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    Clinical Trial Results:
    A Randomized, Double-Masked and Placebo-Controlled Study to Evaluate the Efficacy and Safety of Sarilumab Administered Subcutaneously Every 2 Weeks in Patients with Non-Infectious, Intermediate, Posterior or Pan-Uveitis (NIU)

    Summary
    EudraCT number
    2012-004845-34
    Trial protocol
    CZ   DE   IT   ES  
    Global end of trial date
    19 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    04 May 2017
    First version publication date
    04 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT13480
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01900431
    WHO universal trial number (UTN)
    U1111-1130-6500
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    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
    20 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 200 mg sarilumab every 2 weeks (q2w) at Week 16 in subjects with NIU.
    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
    Following background therapy was given to subjects during the study: Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Oct 2013
    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
    Spain: 7
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Turkey: 16
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    58
    EEA total number of subjects
    31
    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)
    54
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 18 centers in 6 countries. A total of 82 subjects were screened between 30 October 2013 and 17 March 2015 of whom 58 subjects were randomized and 24 were screen failures. Screen failures were mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    Subjects were randomized in 2:1 ratio (Sarilumab : Placebo) and treated for 16 weeks during principal treatment period (Part A), 30 responders treated up to Week 50 with same dose during extension treatment period (Part B) while 10 non-responders and 11 subjects (not completed Part A) treated with open label treatment up to Week 50 (Part C).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo (Part A)
    Arm description
    Placebo (for Sarilumab) subcutaneous (SC) injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for Sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (for Sarilumab) as SC injection in the abdomen, thigh or upper arm.

    Arm title
    Sarilumab 200 mg q2w (Part A)
    Arm description
    Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191, REGN88
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab as SC injection in the abdomen, thigh or upper arm.

    Number of subjects in period 1
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Started
    20
    38
    Completed
    13
    28
    Not completed
    7
    10
         Lack of efficacy
    6
    6
         Other than specified above
    -
    1
         Adverse Event
    1
    3
    Period 2
    Period 2 title
    Extended Treatment Period (Part B)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo (Part B)
    Arm description
    During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with placebo SC injection q2w as per principal treatment period (Part A) up to Week 50.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for Sarilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (for Sarilumab) as SC injection in the abdomen, thigh or upper arm.

    Arm title
    Sarilumab 200 mg q2w (Part B)
    Arm description
    During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with Sarilumab 200 mg SC injection q2w as per principal treatment period (Part A) up to Week 50.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191, REGN88
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab as SC injection in the abdomen, thigh or upper arm.

    Number of subjects in period 2 [1]
    Placebo (Part B) Sarilumab 200 mg q2w (Part B)
    Started
    8
    22
    Completed
    7
    12
    Not completed
    1
    10
         Lack of efficacy
    1
    7
         Other than specified above
    -
    1
         Adverse Event
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of 41 subjects who completed Part A, 30 responders (8 Placebo, 22 Sarilumab) entered Part B.
    Period 3
    Period 3 title
    Open-Label Treatment Period (Part C)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
    Arm description
    During Open-Label Treatment Period (Part C), Non-responders (defined as no decrease in VH ≥2 steps and corticosteroids dose missing at Week 16) and non-completers (not-completed) Part A were treated with Sarilumab 200 mg SC injection q2w for 34 weeks as open-label treatment in open-label treatment period (Part C) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.
    Arm type
    Experimental

    Investigational medicinal product name
    Sarilumab
    Investigational medicinal product code
    SAR153191, REGN88
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab as SC injection in the abdomen, thigh or upper arm.

    Number of subjects in period 3 [2]
    Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
    Started
    10
    Completed
    13
    Not completed
    8
         Withdrawal by Subject
    3
         Lack of efficacy
    3
         Adverse Event
    2
    Joined
    11
         Non-completers from Part A
    11
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Total 21 subjects entered Part C. 10 non-responders as started (5 placebo, 5 Sarilumab) and 11 non-completers (Also non-responders) from Part A as joined (6 placebo, 5 Sarilumab).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Part A)
    Reporting group description
    Placebo (for Sarilumab) subcutaneous (SC) injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.

