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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01061736
Recruitment Status : Completed
First Posted : February 3, 2010
Results First Posted : June 28, 2017
Last Update Posted : June 28, 2017
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Drug: Sarilumab
Drug: Placebo (for sarilumab)
Drug: Methotrexate
Drug: Folic Acid
Enrollment 1675
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 Details 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)
Hide 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 [1] 55 [1] 168 [1]
Completed 37 46 45 48 45 49 0 336 330 354
Not Completed 13 4 6 3 7 3 84 94 97 74
Reason Not Completed
Dose regimen not selected             0             0             0             0             0             0             79             0             0             0
Adverse Event             13             1             3             2             4             1             4             63             67             34
Lack of Efficacy             0             2             1             1             1             2             1             9             9             10
Poor compliance to protocol             0             0             0             0             0             0             0             2             5             9
Not treated             0             0             0             0             1             0             0             2             1             0
Other than specified above             0             1             2             0             1             0             0             18             15             21
[1]
Included both participants who completed and did not complete the study.
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
Hide 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 Number of Baseline Participants 50 50 51 51 52 52 84 430 427 428 1675
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 50 participants 50 participants 51 participants 51 participants 52 participants 52 participants 84 participants 430 participants 427 participants 428 participants 1675 participants
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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 50 participants 50 participants 51 participants 51 participants 52 participants 52 participants 84 participants 430 participants 427 participants 428 participants 1675 participants
Female
41
  82.0%
42
  84.0%
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
  18.0%
8
  16.0%
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%
1.Primary Outcome
Title Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 50 50 51 51 52 52
Measure Type: Number
Unit of Measure: Percentage of participants
62 72 49 66.7 65.4 46.2
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.1155
Comments Threshold for significance = 0.05.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.99
Confidence Interval (2-Sided) 95%
0.85 to 4.64
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg qw, Part A: Placebo qw
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0041
Comments Threshold for significance = 0.05.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.84
Confidence Interval (2-Sided) 95%
1.53 to 9.63
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Part A: SAR 100 mg q2w, Part A: Placebo qw
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7119
Comments Threshold for significance = 0.05.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.17
Confidence Interval (2-Sided) 95%
0.52 to 2.61
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Part A: SAR 150 mg q2w, Part A: Placebo qw
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0363
Comments Threshold for significance = 0.05.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.38
Confidence Interval (2-Sided) 95%
1.06 to 5.35
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Part A: SAR 200 mg q2w, Part A: Placebo qw
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0426
Comments Threshold for significance = 0.05.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.34
Confidence Interval (2-Sided) 95%
1.03 to 5.29
Estimation Comments [Not Specified]
2.Primary Outcome
Title Part B: Percentage of Participants Achieving ACR20 Response at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 400 399 398
Measure Type: Number
Unit of Measure: Percentage of participants
58 66.4 33.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part B: SAR 150 mg q2w, Part B: Placebo 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.773
Confidence Interval (2-Sided) 95%
2.077 to 3.703
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part B: SAR 200 mg q2w, Part B: Placebo q2w
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.975
Confidence Interval (2-Sided) 95%
2.957 to 5.344
Estimation Comments [Not Specified]
3.Primary Outcome
Title Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 362 365 378
Mean (Standard Deviation)
Unit of Measure: units on a scale
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)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part B: SAR 150 mg q2w, Part B: Placebo 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.235
Confidence Interval (2-Sided) 95%
-0.312 to -0.157
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part B: SAR 200 mg q2w, Part B: Placebo q2w
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.258
Confidence Interval (2-Sided) 95%
-0.336 to -0.181
Estimation Comments [Not Specified]
4.Primary Outcome
Title Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 352 359 352
