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RA-MOBILITY: Evaluation of Sarilumab (SAR153191/REGN88) on Top of Methotrexate in Rheumatoid Arthritis Patients

Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT01061736
Collaborator
Regeneron Pharmaceuticals (Industry)
1,675
Enrollment
262
Locations
10
Arms
43
Duration (Months)
6.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objectives:
Part A (dose ranging study):

To demonstrate that sarilumab (SAR153191/REGN88) on top of MTX was effective on reduction of signs and symptoms of rheumatoid arthritis at 12 weeks.

Part B (pivotal study):
To demonstrate that sarilumab added to MTX was effective in:

  • reduction of signs and symptoms of rheumatoid arthritis at 24 weeks

  • inhibition of progression of structural damage at 52 weeks

  • improvement in physical function at 16 weeks

Secondary Objectives:
Part B:

To demonstrate that sarilumab added to MTX was effective in induction of a major clinical response at 52 weeks

To assess the safety of sarilumab added to MTX

To document the pharmacokinetic profile of sarilumab added to MTX in participants with active rheumatoid arthritis who were inadequate responders to MTX therapy.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed Description

The total study duration for a participant was 16-22 weeks (Part A) and 56-62 weeks (Part B) broken down as follows:

  • Screening: Up to 4 weeks

  • Treatment: 12 weeks (Part A) and 52 weeks (Part B)*

  • Follow-up: 6 weeks (for participants who would not continue in the long-term extension study).

'*' Participants successfully completing their treatment period would be offered the opportunity to enter the long term extension study LTS11210 (SARIL-RA-EXTEND) (NCT01146652).

Study Design

Study Type:
Interventional
Actual Enrollment :
1675 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blind, Placebo-controlled, Multicenter, Two-part, Dose Ranging and Confirmatory Study With an Operationally Seamless Design, Evaluating Efficacy and Safety of SAR153191 on Top of Methotrexate (MTX) in Patients With Active Rheumatoid Arthritis Who Are Inadequate Responders to MTX Therapy
Study Start Date :
Mar 1, 2010
Actual Primary Completion Date :
Oct 1, 2013
Actual Study Completion Date :
Oct 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part A: SAR 100 mg qw

Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of MTX for 12 weeks.

Drug: Sarilumab
Pharmaceutical form: solution for injection Route of administration: subcutaneous
Other Names:
  • SAR153191
  • REGN88

    • Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part A: SAR 150 mg qw

    Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks.

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part A: SAR 100 mg q2w

    Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks.

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous

    Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part A: SAR 150 mg q2w

    Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous

    Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part A: SAR 200 mg q2w

    Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous

    Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Placebo Comparator: Part A: Placebo qw

    Placebo (for sarilumab) qw on top of MTX for 12 weeks.

    Drug: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous

    Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part B Cohort 1: Non-selected Doses

    Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210).

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous

    Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2)

    Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2)

    Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Drug: Sarilumab
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
    Other Names:
  • SAR153191
  • REGN88

    • Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard
    Experimental: Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)

    Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.

    Drug: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous

    Drug: Methotrexate
    Same weekly dose as received prior to enrollment

    Drug: Folic Acid
    According to local standard

    Outcome Measures

    Primary Outcome Measures

    1. Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 [Baseline to Week 12]

      ACR20 response was defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF).

    2. Part B: Percentage of Participants Achieving ACR20 Response at Week 24 [Baseline to Week 24]

      ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.

    3. Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 [Baseline, Week 16]

      HAQ-DI was a participant-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Data collected after treatment discontinuation was set to missing.

    4. Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 [Baseline, Week 52]

      The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Missing data were imputed by the linear extrapolation method.