    Reporting group title
    Sarilumab 200 mg q2w (Part A)
    Reporting group description
    Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.

    Reporting group values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A) Total
    Number of subjects
    20 38 58
    Age categorical
    Age categorical is not provided as it was presented in Population of trial subjects under Trial information section.
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.5 ± 13 39.3 ± 15.3 -
    Gender categorical
    Units: Subjects
        Female
    13 23 36
        Male
    7 15 22

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Part A)
    Reporting group description
    Placebo (for Sarilumab) subcutaneous (SC) injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.

    Reporting group title
    Sarilumab 200 mg q2w (Part A)
    Reporting group description
    Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.
    Reporting group title
    Placebo (Part B)
    Reporting group description
    During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with placebo SC injection q2w as per principal treatment period (Part A) up to Week 50.

    Reporting group title
    Sarilumab 200 mg q2w (Part B)
    Reporting group description
    During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with Sarilumab 200 mg SC injection q2w as per principal treatment period (Part A) up to Week 50.
    Reporting group title
    Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
    Reporting group description
    During Open-Label Treatment Period (Part C), Non-responders (defined as no decrease in VH ≥2 steps and corticosteroids dose missing at Week 16) and non-completers (not-completed) Part A were treated with Sarilumab 200 mg SC injection q2w for 34 weeks as open-label treatment in open-label treatment period (Part C) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.

    Subject analysis set title
    Sarilumab 200 mg q2w (Part A + Part B)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B).

    Primary: Percentage of Subjects With at Least 2-step Reduction in Vitreous Haze (VH) or Prednisone Dose <10 mg/Day at Week 16

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    End point title
    Percentage of Subjects With at Least 2-step Reduction in Vitreous Haze (VH) or Prednisone Dose <10 mg/Day at Week 16
    End point description
    At least 2-step reduction in VH per central review from baseline was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 [low opacity] to 8 [more opacity]) images (in increasing order of opacity) are equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Subjects with prednisone dose <10 mg/day (or equivalent oral corticosteroid) were also evaluated. Modified intent-to-treat population (mITT) included all randomized subjects who received at least 1 injection analyzed according to the group to which the subject was allocated by the randomization schedule. Modified multiple imputation approach was used on VH missing adjudicated scores.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    20
    38
    Units: Percentage of subjects
        number (not applicable)
    30
    46.1
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using combined estimate for odds ratio obtained by combining the log-transformation of odds ratio from Cochran Mantel-Haenszel (CMH) analyses of the different imputed datasets, using Rubin's formulae, and then by back-transforming the combined estimate. The CMH analyses were adjusted for randomization stratification factor VH level (VH >= 4 versus VH<4).
    Comparison groups
    Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2354 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    5.6
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in VH Scale at Week 16

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    End point title
    Change From Baseline in VH Scale at Week 16
    End point description
    Change from baseline in VH scale was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 [low opacity] to 8 [more opacity]) images (in increasing order of opacity) were equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Least squares (LS) mean was calculated using mixed model for repeated measurements (MMRM) model with treatment groups, visits and visit-by- treatment groups interaction as fixed categorical effects as well as fixed continuous covariate of baseline adjudicated VH. Analysis was performed on mITT population. Number of subjects analyzed = subjects with VH assessment at baseline and post-baseline visits.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    13
    28
    Units: units on a scale
        least squares mean (standard error)
    -0.1 ± 0.23
    -0.9 ± 0.16
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using mixed effect model with repeated measures (MMRM) with treatment groups, visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline adjudicated VH.
    Comparison groups
    Sarilumab 200 mg q2w (Part A) v Placebo (Part A)
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0127 [2]
    Method
    Mixed models analysis
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.223
         upper limit
    -0.262
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects With Anterior Chamber (AC) Cell Score = 0 or At Least 2-step Reduction in Score at Week 16