Mean (Standard Deviation)
Unit of Measure: units on a scale
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)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part B: SAR 150 mg q2w, Part B: Placebo 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Rank ANCOVA
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part B: SAR 200 mg q2w, Part B: Placebo q2w
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Rank ANCOVA
Comments [Not Specified]
5.Secondary Outcome
Title Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 400 399 398
Measure Type: Number
Unit of Measure: Percentage of participants
12.8 14.8 3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part B: SAR 150 mg q2w, Part B: Placebo 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.661
Confidence Interval (2-Sided) 95%
2.451 to 8.863
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part B: SAR 200 mg q2w, Part B: Placebo q2w
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance = 0.025.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 5.565
Confidence Interval (2-Sided) 95%
2.946 to 10.515
Estimation Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/50 (6.00%)   0/50 (0.00%)   3/51 (5.88%)   0/52 (0.00%)   0/51 (0.00%)   2/51 (3.92%)   2/29 (6.90%)   2/26 (7.69%)   0/29 (0.00%)   35/370 (9.46%)   46/369 (12.47%)   21/259 (8.11%)   7/284 (2.46%) 
Blood and lymphatic system disorders                           
Iron deficiency anemia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Leukopenia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Neutropenia  1  1/50 (2.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  1/29 (3.45%)  0/26 (0.00%)  0/29 (0.00%)  3/370 (0.81%)  4/369 (1.08%)  0/259 (0.00%)  0/284 (0.00%) 
Splenic vein thrombosis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Thrombocytopenia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Cardiac disorders                           
Angina unstable  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Atrial fibrillation  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Cardiac failure  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Cardio-respiratory arrest  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Cardiovascular insufficiency  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Myocardial ischemia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Pericarditis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Right ventricular failure  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  1/284 (0.35%) 
Sick sinus syndrome  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Eye disorders                           
Conjunctivitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Gastrointestinal disorders                           
Abdominal discomfort  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Abdominal wall hematoma  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Alcoholic pancreatitis  1  1/50 (2.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Constipation  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Duodenal ulcer  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Duodenal ulcer hemorrhage  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Duodenal ulcer perforation  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Duodenitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Gastric hemorrhage  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Gastric ulcer hemorrhage  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Gastritis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Hemorrhoids  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Pancreatitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
General disorders                           
Immediate post-injection reaction  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Impaired healing  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Non-cardiac chest pain  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Pyrexia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Hepatobiliary disorders                           
Bile duct stone  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Cholecystitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Cholecystitis chronic  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Cholelithiasis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Drug-induced liver injury  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Hepatitis toxic  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Immune system disorders                           
Hypersensitivity  1  1/50 (2.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Infections and infestations                           
Abscess limb  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Abscess oral  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Appendicitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  2/259 (0.77%)  0/284 (0.00%) 
Arthritis bacterial  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Bronchitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  2/369 (0.54%)  2/259 (0.77%)  0/284 (0.00%) 
Bronchitis fungal  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Cellulitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  3/259 (1.16%)  0/284 (0.00%) 
Clostridium difficile colitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Diverticulitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Endometritis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Erysipelas  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  2/369 (0.54%)  0/259 (0.00%)  1/284 (0.35%) 