    Secondary Outcome Measures

    1. Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 [Baseline up to Week 52]

      Major clinical response was defined as an ACR70 response maintained for at least 24 consecutive weeks. ACR70 response uses the same criteria as for ACR20 but requires 70% improvement. In the primary approach, data collected after treatment discontinuation or rescue was set to missing. No imputation of missing post-baseline values was performed. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria :

    • Diagnosis of rheumatoid arthritis ≥3 months duration

    • Active disease defined as:

    • at least 8/68 tender joints and 6/66 swollen joints,

    • high sensitivity C-reactive protein (hs-CRP) >6 mg/l,

    • continuous treatment with MTX for at least 12 weeks prior to baseline visit and on stable dose for at least 6 weeks prior to screening visit.

    Part B only:

    • Bone erosion based on documented X-ray prior to first study drug intake, or

    • Cyclic Citrullinated Peptide (CCP) positive, or

    • Rheumatoid Factor (RF) positive.

    Exclusion criteria:

    • Age <18 years or >75 years.

    • Treatment with disease-modifying antirheumatic drugs (DMARDs) other than MTX within 4 weeks or 12 weeks prior to screening (depending on DMARDs).

    • Past history of non-response to prior Tumor Necrosis Factor (TNF) or biologic treatment.

    • Any past or current biologic agents for the treatment of rheumatoid arthritis within 3 months.

    • Use of parenteral glucocorticoids or intraarticular glucocorticoids within 4 weeks prior to screening visit.

    • Use of oral glucocorticoid greater than 10mg/day or equivalent/day, or a change in dosage within 4 weeks prior to baseline visit.

    The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Investigational Site Number 840070 Anniston Alabama United States 36207
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    217 Investigational Site Number 643004 Moscow Russian Federation 107014
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    233 Investigational Site Number 710003 Durban South Africa 4001
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    235 Investigational Site Number 710001 Johannesburg South Africa 2013
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    237 Investigational Site Number 710005 Pretoria South Africa 0075
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    240 Investigational Site Number 710010 Stellenbosch South Africa 7600
    241 Investigational Site Number 724010 Barcelona Spain 08025
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    244 Investigational Site Number 724012 Santiago De Compostela Spain 15705
    245 Investigational Site Number 724007 Sevilla Spain 41008
    246 Investigational Site Number 158002 Linkou Taiwan 333
    247 Investigational Site Number 158001 Taipei Taiwan 100
    248 Investigational Site Number 764001 Bangkok Thailand 10400
    249 Investigational Site Number 764003 Bangkok Thailand 10700
    250 Investigational Site Number 792003 Adana Turkey 01330
    251 Investigational Site Number 792002 Ankara Turkey 06100
    252 Investigational Site Number 792005 Ankara Turkey
    253 Investigational Site Number 792004 Antalya Turkey 07059
    254 Investigational Site Number 792001 Izmir Turkey 35340
    255 Investigational Site Number 804003 Dnipropetrovsk Ukraine 49008
    256 Investigational Site Number 804002 Donetsk Ukraine 83114
    257 Investigational Site Number 804010 Kharkov Ukraine 61022
    258 Investigational Site Number 804008 Kyiv Ukraine 01023
    259 Investigational Site Number 804004 Kyiv Ukraine 03151
    260 Investigational Site Number 804005 Lviv Ukraine 79005
    261 Investigational Site Number 804006 Simferopol Ukraine 95017
    262 Investigational Site Number 804009 Zaporizhzhia Ukraine 69600

    Sponsors and Collaborators

    • Sanofi
    • Regeneron Pharmaceuticals

    Investigators

    • Principal Investigator: Mark C Genovese, MD, Professor of Medicine, Division of Immunology and Rheumatology - Stanford University - USA
    • Study Chair: TWJ Huizinga, Prof Dr, Dpt of Rheumatology - Leiden University Medical Center - The Netherlands

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Sanofi
    ClinicalTrials.gov Identifier:
    NCT01061736
    Other Study ID Numbers:
    • EFC11072
    • 2009-016266-90
    First Posted:
    Feb 3, 2010
    Last Update Posted:
    Jun 28, 2017
    Last Verified:
    Jun 1, 2017
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Folic Acid
    Methotrexate