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    End point title
    Percentage of Subjects With Anterior Chamber (AC) Cell Score = 0 or At Least 2-step Reduction in Score at Week 16
    End point description
    Subjects with AC cell score = 0 or with ≥2 step reduction from baseline at Week 16 were evaluated. Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: grade 0 = no cells; grade +0.5 = 1 - 5 cells; grade +1 = 6 - 25 cells; grade +2= 26 - 50 cells; grade +3 = too many to count. Analysis was performed on mITT population. Number of subjects analyzed = subjects with non-missing AC cell score at Week 16.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    15
    29
    Units: Percentage of subjects
        number (not applicable)
    86.7
    86.2
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using common odds ratio which came from CMH analysis adjusted for randomization stratification factor VH level (VH>=4 versus VH<4).
    Comparison groups
    Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.95
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    6.093
    Notes
    [3] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Week 16

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    End point title
    Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Week 16
    End point description
    BCVA score is based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters, and then at 1 meter. The range of ETDRS is 0 to 100 letters. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline BCVA. Analysis was performed on mITT population. Number of subjects analyzed = subjects with BCVA score assessment at baseline and post-baseline visits.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    15
    29
    Units: units on a scale
        least squares mean (standard error)
    3.5 ± 1.84
    9.3 ± 1.36
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline BCVA.
    Comparison groups
    Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0153 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    5.8
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.99
         upper limit
    9.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.26
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in Central Retinal Thickness (CRT) At Week 16

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    End point title
    Change From Baseline in Central Retinal Thickness (CRT) At Week 16
    End point description
    CRT was measured by spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT. Analysis was performed on mITT population. Number of subjects analyzed = subjects with CRT assessment at baseline and post-baseline visits.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    14
    29
    Units: μm (microns)
        least squares mean (standard error)
    -8.9 ± 11.46
    -35.4 ± 8.36
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT (Automatic measurement from SD-OCT).
    Comparison groups
    Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0683 [5]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -26.5
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -50.41
         upper limit
    -2.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.2
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in CRT at Week 16

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    End point title
    Percent Change From Baseline in CRT at Week 16
    End point description
    CRT was measured by SD-OCT, a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT. Analysis was performed on mITT population. Number of subjects analyzed = subjects with CRT assessment at baseline and post-baseline visits.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    14
    29
    Units: percent change
        least squares mean (standard error)
    0 ± 2.9
    -6.4 ± 2.15
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT (Automatic measurement from SD-OCT).
    Comparison groups
    Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0825 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -6.4
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -12.374
         upper limit
    -0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.55
    Notes
    [6] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects With CRT Thickness <300 Microns at Week 16

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    End point title
    Percentage of Subjects With CRT Thickness <300 Microns at Week 16
    End point description
    This endpoint was replaced by the percent change from baseline in CRT at Week 16 as this is more clinically relevant. Zero subject was analyzed.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [7] - Zero subject analyzed as this endpoint was replaced with another more clinically relevant endpoint.
    [8] - Zero subject analyzed as this endpoint was replaced with another more clinically relevant endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Without Retinal Vessel Leakage on Fluorescein Angiography (FA) at Week 16

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    End point title
    Percentage of Subjects Without Retinal Vessel Leakage on Fluorescein Angiography (FA) at Week 16
    End point description
    Analysis of this endpoint was not performed as no retinal vessel leakage data was collected at Week 16. Zero subjects were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [9] - No retinal vessel leakage data was collected at Week 16.
    [10] - No retinal vessel leakage data was collected at Week 16.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Prednisone Dose of ≤ 5 mg/Day (or Equivalent Oral Corticosteroid) at Week 16

