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

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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

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 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)
Arm/Group Description	Sarilumab 100 mg subcutaneous (SC) ...	Sarilumab 150 mg SC injection qw on...	Sarilumab 100 mg SC injection every...	Sarilumab 150 mg SC injection q2w a...	Sarilumab 200 mg SC injection q2w a...	Placebo (for sarilumab) qw on top o...	Sarilumab 100 mg qw, 150 mg qw or 1...	Sarilumab 150 mg SC injection q2w o...	Sarilumab 200 mg SC injection q2w o...	Placebo (for sarilumab) q2w on top ...
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.

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...	Sarilumab 150 mg SC injection qw on...	Sarilumab 100 mg SC injection q2w a...	Sarilumab 150 mg SC injection q2w a...	Sarilumab 200 mg SC injection q2w a...	Placebo (for sarilumab) qw on top o...	Sarilumab 100 mg qw, 150 mg qw or 1...	Sarilumab 150 mg SC injection q2w o...	Sarilumab 200 mg SC injection q2w o...	Placebo (for sarilumab) q2w on top ...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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%

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 Ameri...
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...	Sarilumab 150 mg SC injection qw on...	Sarilumab 100 mg SC injection q2w a...	Sarilumab 150 mg SC injection q2w a...	Sarilumab 200 mg SC injection q2w a...	Placebo (for sarilumab) qw on top o...
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

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]

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]

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]

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]

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
Description	ACR20 improvement responses were determined without imputation of miss...
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 ...	Participants randomized after dose ...	Participants randomized after dose ...
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

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]

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
Description	HAQ-DI was a participant-reported questionnaire that assesses the diff...
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 ...	Participants randomized after dose ...	Participants randomized after dose ...
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)

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]

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
Description	The Sharp method modified by D. van der Heijde involves separate score...
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 ...	Participants randomized after dose ...	Participants randomized after dose ...
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)

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]

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
Description	Major clinical response was defined as an ACR70 response maintained fo...
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 ...	Participants randomized after dose ...	Participants randomized after dose ...
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

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]

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]

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 (%)

Total

--/--

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 (%)

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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/29 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/29 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

1/51 (1.96%)

0/52 (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%)

0/51 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

1/51 (1.96%)

0/52 (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%)

0/51 (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%)

0/51 (0.00%)

0/52 (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%)

1/51 (1.96%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

1/51 (1.96%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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%)

0/51 (0.00%)

0/52 (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

Term from vocabulary, MedDRA 16.0

Other (Not Including Serious) Adverse Events

Frequency Threshold for Reporting Other 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 (%)

Total

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%)

1/51 (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%)

0/29 (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%)

1/51 (1.96%)

0/52 (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%)

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%)

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%)

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

Term from vocabulary, MedDRA 16.0

Limitations and Caveats

[Not Specified]

More Information

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 of Results:

Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N, Genovese MC. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014 Sep;73(9):1626-34. doi: 10.1136/annrheumdis-2013-204405. Epub 2013 Dec 2.

Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, Rohane P, van Hoogstraten H, Garg A, Fan C, van Adelsberg J, Weinstein SP, Graham NM, Stahl N, Yancopoulos GD, Huizinga TW, van der Heijde D. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol. 2015 Jun;67(6):1424-37. doi: 10.1002/art.39093.

Other Publications:

Strand V, Kosinski M, Chen CI, Joseph G, Rendas-Baum R, Graham NM, van Hoogstraten H, Bayliss M, Fan C, Huizinga T, Genovese MC. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016 Sep 6;18:198. doi: 10.1186/s13075-016-1096-9.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Genovese MC, Burmester GR, Hagino O, Thangavelu K, Iglesias-Rodriguez M, John GS, González-Gay MA, Mandrup-Poulsen T, Fleischmann R. Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials. Arthritis Res Ther. 2020 Sep 9;22(1):206. doi: 10.1186/s13075-020-02229-5.

Genovese MC, Fleischmann R, Kivitz A, Lee EB, van Hoogstraten H, Kimura T, St John G, Mangan EK, Burmester GR. Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies. Arthritis Res Ther. 2020 Jun 10;22(1):139. doi: 10.1186/s13075-020-02194-z.

Boyapati A, Schwartzman S, Msihid J, Choy E, Genovese MC, Burmester GR, Lam G, Kimura T, Sadeh J, Weinreich DM, Yancopoulos GD, Graham NMH. Association of High Serum Interleukin-6 Levels With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab From Adalimumab or Methotrexate in a Post Hoc Analysis. Arthritis Rheumatol. 2020 Sep;72(9):1456-1466. doi: 10.1002/art.41299. Epub 2020 Aug 25.

Genovese MC, van der Heijde D, Lin Y, St John G, Wang S, van Hoogstraten H, Gómez-Reino JJ, Kivitz A, Maldonado-Cocco JA, Seriolo B, Stanislav M, Burmester GR. Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD Open. 2019 Aug 1;5(2):e000887. doi: 10.1136/rmdopen-2018-000887. eCollection 2019.

Muszbek N, Proudfoot C, Fournier M, Chen CI, Kuznik A, Kiss Z, Gal P, Michaud K. Economic Evaluation of Sarilumab in the Treatment of Adult Patients with Moderately-to-Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs. Adv Ther. 2019 Jun;36(6):1337-1357. doi: 10.1007/s12325-019-00946-1. Epub 2019 Apr 19.

Boyapati A, Msihid J, Fiore S, van Adelsberg J, Graham NM, Hamilton JD. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016 Oct 6;18(1):225.

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

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