    Study Results

    Participant Flow

    Recruitment Details The study was conducted at 247 centers in 36 countries. Overall, 3715 participants were screened between March 2010 and July 2012, 2040 of whom were screen failures. Screen failures were mainly due to failure to meet the inclusion criterion for severity of the disease and/or due to meeting the exclusion criterion.
    Pre-assignment Detail Randomization was performed centrally with allocation generated by Interactive Voice/Web Response System, stratified by geographical region and prior biological use. 306 participants were randomized in Part A. 1369 participants were randomized in part B, 172 before dose selection (cohort 1) and 1197 after dose selection (cohort 2).
    Arm/Group Title Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw Part B Cohort 1: Non-selected Doses Part B: SAR 150 mg q2w (Cohort 1 [Selected Dose]+Cohort 2) Part B: SAR 200 mg q2w (Cohort 1 [Selected Dose]+Cohort 2) Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)
    Arm/Group Description Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of methotrexate (MTX) for 12 weeks. Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks. Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks. Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Placebo (for sarilumab) qw on top of MTX for 12 weeks. Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210). Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w).
    Period Title: Overall Study
    STARTED 50 50 51 51 52 52 84 430 427 428
    Treated 50 50 51 51 51 52 84 428 426 428
    Rescued 0 0 0 0 0 0 0 61 55 168
    COMPLETED 37 46 45 48 45 49 0 336 330 354
    NOT COMPLETED 13 4 6 3 7 3 84 94 97 74

    Baseline Characteristics

    Arm/Group Title Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw Part B Cohort 1: Non-selected Doses Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) Total
    Arm/Group Description Sarilumab 100 mg SC injection qw on top of MTX for 12 weeks. Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks. Sarilumab 100 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Placebo (for sarilumab) qw on top of MTX for 12 weeks. Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210). Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). Total of all reporting groups
    Overall Participants 50 50 51 51 52 52 84 430 427 428 1675
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    53.9
    (12.3)
    50.9
    (11.1)
    53.5
    (11.8)
    51.2
    (12.9)
    48.7
    (12.4)
    55.2
    (12.5)
    51.1
    (11.5)
    50.3
    (11.9)
    50.8
    (12.0)
    51.1
    (11.2)
    51.04
    (11.79)
    Sex: Female, Male (Count of Participants)
    Female
    41
    82%
    42
    84%
    38
    74.5%
    42
    82.4%
    42
    80.8%
    38
    73.1%
    69
    82.1%
    345
    80.2%
    359
    84.1%
    346
    80.8%
    1362
    81.3%
    Male
    9
    18%
    8
    16%
    13
    25.5%
    9
    17.6%
    10
    19.2%
    14
    26.9%
    15
    17.9%
    85
    19.8%
    68
    15.9%
    82
    19.2%
    313
    18.7%