Gastroenteritis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Herpes zoster  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Incision site infection  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Infected skin ulcer  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Necrotising fasciitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Osteomyelitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Otitis media acute  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Otitis media chronic  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  1/284 (0.35%) 
Pelvic abscess  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Pharyngitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Pneumonia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  2/369 (0.54%)  1/259 (0.39%)  0/284 (0.00%) 
Pneumonia streptococcal  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Pyelonephritis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  1/284 (0.35%) 
Pyelonephritis chronic  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Septic shock  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Sinusitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  1/284 (0.35%) 
Subacute endocarditis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Tinea cruris  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Upper respiratory tract infection  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  1/284 (0.35%) 
Urinary tract infection  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Injury, poisoning and procedural complications                           
Femur fracture  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Hip fracture  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  1/29 (3.45%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Joint dislocation  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Ligament rupture  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Procedural pain  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Road traffic accident  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  1/284 (0.35%) 
Tendon rupture  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Wound hemorrhage  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Investigations                           
Alanine aminotransferase increased  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Blood alkaline phosphatase increased  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Hepatic enzyme increased  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Transaminases increased  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Metabolism and nutrition disorders                           
Dehydration  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Diabetes mellitus  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Hypercalcemia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Type 2 diabetes mellitus  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Musculoskeletal and connective tissue disorders                           
Arthralgia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  1/51 (1.96%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Lumbar spinal stenosis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Osteoarthritis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  2/369 (0.54%)  3/259 (1.16%)  0/284 (0.00%) 
Pathological fracture  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Rheumatoid arthritis  1  0/50 (0.00%)  0/50 (0.00%)  1/51 (1.96%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  2/369 (0.54%)  1/259 (0.39%)  1/284 (0.35%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                           
Basal cell carcinoma  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  1/51 (1.96%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Breast cancer  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Breast cancer metastatic  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Invasive lobular breast carcinoma  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Malignant melanoma  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Meningioma  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  2/259 (0.77%)  0/284 (0.00%) 
Neoplasm of appendix  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Plasmacytoma  1  0/50 (0.00%)  0/50 (0.00%)  1/51 (1.96%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Squamous cell carcinoma of skin  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  1/51 (1.96%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Nervous system disorders                           
Brain oedema  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Cerebrovascular accident  1  0/50 (0.00%)  0/50 (0.00%)  1/51 (1.96%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Dizziness  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Embolic cerebral infarction  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Ischemic stroke  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Syncope  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Transient ischemic attack  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Pregnancy, puerperium and perinatal conditions                           
Abortion spontaneous  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Psychiatric disorders                           
Completed suicide  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Depression  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  2/369 (0.54%)  0/259 (0.00%)  0/284 (0.00%) 