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    End point title
    Percentage of Subjects With Prednisone Dose of ≤ 5 mg/Day (or Equivalent Oral Corticosteroid) at Week 16
    End point description
    Subjects with prednisone dose ≤5mg/day (or equivalent oral corticosteroid) at Week 16 were evaluated. Analysis was performed on mITT population. Number of subjects analyzed = subjects with non-missing data for prednisone (or equivalent oral corticosteroid) dose at Week 16.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo (Part A) Sarilumab 200 mg q2w (Part A)
    Number of subjects analysed
    15
    29
    Units: percentage of subjects
        number (not applicable)
    40
    41.4
    Statistical analysis title
    Sarilumab 200 mg q2w (Part A) vs Placebo (Part A)
    Statistical analysis description
    Analysis was performed using common odds ratio which came from CMH analysis adjusted for randomization stratification factor VH level (VH>=4 versus VH<4).
    Comparison groups
    Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.306
         upper limit
    3.845
    Notes
    [11] - Threshold for significance at 0.05 level.

    Secondary: Pharmacokinetics (PK) Assessment: Serum Functional Sarilumab Concentration

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    End point title
    Pharmacokinetics (PK) Assessment: Serum Functional Sarilumab Concentration
    End point description
    Serum functional (unbound) sarilumab concentrations were determined using enzyme-linked immunosorbent assay (ELISA) method with a lower limit of quantification (LLOQ) of 294 ng/mL. Concentrations below LLOQ were set to zero for samples at pre-dose. Post-treatment concentrations below LLOQ were replaced by LLOQ/2. The samples were considered non-eligible for analysis if previous dosing time was <11 days or >17 days before sampling time for every other week regimens. PK population: all subjects who received at least one dose or part of a dose of investigational medicinal product (IMP) with at least one post-dose, non-missing serum concentration value & were analyzed according to treatment actually received. Data of this endpoint was planned to be analyzed for Sarilumab 200 mg q2w arm in Part A & B only. Here, 'n' signifies number of subjects with available data for specified category. 99999 represents that only one subject was analyzed at EOS, standard deviation could not be calculated.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 (Baseline), Week 2, 4, 8, 12, 16, 24, 36, 52, and end of study (EOS) (Week 56)
    End point values
    Sarilumab 200 mg q2w (Part A + Part B)
    Number of subjects analysed
    38
    Units: ng/mL
    arithmetic mean (standard deviation)
        At Baseline (n=37)
    0 ± 0
        At Week 2 (n=29)
    7383.3 ± 6547.1
        At Week 4 (n=32)
    9876.6 ± 8262.9
        At Week 8 (n=31)
    15958.9 ± 12813.1
        At Week 12 (n=26)
    19705.2 ± 15480.9
        At Week 16 (n=26)
    19598.4 ± 17280.8
        At Week 24 (n=19)
    22406.8 ± 14584.2
        At Week 36 (n=14)
    24375.4 ± 19121.7
        At Week 52 (n=5)
    25046 ± 17870.7
        EOS (Week 56) (n=1)
    1730 ± 99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (6 weeks after the last treatment administration [Week 56]) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of IMP to the last injection of IMP + 6 weeks).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo (Part A + Part B)
    Reporting group description
    Placebo (for Sarilumab) SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B).

    Reporting group title
    Sarilumab 200mg q2w (Part A + Part B)
    Reporting group description
    Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B).

    Reporting group title
    Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
    Reporting group description
    Non-responders and non-completers observed in Part A were proposed to be treated with Sarilumab 200 mg SC injection q2w for 34 weeks as open-label treatment in open-label treatment period (Part C) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice.