    Outcome Measures

    1. Primary Outcome
    Title Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
    Description ACR20 response was defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF).
    Time Frame Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Part A Intent-to-treat (ITT) population defined as all randomized participants.
    Arm/Group Title Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw
    Arm/Group Description Sarilumab 100 mg SC injection qw on top of MTX for 12 weeks. Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks. Sarilumab 100 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. Placebo (for sarilumab) qw on top of MTX for 12 weeks.
    Measure Participants 50 50 51 51 52 52
    Number [Percentage of participants]
    62
    124%
    72
    144%
    49
    96.1%
    66.7
    130.8%
    65.4
    125.8%
    46.2
    88.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg qw, Part A: Placebo qw
    Comments Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo were derived. The multiplicity issues were addressed by using the Hommel-procedure.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1155
    Comments Threshold for significance = 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.99
    Confidence Interval (2-Sided) 95%
    0.85 to 4.64
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg qw, Part A: Placebo qw
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0041
    Comments Threshold for significance = 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 3.84
    Confidence Interval (2-Sided) 95%
    1.53 to 9.63
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg q2w, Part A: Placebo qw
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7119
    Comments Threshold for significance = 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.17
    Confidence Interval (2-Sided) 95%
    0.52 to 2.61
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg q2w, Part A: Placebo qw
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0363
    Comments Threshold for significance = 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.38
    Confidence Interval (2-Sided) 95%
    1.06 to 5.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 200 mg q2w, Part A: Placebo qw
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0426
    Comments Threshold for significance = 0.05.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.34
    Confidence Interval (2-Sided) 95%
    1.03 to 5.29
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Part B: Percentage of Participants Achieving ACR20 Response at Week 24
    Description ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    ITT population which included all participants randomized after dose selection (cohort 2).
    Arm/Group Title Part B: SAR 150 mg q2w Part B: SAR 200 mg q2w Part B: Placebo q2w
    Arm/Group Description Participants randomized after dose selection received Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks
    Measure Participants 400 399 398
    Number [Percentage of participants]
    58
    116%
    66.4
    132.8%
    33.4
    65.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg qw, Part A: SAR 100 mg q2w
    Comments Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo was derived. The multiplicity issues for part B were addressed by using a Bonferroni correction for each dose together with a hierarchical testing procedure across the 3 co-primary and the main secondary endpoints. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.773
    Confidence Interval (2-Sided) 95%
    2.077 to 3.703
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg qw, Part A: SAR 100 mg q2w
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 3.975
    Confidence Interval (2-Sided) 95%
    2.957 to 5.344
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Primary Outcome
    Title Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16
    Description HAQ-DI was a participant-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Data collected after treatment discontinuation was set to missing.
    Time Frame Baseline, Week 16

    Outcome Measure Data

    Analysis Population Description
    Cohort 2 ITT population only and included participants with available data of HAQ-DI at baseline and on or before Week 16.
    Arm/Group Title Part B: SAR 150 mg q2w Part B: SAR 200 mg q2w Part B: Placebo q2w
    Arm/Group Description Participants randomized after dose selection received Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks.
    Measure Participants 362 365 378
    Baseline
    1.63
    (0.63)
    1.69
    (0.63)
    1.61
    (0.65)
    Week 16
    1.08
    (0.67)
    1.11
    (0.7)
    1.31
    (0.67)
    Change from baseline at Week 16
    -0.54
    (0.55)
    -0.58
    (0.63)
    -0.3
    (0.58)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg qw, Part A: SAR 100 mg q2w
    Comments Analysis was performed using a mixed model for repeated measures (MMRM). Differences in least square (LS) mean between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (performed only when the previous endpoint was statistically significant).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS mean difference
    Estimated Value -0.235
    Confidence Interval (2-Sided) 95%
    -0.312 to -0.157
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg qw, Part A: SAR 100 mg q2w
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS mean difference
    Estimated Value -0.258
    Confidence Interval (2-Sided) 95%
    -0.336 to -0.181
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Primary Outcome
    Title Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52
    Description The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Missing data were imputed by the linear extrapolation method.
    Time Frame Baseline, Week 52

    Outcome Measure Data

    Analysis Population Description
    Cohort 2 ITT population and included participants with available data of mTSS at baseline and on or before Week 52.
    Arm/Group Title Part B: SAR 150 mg q2w Part B: SAR 200 mg q2w Part B: Placebo q2w
    Arm/Group Description Participants randomized after dose selection received Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks.
    Measure Participants 352 359 352
    Baseline
    54.67
    (63.42)
    46.34
    (57.43)
    48.01
    (65.23)
    Week 52
    55.57
    (63.73)
    46.59
    (57.63)
    50.79
    (65.82)
    Change from baseline at Week 52
    0.90
    (4.66)
    0.25
    (4.61)
    2.78
    (7.73)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg qw, Part A: SAR 100 mg q2w
    Comments Analysis was performed using two-sided rank-based ANCOVA model. Testing was performed according to the hierarchical testing procedure (performed only when the previous endpoints were statistically significant).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Rank ANCOVA
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg qw, Part A: SAR 100 mg q2w
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Rank ANCOVA
    Comments
    5. Secondary Outcome
    Title Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52
    Description Major clinical response was defined as an ACR70 response maintained for at least 24 consecutive weeks. ACR70 response uses the same criteria as for ACR20 but requires 70% improvement. In the primary approach, data collected after treatment discontinuation or rescue was set to missing. No imputation of missing post-baseline values was performed. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.
    Time Frame Baseline up to Week 52

