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Clinical Trial Results:
A Multi-center, Uncontrolled Extension Study Evaluating Efficacy and Safety of SAR153191 in Patients With Active Rheumatoid Arthritis (RA)

Summary
EudraCT number	2010-019262-86
Trial protocol	ES FI EE HU NL DE GR NO LT CZ IT AT PT SK GB BE SE
Global end of trial date	31 Dec 2020

Results information
Results version number	v2(current)
This version publication date	06 Jan 2023
First version publication date	11 Jan 2022
Other versions	v1
Version creation reason	Correction of full data set Updated safety optional field

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

LTS11210

ISRCTN number

-

US NCT number

NCT01146652

WHO universal trial number (UTN)

-

Sponsor organisation name

Sanofi-aventis Recherche & Développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly Mazarin Cedex, France, 91380

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

08 Feb 2021

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2020

Was the trial ended prematurely?

No

Main objective of the trial

To evaluate the long-term safety of sarilumab in subjects with RA.

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Subjects who completed any of the initial studies EFC11072 (2009-016266-90), ACT11575 (2010-021020-94), EFC10832 (2011-003538-16), SFY13370 (2012-003536-23), EFC13752 (2013-002790-22) were enrolled in study LTS11210.

Evidence for comparator

-

Actual start date of recruitment

21 Jun 2010

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 26

Country: Number of subjects enrolled

Belarus: 11

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Colombia: 61

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Chile: 123

Country: Number of subjects enrolled

Greece: 3

Country: Number of subjects enrolled

Israel: 6

Country: Number of subjects enrolled

Korea, Republic of: 36

Country: Number of subjects enrolled

Mexico: 223

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

New Zealand: 18

Country: Number of subjects enrolled

Poland: 224

Country: Number of subjects enrolled

Thailand: 2

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Peru: 43

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Brazil: 65

Country: Number of subjects enrolled

Czechia: 31

Country: Number of subjects enrolled

Estonia: 36

Country: Number of subjects enrolled

Malaysia: 3

Country: Number of subjects enrolled

Philippines: 6

Country: Number of subjects enrolled

Ukraine: 60

Country: Number of subjects enrolled

South Africa: 85

Country: Number of subjects enrolled

Argentina: 182

Country: Number of subjects enrolled

Guatemala: 12

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Romania: 46

Country: Number of subjects enrolled

Spain: 36

Country: Number of subjects enrolled

Finland: 9

Country: Number of subjects enrolled

Hungary: 70

Country: Number of subjects enrolled

Russian Federation: 228

Country: Number of subjects enrolled

Turkey: 1

Country: Number of subjects enrolled

United States: 284

Country: Number of subjects enrolled

Germany: 39

Country: Number of subjects enrolled

Ecuador: 11

Country: Number of subjects enrolled

Lithuania: 12

Worldwide total number of subjects

2023

EEA total number of subjects

514

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

1732

From 65 to 84 years

290

85 years and over

1

Subject disposition

Top of page

Recruitment details

2023 subjects who completed any of studies EFC11072, ACT11575, EFC10832, SFY13370, EFC13752 were eligible and enrolled in study LTS11210 between 21-Jun-2010 and 04-May-2015. From Week 24 of LTS11210, willing subjects were enrolled in a 12-week sub-study (part of main study only) to assess usability of pre-filled syringe with safety system (PFS-S).

Screening details

Exposure to sarilumab: for 12 weeks (W) if they were initially randomised (R) in EFC11072 Part A or ACT11575; up to 52 W if initially R in EFC11072 Part B; up to 24 W if initially R in EFC10832; or for 24 W if initially R in SFY13370 or EFC13752. Subject's end-of-treatment visit in initial study corresponded to initial visit in study LTS11210.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)

Arm description

Subjects who completed any of initial studies:Part A or B of EFC11072, ACT11575, EFC10832 or SFY13370 were enrolled in LTS11210 and received sarilumab 150 milligrams (mg) subcutaneously (SC) once weekly (qw). Dose could be reduced to 150 mg every 2 weeks (q2w) due to neutropenia, thrombocytopenia or increase in liver enzymes (alanine aminotransferase [ALT]). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

SAR153191 (REGN88)

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 150 mg, SC injection qw. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), 150 mg qw was switched to sarilumab 200 mg q2w.