    Serious adverse events
    Placebo (Part A + Part B) Sarilumab 200mg q2w (Part A + Part B) Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    5 / 38 (13.16%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion Induced
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Intraocular Pressure Increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Staphylococcal Sepsis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Part A + Part B) Sarilumab 200mg q2w (Part A + Part B) Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 20 (65.00%)
    25 / 38 (65.79%)
    15 / 21 (71.43%)
    Vascular disorders
    Behcet's Syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 38 (2.63%)
    3 / 21 (14.29%)
         occurrences all number
    1
    1
    4
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 38 (7.89%)
    0 / 21 (0.00%)
         occurrences all number
    0
    4
    0
    Injection Site Bruising
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    Injection Site Swelling
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    10
    0
    Pyrexia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 38 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Psychiatric disorders
    Middle Insomnia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    4 / 20 (20.00%)
    3 / 38 (7.89%)
    1 / 21 (4.76%)
         occurrences all number
    5
    3
    1
    Contusion
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    7
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 20 (15.00%)
    4 / 38 (10.53%)
    0 / 21 (0.00%)
         occurrences all number
    3
    4
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 38 (10.53%)
    1 / 21 (4.76%)
         occurrences all number
    0
    5
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 38 (7.89%)
    0 / 21 (0.00%)
         occurrences all number
    0
    4
    0
    Headache
         subjects affected / exposed
    2 / 20 (10.00%)
    4 / 38 (10.53%)
    2 / 21 (9.52%)
         occurrences all number
    2
    5
    2
    Hypoaesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Retinal Infiltrates
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Uveitis
         subjects affected / exposed
    2 / 20 (10.00%)
    6 / 38 (15.79%)
    1 / 21 (4.76%)
         occurrences all number
    3
    6
    1
    Visual Impairment
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 38 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Gastrointestinal disorders
    Aphthous Ulcer
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    2
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 38 (2.63%)
    3 / 21 (14.29%)
         occurrences all number
    0
    2
    4
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 38 (7.89%)
    1 / 21 (4.76%)
         occurrences all number
    1
    4
    1
    Hepatobiliary disorders
    Hepatic Steatosis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 38 (2.63%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Ear Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    Influenza
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 38 (10.53%)
    2 / 21 (9.52%)
         occurrences all number
    0
    4
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 38 (5.26%)
    6 / 21 (28.57%)
         occurrences all number
    1
    2
    8
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 38 (5.26%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 38 (5.26%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2013
    Following were the changes: • Facilitate the enrollment of subjects, with fewer constraints, on the dose of corticosteroids as background therapy before randomization. • Added a clear definition of worsening and to consider sensitivity analysis. • Revised and added treatment failure and non-responder definitions. • Address the comments from some Ethic Committees regarding the continuation of non-responder subjects in the optional open-label treatment part of the study (part C, open-label administration of sarilumab) without breaking the randomization code. • Considered more appropriate rules for corticosteroid tapering depending on the activity status of the disease at study entry (active disease and recently active disease) in order to prevent inducing disease flare ups that may be a consequence of tapering the corticosteroid dose too fast. • Revised the safety follow-up of subjects receiving sarilumab in the optional open-label part C with the addition of safety visits at Week 6, Week 10, and Week 14 and to include additional blood samples to measure antinuclear antibodies and anti-ds-DNA antibody in order to assess the effect of sarilumab to induce autoimmune disorders, more specifically systemic lupus erythematosus. • Added specific ocular AEs on the list of AEs of Special Interest list.
    09 Sep 2014
    Following were the changes: • Added other conventional standard of care immunomodulatory therapies to methotrexate and corticosteroids as therapies allowed at study entry and during the study treatment period. • Facilitated and hastened the enrollment of subjects by removing the restriction of the number of subjects in the VH <4 and VH ≥4 categories. • Facilitated enrollment by allowing subjects presenting with more severe ‘active disease’ that was not adequately controlled by the existing standard of care. • Revisions were implemented in order to ensure consistency with the ongoing rheumatoid arthritis clinical trials with Sarilumab including infliximab and etanercept washout periods, management of alanine aminotransferase elevation, updates to laboratories values exclusion criterion, changes to blood pressure measurements, and chest X-ray only mandatory at screening or within the 90 days preceding screening. • The role of the Reading Center in the selection of the subjects was clarified. • The selection of the study eye was clarified. • Steroids tapering could begin as early as Visit 4 (ie, after 2 treatment injections). • Exclusion criterion, E11 (glaucoma treatment) and E35 (magnetic resonance imaging in intermediate uveitis subjects) were rewritten to be clearer. • The flow chart was updated in order to clarify some items.

    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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