    Outcome Measure Data

    Analysis Population Description
    ITT population which included all participants randomized after dose selection (cohort 2).
    Arm/Group Title Part B: SAR 150 mg q2w Part B: SAR 200 mg q2w Part B: Placebo q2w
    Arm/Group Description Participants randomized after dose selection received Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants randomized after dose selection received Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks.
    Measure Participants 400 399 398
    Number [Percentage of participants]
    12.8
    25.6%
    14.8
    29.6%
    3
    5.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg qw, Part A: SAR 100 mg q2w
    Comments Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (performed only when the previous endpoints were statistically significant).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.661
    Confidence Interval (2-Sided) 95%
    2.451 to 8.863
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg qw, Part A: SAR 100 mg q2w
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance = 0.025.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.565
    Confidence Interval (2-Sided) 95%
    2.946 to 10.515
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame All Adverse Events (AE) were collected from signature of the informed consent form up to study completion regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse Event Reporting Description Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (from the first IMP injection up to the end of the study). Safety population defined as all randomized participants who received at least one dose of IMP.
    Arm/Group Title Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw Part B: SAR 100 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 150 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 100 mg q2w Cohort 1 (Non-selected Dose) Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) Part B Sarilumab Rescue: Cohort 1(Selected Doses)+Cohort2
    Arm/Group Description Part A participants exposed to sarilumab 100 mg qw on top of MTX (mean exposure of 10 weeks). Part A participants exposed to sarilumab 150 mg qw on top of MTX (mean exposure of 12 weeks). Part A participants exposed to sarilumab 100 mg q2w on top of MTX (mean exposure of 11 weeks). Part A participants exposed to sarilumab 150 mg q2w on top of MTX (mean exposure of 12 weeks). Included the participant randomized to placebo qw who received sarilumab 150 mg q2w in error. Part A participants exposed to sarilumab 200 mg q2w on top of MTX (mean exposure of 11 weeks). Part A participants exposed to placebo on top of MTX (mean exposure of 12 weeks). Excluded 1 participant who received an erroneous IMP kit with sarilumab 150 mg q2w. He/she was considered in the 150 mg q2w treatment group for safety analysis. Part B participants exposed to sarilumab 100 mg qw on top of MTX (mean exposure of 10 weeks). Part B participants exposed to sarilumab 150 mg qw on top of MTX (mean exposure of 12 weeks). Excluded 1 participant who received sarilumab 100 mg q2w in error. He/she was considered in the 100 mg q2w treatment group for safety analysis. Part B participants exposed to sarilumab 100 mg q2w on top of MTX (mean exposure of 13 weeks). Included 1 participant who received sarilumab 100 mg q2w in error. Part B participants exposed to sarilumab 150 mg q2w on top of MTX (mean exposure of 42 weeks). 61 participants with inadequate response from Week 16 rescued with high dose of sarilumab (SAR 200 mg q2w) were not included. Included 3 participants randomized to sarilumab 200 mg q2w who received at least one dose of sarilumab 150 mg q2w in error. Part B participants exposed to sarilumab 200 mg q2w on top of MTX (mean exposure of 42 weeks). 55 participants with inadequate response from Week 16 rescued with high dose of sarilumab (SAR 200 mg q2w) were not included. Excluded 3 participants randomized to sarilumab 200 mg q2w who received at least one dose of sarilumab 150 mg q2w in error and included a participant randomized to placebo q2w who received sarilumab 200 mg q2w in error. Part B participants exposed to placebo q2w on top of MTX (mean exposure of 40 weeks). 168 participants with inadequate response from Week 16 rescued with high dose of sarilumab (SAR 200 mg q2w) were not included. Excluded 1 participant randomized to placebo q2w who received sarilumab 200 mg q2w in error. He/she was considered in the 200 mg q2w treatment group for safety analysis. Part B participants exposed to sarilumab 150 mg q2w or 200 mg q2w or placebo q2w, without adequate response from Week 16, rescued with high dose of sarilumab (SAR 200 mg q2w) (mean exposure of 49 weeks from beginning of randomization to the end of rescue treatment).
    All Cause Mortality
    Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw Part B: SAR 100 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 150 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 100 mg q2w Cohort 1 (Non-selected Dose) Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) Part B Sarilumab Rescue: Cohort 1(Selected Doses)+Cohort2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw Part B: SAR 100 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 150 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 100 mg q2w Cohort 1 (Non-selected Dose) Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) Part B Sarilumab Rescue: Cohort 1(Selected Doses)+Cohort2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/50 (6%) 0/50 (0%) 3/51 (5.9%) 0/52 (0%) 0/51 (0%) 2/51 (3.9%) 2/29 (6.9%) 2/26 (7.7%) 0/29 (0%) 35/370 (9.5%) 46/369 (12.5%) 21/259 (8.1%) 7/284 (2.5%)
    Blood and lymphatic system disorders
    Iron deficiency anemia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Leukopenia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Neutropenia 1/50 (2%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 1/29 (3.4%) 0/26 (0%) 0/29 (0%) 3/370 (0.8%) 4/369 (1.1%) 0/259 (0%) 0/284 (0%)
    Splenic vein thrombosis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Thrombocytopenia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Cardiac disorders
    Angina unstable 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Atrial fibrillation 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Cardiac failure 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Cardio-respiratory arrest 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Cardiovascular insufficiency 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Myocardial ischemia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Pericarditis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Right ventricular failure 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 1/284 (0.4%)
    Sick sinus syndrome 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Eye disorders
    Conjunctivitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Gastrointestinal disorders
    Abdominal discomfort 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Abdominal wall hematoma 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Alcoholic pancreatitis 1/50 (2%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Constipation 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Duodenal ulcer 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Duodenal ulcer hemorrhage 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Duodenal ulcer perforation 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Duodenitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Gastric hemorrhage 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Gastric ulcer hemorrhage 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Gastritis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Hemorrhoids 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Pancreatitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    General disorders
    Immediate post-injection reaction 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Impaired healing 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Non-cardiac chest pain 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Pyrexia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Hepatobiliary disorders
    Bile duct stone 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Cholecystitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Cholecystitis chronic 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Cholelithiasis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Drug-induced liver injury 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Hepatitis toxic 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Immune system disorders
    Hypersensitivity 1/50 (2%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Infections and infestations
    Abscess limb 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Abscess oral 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Appendicitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 2/259 (0.8%) 0/284 (0%)
    Arthritis bacterial 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Bronchitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 2/369 (0.5%) 2/259 (0.8%) 0/284 (0%)
    Bronchitis fungal 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Cellulitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 3/259 (1.2%) 0/284 (0%)
    Clostridium difficile colitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Diverticulitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Endometritis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Erysipelas 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 2/369 (0.5%) 0/259 (0%) 1/284 (0.4%)