Sarilumab monotherapy

Arm description

Subjects who completed study EFC13752 were enrolled in LTS11210 and received sarilumab 200 mg q2w. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks).

Arm type

Experimental

Investigational medicinal product name

Sarilumab

Investigational medicinal product code

SAR153191 (REGN88)

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sarilumab 150 mg, SC injection qw. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), 150 mg qw was switched to sarilumab 200 mg q2w.

Number of subjects in period 1	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Started	1912	111
Treated	1910	111
Enrolled in the sub-study	110 ^[1]	14 ^[2]
Discontinued from the sub-study	1 ^[3]	2 ^[4]
Switched back to main study	108 ^[5]	13 ^[6]
Completed	961	66
Not completed	951	45
Adverse event, non-fatal	506	15
Poor compliance to protocol	38	1
Other unspecified reasons	314	22
Enrolled but not treated	2	-
Lack of efficacy	91	7

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects who were eligible and entered sub-study from Week 24 of main study.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects who were eligible and entered sub-study from Week 24 of main study.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Sub-study discontinued subjects were included in the discontinuation count of the main study.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Sub-study discontinued subjects were included in the discontinuation count of the main study.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects who were willing to switch back to the main study regardless of if they completed the sub-study.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subjects who were willing to switch back to the main study regardless of if they completed the sub-study.

Baseline characteristics

Top of page

Reporting group title

Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)

Reporting group description

Subjects who completed any of initial studies:Part A or B of EFC11072, ACT11575, EFC10832 or SFY13370 were enrolled in LTS11210 and received sarilumab 150 milligrams (mg) subcutaneously (SC) once weekly (qw). Dose could be reduced to 150 mg every 2 weeks (q2w) due to neutropenia, thrombocytopenia or increase in liver enzymes (alanine aminotransferase [ALT]). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Reporting group title

Sarilumab monotherapy

Reporting group description

Subjects who completed study EFC13752 were enrolled in LTS11210 and received sarilumab 200 mg q2w. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks).

Reporting group values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy	Total
Number of subjects	1912	111
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	52.1 ± 11.8	52.9 ± 13.1	-
Gender categorical
Units: Subjects
Female	1550	88	1638
Male	362	23	385
Race/Ethnicity, Customized
Units: Subjects
Caucasian/White	1639	108	1747
Black	48	1	49
Asian/Oriental	69	1	70
Other	156	1	157

End points

Top of page

Reporting group title

Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)

Reporting group description

Subjects who completed any of initial studies:Part A or B of EFC11072, ACT11575, EFC10832 or SFY13370 were enrolled in LTS11210 and received sarilumab 150 milligrams (mg) subcutaneously (SC) once weekly (qw). Dose could be reduced to 150 mg every 2 weeks (q2w) due to neutropenia, thrombocytopenia or increase in liver enzymes (alanine aminotransferase [ALT]). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Reporting group title

Sarilumab monotherapy

Reporting group description

Subjects who completed study EFC13752 were enrolled in LTS11210 and received sarilumab 200 mg q2w. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks).