Psychotic disorder  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Suicide attempt  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Renal and urinary disorders                           
Renal failure  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Renal failure acute  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  2/369 (0.54%)  1/259 (0.39%)  0/284 (0.00%) 
Reproductive system and breast disorders                           
Metrorrhagia  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Respiratory, thoracic and mediastinal disorders                           
Acute respiratory distress syndrome  1  0/50 (0.00%)  0/50 (0.00%)  1/51 (1.96%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Acute respiratory failure  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Bronchial secretion retention  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Chronic obstructive pulmonary disease  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  1/284 (0.35%) 
Dyspnoea  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Interstitial lung disease  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Pneumonitis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Pulmonary oedema  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Respiratory distress  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Skin and subcutaneous tissue disorders                           
Cutaneous lupus erythematosus  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Vascular disorders                           
Aortic thrombosis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Deep vein thrombosis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Embolism arterial  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  0/259 (0.00%)  0/284 (0.00%) 
Hypertension  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  0/369 (0.00%)  1/259 (0.39%)  0/284 (0.00%) 
Hypertensive crisis  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  0/370 (0.00%)  2/369 (0.54%)  0/259 (0.00%)  0/284 (0.00%) 
Shock hemorrhagic  1  0/50 (0.00%)  0/50 (0.00%)  0/51 (0.00%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  1/370 (0.27%)  1/369 (0.27%)  0/259 (0.00%)  0/284 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   16/50 (32.00%)   16/50 (32.00%)   7/51 (13.73%)   12/52 (23.08%)   19/51 (37.25%)   11/51 (21.57%)   6/29 (20.69%)   8/26 (30.77%)   6/29 (20.69%)   163/370 (44.05%)   194/369 (52.57%)   95/259 (36.68%)   83/284 (29.23%) 
Blood and lymphatic system disorders                           
Neutropenia  1  6/50 (12.00%)  5/50 (10.00%)  0/51 (0.00%)  1/52 (1.92%)  10/51 (19.61%)  0/51 (0.00%)  1/29 (3.45%)  2/26 (7.69%)  1/29 (3.45%)  36/370 (9.73%)  55/369 (14.91%)  0/259 (0.00%)  5/284 (1.76%) 
General disorders                           
Injection site erythema  1  1/50 (2.00%)  1/50 (2.00%)  1/51 (1.96%)  0/52 (0.00%)  1/51 (1.96%)  0/51 (0.00%)  1/29 (3.45%)  3/26 (11.54%)  0/29 (0.00%)  20/370 (5.41%)  24/369 (6.50%)  2/259 (0.77%)  12/284 (4.23%) 
Infections and infestations                           
Bronchitis  1  1/50 (2.00%)  2/50 (4.00%)  0/51 (0.00%)  1/52 (1.92%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  12/370 (3.24%)  21/369 (5.69%)  12/259 (4.63%)  7/284 (2.46%) 
Influenza  1  0/50 (0.00%)  0/50 (0.00%)  1/51 (1.96%)  0/52 (0.00%)  0/51 (0.00%)  0/51 (0.00%)  0/29 (0.00%)  0/26 (0.00%)  0/29 (0.00%)  15/370 (4.05%)  11/369 (2.98%)  14/259 (5.41%)  3/284 (1.06%) 
Nasopharyngitis  1  2/50 (4.00%)  1/50 (2.00%)  2/51 (3.92%)  2/52 (3.85%)  2/51 (3.92%)  3/51 (5.88%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  20/370 (5.41%)  20/369 (5.42%)  12/259 (4.63%)  13/284 (4.58%) 
Upper respiratory tract infection  1  1/50 (2.00%)  2/50 (4.00%)  0/51 (0.00%)  2/52 (3.85%)  3/51 (5.88%)  2/51 (3.92%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  31/370 (8.38%)  35/369 (9.49%)  16/259 (6.18%)  14/284 (4.93%) 
Urinary tract infection  1  3/50 (6.00%)  0/50 (0.00%)  1/51 (1.96%)  1/52 (1.92%)  1/51 (1.96%)  1/51 (1.96%)  0/29 (0.00%)  0/26 (0.00%)  1/29 (3.45%)  20/370 (5.41%)  22/369 (5.96%)  10/259 (3.86%)  8/284 (2.82%) 
Injury, poisoning and procedural complications                           
Accidental overdose  1  2/50 (4.00%)  3/50 (6.00%)  1/51 (1.96%)  3/52 (5.77%)  2/51 (3.92%)  5/51 (9.80%)  2/29 (6.90%)  1/26 (3.85%)  3/29 (10.34%)  23/370 (6.22%)  26/369 (7.05%)  17/259 (6.56%)  15/284 (5.28%) 
Investigations                           
Alanine aminotransferase increased  1  2/50 (4.00%)  2/50 (4.00%)  0/51 (0.00%)  3/52 (5.77%)  2/51 (3.92%)  0/51 (0.00%)  0/29 (0.00%)  1/26 (3.85%)  0/29 (0.00%)  31/370 (8.38%)  30/369 (8.13%)  11/259 (4.25%)  9/284 (3.17%) 
Musculoskeletal and connective tissue disorders                           
Rheumatoid arthritis  1  0/50 (0.00%)  3/50 (6.00%)  1/51 (1.96%)  0/52 (0.00%)  0/51 (0.00%)  1/51 (1.96%)  2/29 (6.90%)  0/26 (0.00%)  0/29 (0.00%)  2/370 (0.54%)  10/369 (2.71%)  9/259 (3.47%)  12/284 (4.23%) 
Vascular disorders                           
Hypertension  1  0/50 (0.00%)  0/50 (0.00%)  2/51 (3.92%)  0/52 (0.00%)  0/51 (0.00%)  1/51 (1.96%)  1/29 (3.45%)  2/26 (7.69%)  2/29 (6.90%)  15/370 (4.05%)  14/369 (3.79%)  10/259 (3.86%)  5/284 (1.76%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Trial Transparency Team
Organization: Sanofi
EMail: Contact-US@sanofi.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT01061736    
Other Study ID Numbers: EFC11072
2009-016266-90 ( EudraCT Number )
First Submitted: February 2, 2010
First Posted: February 3, 2010
Results First Submitted: May 23, 2017
Results First Posted: June 28, 2017
Last Update Posted: June 28, 2017