    Gastroenteritis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Herpes zoster 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Incision site infection 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Infected skin ulcer 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Necrotising fasciitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Osteomyelitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Otitis media acute 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Otitis media chronic 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 1/284 (0.4%)
    Pelvic abscess 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Pharyngitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Pneumonia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 2/369 (0.5%) 1/259 (0.4%) 0/284 (0%)
    Pneumonia streptococcal 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Pyelonephritis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 1/284 (0.4%)
    Pyelonephritis chronic 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Septic shock 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Sinusitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 1/284 (0.4%)
    Subacute endocarditis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Tinea cruris 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Upper respiratory tract infection 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 1/284 (0.4%)
    Urinary tract infection 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Injury, poisoning and procedural complications
    Femur fracture 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Hip fracture 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 1/29 (3.4%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Joint dislocation 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Ligament rupture 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Procedural pain 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Road traffic accident 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 1/284 (0.4%)
    Tendon rupture 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Wound hemorrhage 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Investigations
    Alanine aminotransferase increased 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Blood alkaline phosphatase increased 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Hepatic enzyme increased 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Transaminases increased 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Diabetes mellitus 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Hypercalcemia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Type 2 diabetes mellitus 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 1/51 (2%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Lumbar spinal stenosis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Osteoarthritis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 2/369 (0.5%) 3/259 (1.2%) 0/284 (0%)
    Pathological fracture 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Rheumatoid arthritis 0/50 (0%) 0/50 (0%) 1/51 (2%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 2/369 (0.5%) 1/259 (0.4%) 1/284 (0.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 1/51 (2%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Breast cancer 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Breast cancer metastatic 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Invasive lobular breast carcinoma 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Malignant melanoma 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Meningioma 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 2/259 (0.8%) 0/284 (0%)
    Neoplasm of appendix 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Plasmacytoma 0/50 (0%) 0/50 (0%) 1/51 (2%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Squamous cell carcinoma of skin 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 1/51 (2%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Nervous system disorders
    Brain oedema 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Cerebrovascular accident 0/50 (0%) 0/50 (0%) 1/51 (2%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Dizziness 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Embolic cerebral infarction 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Ischemic stroke 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Syncope 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Transient ischemic attack 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Psychiatric disorders
    Completed suicide 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Depression 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 2/369 (0.5%) 0/259 (0%) 0/284 (0%)
    Psychotic disorder 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Suicide attempt 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Renal and urinary disorders