Subject analysis set title

Sarilumab + DMARD: EFC11072 Part B

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects who completed EFC11072 Part B were enrolled in LTS11210 and received sarilumab 150 mg SC qw. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Subject analysis set title

Sarilumab + DMARD: EFC11072, ACT11575 and EFC10832

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects who completed any of the initial studies: Part A or Part B of EFC11072, ACT11575, and EFC10832 were enrolled in LTS11210 and received sarilumab 150 mg SC qw. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Subject analysis set title

Sarilumab + DMARD: EFC11072, and ACT11575

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects who completed any of the initial studies: Part A or Part B of EFC11072, and ACT11575 were enrolled in LTS11210 and received sarilumab 150 mg SC qw. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Subject analysis set title

Sarilumab + DMARD: EFC10832

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects who completed study EFC10832 were enrolled in LTS11210 and received sarilumab 150 mg SC qw. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Subject analysis set title

PFS-S Sarilumab 150 mg q2w

Subject analysis set type

Sub-group analysis

Subject analysis set description

From Week 24 of main study, eligible subjects entered sub-study and received sarilumab 150 mg SC q2w for 12 weeks (i.e., from main study Week 24 to Week 36) using PFS-S.

Subject analysis set title

PFS-S Sarilumab 200 mg q2w

Subject analysis set type

Sub-group analysis

Subject analysis set description

From Week 24 of main study, eligible subjects entered sub-study and received sarilumab 200 mg SC q2w for 12 weeks (i.e., from main study Week 24 to Week 36) using PFS-S.

Subject analysis set title

PFS-S Sarilumab 200 to 150 mg q2w

Subject analysis set type

Sub-group analysis

Subject analysis set description

From Week 24 of main study, eligible subjects entered sub-study and received sarilumab 200 mg SC q2w for 12 weeks (i.e., from main study Week 24 to Week 36) using PF-S. The dose might be reduced to 150 mg q2w due to neutropenia, thrombocytopenia, or an increase in liver enzymes.

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Top of page

End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) ^[1]

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical study subject administered a medicinal product and which did not necessarily have to have a causal relationship with the treatment. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that developed or worsened or became serious during the TEAE period (defined as the time from the first dose of the investigational medicinal product (IMP) in study LTS11210 to the last dose of the IMP +60 days). Analysis was performed on safety population which included all enrolled subjects who had received at least one dose of the study treatment in LTS11210.

End point type

Primary

End point timeframe

From first dose (i.e., Day 1 of study LTS11210) up to 60 days after last dose (maximum duration: up to 523 weeks)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the end-point was descriptive in nature no statistical analysis was provided.

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1910	111
Units: subjects
Any TEAE	1760	98
Any TE SAE	617	27

No statistical analyses for this end point

Primary: Sub-study: Number of Subjects Reported Product Technical Complaints (PTC), Product Technical Failures (PTF) and/or Failed Drug Deliveries (FDD) With Pre-filled Syringe With Safety System

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End point title

Sub-study: Number of Subjects Reported Product Technical Complaints (PTC), Product Technical Failures (PTF) and/or Failed Drug Deliveries (FDD) With Pre-filled Syringe With Safety System ^[2]

End point description

A PTF was defined as any product technical complaint (PTC) related to the use of the PFS-S that had a validated technical cause. FDD was defined as subject’s failure to administer the full dose at a given attempt. A PTC was defined as any subject- or healthcare provider-reported complaint regarding the use of the PFS-S syringe and collected via the completion of the injection diary. The injection diary comprised specific questions: 1. Were you able to remove the cap? 2. Was the needle safety system activated?, 3. Did the safety system entirely cover the needle, and 4. Was the person who performed the injection the person who was trained by the site staff?, where each question was given the option yes/no. Subjects who answered “no” for any of the questions of PTC, had PTF and/or FDD were reported in this endpoint. Analysis was performed on all subjects who were enrolled in the sub-study.

End point type

Primary

End point timeframe

From Week 24 to 36

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the end-point was descriptive in nature no statistical analysis was provided.

