0
        pH ≥8
    3
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-drug Antibodies (ADA) to SAR441344

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    End point title
    Number of Participants With Anti-drug Antibodies (ADA) to SAR441344 [7]
    End point description
    Serum samples were collected at the specified timepoints for the assessment of ADAs to SAR441344. Number of participants with treatment-emergent ADA defined as at least 1 treatment-induced/boosted ADA during the treatment-emergent period, i.e. from the time of the IMP administration up to the end of study visit are reported. Number of participants with positive ADA are reported. ADA population included all randomized participants treated with SAR441344 with at least 1 post-baseline ADA result (positive, negative or inconclusive). Here, n= number of participants analyzed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8, Week 12, and Week 24
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants in the SAR441344 arm were analyzed in this endpoint.
    End point values
    SAR441344
    Number of subjects analysed
    42
    Units: participants
        Baseline (n=42)
    2
        Week 4 (n=41)
    2
        Week 8 (n=38)
    2
        Week 12 (n=42)
    0
        Week 24 (n=41)
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of IMP (Day 1) up to end of follow-up period (Week 24)
    Adverse event reporting additional description
    Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    SAR441344
    Reporting group description
    Participants received a single IV loading dose of SAR441344 1200 mg on Day 1, followed by an SC dose of SAR441344 600 mg administered q2w at Weeks 2, 4, 6, 8 and 10.

    Reporting group title
    Placebo
    Reporting group description
    Participants received a single IV loading dose of placebo matched to SAR441344 on Day 1, followed by an SC dose of placebo matched to SAR441344 administered q2w at Weeks 2, 4, 6, 8 and 10.

    Serious adverse events
    SAR441344 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 42 (2.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Product issues
    Device Breakage
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Osteomyelitis Acute
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SAR441344 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 42 (35.71%)
    20 / 42 (47.62%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 42 (11.90%)
         occurrences all number
    5
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 42 (4.76%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 42 (2.38%)
         occurrences all number
    7
    3
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Infections and infestations
    Covid-19
         subjects affected / exposed
    4 / 42 (9.52%)
    4 / 42 (9.52%)
         occurrences all number
    4
    4
    Nasopharyngitis
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Urinary Tract Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    6 / 42 (14.29%)
         occurrences all number
    1
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Aug 2020
    The purpose of the amendment was to have minor adjustments in the exclusion criteria E01, E11, E14, and E30 to address comments raised by the European Union participating National Competent Authorities during review of the clinical trial application, via the Voluntary Harmonisation Procedure. Clarification of minor discrepancies were also addressed, as well as minor editorial and document formatting revisions were made.
    28 Jul 2021
    The purpose of the amendment was to have an adjustment in the inclusion criterion I03 and to allow re-screening for I06 to better reflect the participant population to aid recruitment without compromising on safety requirements. Section 9.5 (Interim analysis) was extended with an early analysis after all participants have completed their End of Treatment/Week 12 visit, to allow for internal decision making. Section 6.2 was adapted to allow destruction of vials according to local regulations and a reference to the pharmacy manual was added. Clarification of discrepancies were also addressed, as well as minor editorial and document formatting revisions were made.
    05 Apr 2022
    The purpose of the amendment was to adapt inclusion/exclusion criteria I06, E17, E18, and E22 to better account for the required characteristics of Sjögren's syndrome (ESSDAI >5 and baseline treatment) to facilitate recruitment, without compromising safety requirements. The discontinuation due to Coronavirus Disease 2019 was adjusted. Section 9.5 (Interim analysis) was revised with an option of additional analysis. Discrepancies were also addressed, as well as minor corrections and clarifications were made.

    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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