    Renal failure 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Renal failure acute 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 2/369 (0.5%) 1/259 (0.4%) 0/284 (0%)
    Reproductive system and breast disorders
    Metrorrhagia 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/50 (0%) 0/50 (0%) 1/51 (2%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Acute respiratory failure 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Bronchial secretion retention 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Chronic obstructive pulmonary disease 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 1/284 (0.4%)
    Dyspnoea 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Interstitial lung disease 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Pneumonitis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Pulmonary oedema 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Respiratory distress 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Vascular disorders
    Aortic thrombosis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Deep vein thrombosis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Embolism arterial 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 0/259 (0%) 0/284 (0%)
    Hypertension 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 0/369 (0%) 1/259 (0.4%) 0/284 (0%)
    Hypertensive crisis 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 0/370 (0%) 2/369 (0.5%) 0/259 (0%) 0/284 (0%)
    Shock hemorrhagic 0/50 (0%) 0/50 (0%) 0/51 (0%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 1/370 (0.3%) 1/369 (0.3%) 0/259 (0%) 0/284 (0%)
    Other (Not Including Serious) Adverse Events
    Part A: SAR 100 mg qw Part A: SAR 150 mg qw Part A: SAR 100 mg q2w Part A: SAR 150 mg q2w Part A: SAR 200 mg q2w Part A: Placebo qw Part B: SAR 100 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 150 mg qw Cohort 1 (Non-selected Dose) Part B: SAR 100 mg q2w Cohort 1 (Non-selected Dose) Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) Part B Sarilumab Rescue: Cohort 1(Selected Doses)+Cohort2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 16/50 (32%) 16/50 (32%) 7/51 (13.7%) 12/52 (23.1%) 19/51 (37.3%) 11/51 (21.6%) 6/29 (20.7%) 8/26 (30.8%) 6/29 (20.7%) 163/370 (44.1%) 194/369 (52.6%) 95/259 (36.7%) 83/284 (29.2%)
    Blood and lymphatic system disorders
    Neutropenia 6/50 (12%) 5/50 (10%) 0/51 (0%) 1/52 (1.9%) 10/51 (19.6%) 0/51 (0%) 1/29 (3.4%) 2/26 (7.7%) 1/29 (3.4%) 36/370 (9.7%) 55/369 (14.9%) 0/259 (0%) 5/284 (1.8%)
    General disorders
    Injection site erythema 1/50 (2%) 1/50 (2%) 1/51 (2%) 0/52 (0%) 1/51 (2%) 0/51 (0%) 1/29 (3.4%) 3/26 (11.5%) 0/29 (0%) 20/370 (5.4%) 24/369 (6.5%) 2/259 (0.8%) 12/284 (4.2%)
    Infections and infestations
    Bronchitis 1/50 (2%) 2/50 (4%) 0/51 (0%) 1/52 (1.9%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 12/370 (3.2%) 21/369 (5.7%) 12/259 (4.6%) 7/284 (2.5%)
    Influenza 0/50 (0%) 0/50 (0%) 1/51 (2%) 0/52 (0%) 0/51 (0%) 0/51 (0%) 0/29 (0%) 0/26 (0%) 0/29 (0%) 15/370 (4.1%) 11/369 (3%) 14/259 (5.4%) 3/284 (1.1%)
    Nasopharyngitis 2/50 (4%) 1/50 (2%) 2/51 (3.9%) 2/52 (3.8%) 2/51 (3.9%) 3/51 (5.9%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 20/370 (5.4%) 20/369 (5.4%) 12/259 (4.6%) 13/284 (4.6%)
    Upper respiratory tract infection 1/50 (2%) 2/50 (4%) 0/51 (0%) 2/52 (3.8%) 3/51 (5.9%) 2/51 (3.9%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 31/370 (8.4%) 35/369 (9.5%) 16/259 (6.2%) 14/284 (4.9%)
    Urinary tract infection 3/50 (6%) 0/50 (0%) 1/51 (2%) 1/52 (1.9%) 1/51 (2%) 1/51 (2%) 0/29 (0%) 0/26 (0%) 1/29 (3.4%) 20/370 (5.4%) 22/369 (6%) 10/259 (3.9%) 8/284 (2.8%)
    Injury, poisoning and procedural complications
    Accidental overdose 2/50 (4%) 3/50 (6%) 1/51 (2%) 3/52 (5.8%) 2/51 (3.9%) 5/51 (9.8%) 2/29 (6.9%) 1/26 (3.8%) 3/29 (10.3%) 23/370 (6.2%) 26/369 (7%) 17/259 (6.6%) 15/284 (5.3%)
    Investigations
    Alanine aminotransferase increased 2/50 (4%) 2/50 (4%) 0/51 (0%) 3/52 (5.8%) 2/51 (3.9%) 0/51 (0%) 0/29 (0%) 1/26 (3.8%) 0/29 (0%) 31/370 (8.4%) 30/369 (8.1%) 11/259 (4.2%) 9/284 (3.2%)
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis 0/50 (0%) 3/50 (6%) 1/51 (2%) 0/52 (0%) 0/51 (0%) 1/51 (2%) 2/29 (6.9%) 0/26 (0%) 0/29 (0%) 2/370 (0.5%) 10/369 (2.7%) 9/259 (3.5%) 12/284 (4.2%)
    Vascular disorders
    Hypertension 0/50 (0%) 0/50 (0%) 2/51 (3.9%) 0/52 (0%) 0/51 (0%) 1/51 (2%) 1/29 (3.4%) 2/26 (7.7%) 2/29 (6.9%) 15/370 (4.1%) 14/369 (3.8%) 10/259 (3.9%) 5/284 (1.8%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.

    Results Point of Contact

    Name/Title Trial Transparency Team
    Organization Sanofi
    Phone
    Email Contact-US@sanofi.com
    Responsible Party:
    Sanofi
    ClinicalTrials.gov Identifier:
    NCT01061736
    Other Study ID Numbers:
    • EFC11072
    • 2009-016266-90
    First Posted:
    Feb 3, 2010
    Last Update Posted:
    Jun 28, 2017
    Last Verified:
    Jun 1, 2017