End point values	PFS-S Sarilumab 150 mg q2w	PFS-S Sarilumab 200 mg q2w	PFS-S Sarilumab 200 to 150 mg q2w
Number of subjects analysed	25	98	1
Units: subjects
PFS-S-associated PTF	0	0	0
PFS-S-associated FDD	0	5	0
PFS-S-associated PTC	0	5	0

No statistical analyses for this end point

Primary: Sub-study: Number of Product Technical Complaints - Product Technical Failures With Pre-filled Syringe With Safety System

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End point title

Sub-study: Number of Product Technical Complaints - Product Technical Failures With Pre-filled Syringe With Safety System ^[3]

End point description

A PTF was defined as any PTC (defined as any subject- or healthcare provider-reported complaint regarding the use of the PFS-S syringe and collected via the completion of the injection diary) related to the use of the PFS-S that had a validated technical cause. Number of PTF in the subjects enrolled in sub-study were reported in this endpoint. Analysis was performed on all subjects who were enrolled in the sub-study.

End point type

Primary

End point timeframe

From Week 24 to 36

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the end-point was descriptive in nature no statistical analysis was provided.

End point values	PFS-S Sarilumab 150 mg q2w	PFS-S Sarilumab 200 mg q2w	PFS-S Sarilumab 200 to 150 mg q2w
Number of subjects analysed	25	98	1
Units: PTF	0	0	0

No statistical analyses for this end point

Primary: Sub-study: Number of Failed Drug Deliveries Associated With Pre-filled Syringe With Safety System

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End point title

Sub-study: Number of Failed Drug Deliveries Associated With Pre-filled Syringe With Safety System ^[4]

End point description

FDD was defined as subject’s failure to administer the full dose at a given attempt. Number of FDD in the subjects enrolled in sub-study were reported in this endpoint. Analysis was performed on all subjects who were enrolled in the sub-study.

End point type

Primary

End point timeframe

From Week 24 to 36

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the end-point was descriptive in nature no statistical analysis was provided.

End point values	PFS-S Sarilumab 150 mg q2w	PFS-S Sarilumab 200 mg q2w	PFS-S Sarilumab 200 to 150 mg q2w
Number of subjects analysed	25	98	1
Units: FDD	0	5	0

No statistical analyses for this end point

Primary: Sub-study: Number of Product Technical Complaints With Pre-filled Syringe With Safety System

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End point title

Sub-study: Number of Product Technical Complaints With Pre-filled Syringe With Safety System ^[5]

End point description

A PTC was defined as any subject- or healthcare provider-reported complaint regarding the use of the PFS-S syringe and collected via the completion of the injection diary. The injection diary comprised specific questions: 1. Were you able to remove the cap? 2. Was the needle safety system activated?, 3. Did the safety system entirely cover the needle, and 4. Was the person who performed the injection the person who was trained by the site staff?, where each question was given the option yes/no. Number of PTC (based on subject’s answer to “no” for any of the questions of PTC) in the subjects enrolled in sub-study were reported in this endpoint. Analysis was performed on all subjects who were enrolled in the sub-study.

End point type

Primary

End point timeframe

From Week 24 to 36

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the end-point was descriptive in nature no statistical analysis was provided.

End point values	PFS-S Sarilumab 150 mg q2w	PFS-S Sarilumab 200 mg q2w	PFS-S Sarilumab 200 to 150 mg q2w
Number of subjects analysed	25	98	1
Units: PTC	0	5	0

No statistical analyses for this end point

Secondary: Percentage of Subjects Achieving American College of Rheumatology 20 (ACR20) Response

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End point title

Percentage of Subjects Achieving American College of Rheumatology 20 (ACR20) Response

End point description

ACR20 response: greater than or equal to (>=) 20% improvement in both tender joint count and swollen joint count and >=20% improvement in at least 3 of 5 remaining ACR core measures assessments: C-reactive protein [CRP] level (mg/litre [mg/L]); subject's assessment of pain (measured on 0 [no pain] to 100 mm [worst pain] visual analog scale [VAS]); subject’s global assessment of disease activity (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by health assessment questionnaire disability index, with scoring range of 0 [better physical function] to 3 [worst physical function]). Higher score = worse outcomes. Safety population: subjects who had at least 1 dose of study treatment in LTS11210. Here, number of subjects analysed=subjects evaluable and n=subjects with data.

End point type

Secondary

End point timeframe

At Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1898	111
Units: percentage of subjects
number (confidence interval 95%)
Week 0 (1898, 111)	69.4 (67.3 to 71.5)	82.0 (73.6 to 88.6)
Week 4 (n=1885, 106)	77.8 (75.8 to 79.6)	85.8 (77.7 to 91.9)
Week 8 (n=1852, 106)	80.2 (78.3 to 82.0)	92.5 (85.7 to 96.7)
Week 12 (n=1829, 109)	80.3 (78.4 to 82.1)	91.7 (84.9 to 96.2)
Week 24 (n=1787, 109)	82.9 (81.1 to 84.6)	88.1 (80.5 to 93.5)
Week 36 (n= 1730, 109)	82.8 (80.9 to 84.5)	91.7 (84.9 to 96.2)
Week 48 (n=1670, 107)	82.9 (81.0 to 84.7)	85.0 (76.9 to 91.2)
Week 60 (n=1618, 103)	84.6 (82.8 to 86.3)	93.2 (86.5 to 97.2)
Week 72 (n=1586, 101)	84.4 (82.5 to 86.1)	94.1 (87.5 to 97.8)
Week 84 (n=1550, 95)	84.5 (82.6 to 86.2)	94.7 (88.1 to 98.3)
Week 96 (n=1510, 92)	85.2 (83.3 to 87.0)	91.3 (83.6 to 96.2)
Week 120 (n=1456, 88)	84.9 (82.9 to 86.7)	90.9 (82.9 to 96.0)
Week 144 (n=1389, 83)	86.4 (84.5 to 88.2)	94.0 (86.5 to 98.0)
Week 168 (n=1322,81)	86.0 (84.0 to 87.8)	90.1 (81.5 to 95.6)
Week 192 (n=1263, 75)	85.7 (83.7 to 87.6)	89.3 (80.1 to 95.3)
Week 216 (n=1189, 74)	87.1 (85.1 to 89.0)	89.2 (79.8 to 95.2)
Week 240 (n=1125, 74)	86.4 (84.3 to 88.4)	91.9 (83.2 to 97.0)
Week 264 (n=1049, 61)	88.5 (86.4 to 90.3)	90.2 (79.8 to 96.3)

No statistical analyses for this end point

Secondary: Percentage of Subjects Achieving American College of Rheumatology 50 (ACR50) Response

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End point title

Percentage of Subjects Achieving American College of Rheumatology 50 (ACR50) Response

End point description

ACR50 response: >=50% improvement in both TJC and SJC, and >=50% improvement in at least 3 of the 5 remaining ACR core measures assessments: CRP level (in mg/L); subject’s assessment of pain (measured on 0 [no pain] to 100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by HAQ-DI, with scoring range of 0 [better physical function] to 3 [worst physical function]). Higher score indicated worse outcomes. Analysis was performed on safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

At Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1897	111
Units: percentage of subjects
number (confidence interval 95%)
Week 0 (n=1897, 111)	43.4 (41.2 to 45.7)	58.6 (48.8 to 67.8)
Week 4 (n=1884, 108)	51.3 (49.0 to 53.6)	59.3 (49.4 to 68.6)
Week 8 (n=1850, 105)	55.1 (52.8 to 57.4)	59.0 (49.0 to 68.5)
Week 12 (n=1830, 108)	58.1 (55.8 to 60.4)	66.7 (56.9 to 75.4)
Week 24 (n=1782, 109)	60.5 (58.2 to 62.8)	64.2 (54.5 to 73.2)
Week 36 (n=1729, 109)	62.1 (59.8 to 64.4)	64.2 (54.5 to 73.2)
Week 48 (n=1669, 107)	62.4 (60.0 to 64.7)	69.2 (59.5 to 77.7)
Week 60 (n=1620, 103)	63.2 (60.8 to 65.6)	68.9 (59.1 to 77.7)
Week 72 (n=1585, 101)	64.8 (62.4 to 67.1)	71.3 (61.4 to 79.9)
Week 84 (n=1546, 94)	63.6 (61.2 to 66.1)	73.4 (63.3 to 82.0)
Week 96 (n=1511, 92)	65.3 (62.8 to 67.7)	71.7 (61.4 to 80.6)
Week 120 (n=1455, 87)	65.6 (63.1 to 68.0)	73.6 (63.0 to 82.4)
Week 144 (n=1385, 84)	65.7 (63.1 to 68.2)	70.2 (59.3 to 79.7)
Week 168 (n=1320, 80)	66.2 (63.6 to 68.8)	70.0 (58.7 to 79.7)
Week 192 (n=1257, 75)	68.4 (65.8 to 71.0)	70.7 (59.0 to 80.6)
Week 216 (n=1189, 74)	69.0 (66.3 to 71.7)	75.7 (64.3 to 84.9)
Week 240 (n=1125, 74)	68.3 (65.5 to 71.0)	79.7 (68.8 to 88.2)
Week 264 (n=1040, 60)	69.6 (66.7 to 72.4)	71.7 (58.6 to 82.5)

No statistical analyses for this end point

Secondary: Percentage of Subjects Achieving American College of Rheumatology 70 (ACR70) Response

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End point title

Percentage of Subjects Achieving American College of Rheumatology 70 (ACR70) Response

End point description

ACR70 response: >=70% improvement in both TJC and SJC, and >=70% improvement in at least 3 of the 5 remaining ACR core measures assessments: CRP level (in mg/L); subject’s assessment of pain (measured on 0 [no pain] to 100 mm [worst pain] VAS); subject’s global assessment of disease activity (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS); physician’s global assessment of disease activity (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS); subject’s assessment of physical function (measured by HAQ-DI, with scoring range of 0 [better physical function] to 3 [worst physical function]). Higher score indicated worse outcomes. Analysis was performed on safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subject with available data for each specified category.

End point type

Secondary

End point timeframe

At Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1901	111
Units: percentage of subjects
number (confidence interval 95%)
Week 0 (n=1901, 111)	22.9 (21.0 to 24.8)	32.4 (23.9 to 42.0)
Week 4 (n=1879, 108)	27.8 (25.8 to 29.9)	31.5 (22.9 to 41.1)
Week 8 (n=1854, 105)	32.1 (30.0 to 34.3)	36.2 (27.0 to 46.1)
Week 12 (n=1829, 107)	34.1 (31.9 to 36.3)	43.0 (33.5 to 52.9)
Week 24 (n=1781, 107)	38.7 (36.4 to 41.0)	37.4 (28.2 to 47.3)
Week 36 (n=1726, 109)	40.2 (37.9 to 42.6)	40.4 (31.1 to 50.2)
Week 48 (n=1666, 105)	40.6 (38.3 to 43.0)	43.8 (34.1 to 53.8)
Week 60 (n=1618, 103)	41.6 (39.2 to 44.0)	45.6 (35.8 to 55.7)
Week 72 (n=1585, 100)	42.1 (39.6 to 44.6)	49.0 (38.9 to 59.2)
Week 84 (n=1541, 94)	41.8 (39.3 to 44.3)	52.1 (41.6 to 62.5)
Week 96 (n=1510, 92)	43.4 (40.9 to 45.9)	55.4 (44.7 to 65.8)
Week 120 (n=1449, 88)	42.9 (40.3 to 45.5)	56.8 (45.8 to 67.3)
Week 144 (n=1386, 84)	44.7 (42.0 to 47.3)	50.0 (38.9 to 61.1)
Week 168 (n=1317, 80)	45.6 (42.9 to 48.4)	51.3 (39.8 to 62.6)
Week 192 (n=1262, 76)	47.9 (45.1 to 50.7)	53.9 (42.1 to 65.5)
Week 216 (n=1186, 71)	46.8 (43.9 to 49.7)	62.0 (49.7 to 73.2)
Week 240 (n=1123, 74)	47.9 (44.9 to 50.9)	60.8 (48.8 to 72.0)
Week 264 (n=1030, 60)	48.8 (45.7 to 51.9)	58.3 (44.9 to 70.9)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Disease Activity Score for 28 Joints (DAS28) Remission

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End point title

Percentage of Subjects With Disease Activity Score for 28 Joints (DAS28) Remission

End point description

Disease activity score based on 28 joints and C-reactive protein (DAS28-CRP) was a composite score which included 4 components: TJC with 28 joints assessed; SJC with 28 joints assessed; high-sensitivity CRP (in mg/L) and general health assessment by the subject using subject global assessment (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS). DAS28-CRP total score ranges from 0 to 10, where higher scores indicated greater disease activity. Percentage of subjects with DAS28 remission were reported. Analysis was performed on safety population. Here, 'number of subjects analysed' = subjects evaluable for endpoint and n’ = subject with available data for each specified category and “99999” was used as space filler which indicates that data was not planned to be collected and analysed for the specified time-points in the respective groups.

End point type

Secondary

End point timeframe

At Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1873	110
Units: percentage of subjects
number (confidence interval 95%)
Week 0 (n=1873, 110)	30.4 (28.3 to 32.5)	46.4 (36.8 to 56.1)
Week 4 (n=1867, 106)	39.2 (36.9 to 41.4)	51.9 (42.0 to 61.7)
Week 8 (n=1804, 105)	44.6 (42.3 to 46.9)	49.5 (39.6 to 59.5)
Week 12 (n=1819, 109)	47.9 (45.6 to 50.3)	55.0 (45.2 to 64.6)
Week 24 (n=1778, 109)	50.6 (48.2 to 52.9)	59.6 (49.8 to 68.9)
Week 36 (n=1721, 109)	51.7 (49.3 to 54.1)	59.6 (49.8 to 68.9)
Week 48 (n=1661, 107)	53.7 (51.3 to 56.1)	56.1 (46.1 to 65.7)
Week 60 (n=1608, 102)	56.5 (54.1 to 59.0)	61.8 (51.6 to 71.2)
Week 72 (n=1580, 101)	55.8 (53.3 to 58.3)	68.3 (58.3 to 77.2)
Week 84 (n=1537, 95)	55.8 (53.2 to 58.3)	70.5 (60.3 to 79.4)
Week 96 (n=1506, 92)	57.0 (54.5 to 59.6)	71.7 (61.4 to 80.6)
Week 120 (n=1444, 88)	59.2 (56.6 to 61.8)	73.9 (63.4 to 82.7)
Week 144 (n=1381, 83)	59.3 (56.7 to 61.9)	72.3 (61.4 to 81.6)
Week 168 (n=1309, 81)	59.7 (56.9 to 62.3)	70.4 (59.2 to 80.0)
Week 192 (n=1250, 76)	62.1 (59.3 to 64.8)	67.1 (55.4 to 77.5)
Week 216 (n=1175, 73)	63.6 (60.7 to 66.3)	71.2 (59.4 to 81.2)
Week 240 (n=1118, 73)	61.6 (58.7 to 64.5)	82.2 (71.5 to 90.2)
Week 264 (n=1036, 62)	64.4 (61.4 to 67.3)	75.8 (63.3 to 85.8)
Week 288 (n=715, 26)	68.7 (65.1 to 72.1)	73.1 (52.2 to 88.4)
Week 312 (n=655, 7)	69.0 (65.3 to 72.5)	85.7 (42.1 to 99.6)
Week 336 (n=540, 0)	72.2 (68.2 to 76.0)	99999 (99999 to 99999)
Week 360 (n=424, 0)	71.7 (67.2 to 75.9)	99999 (99999 to 99999)
Week 384 (n=334, 0)	71.6 (66.4 to 76.3)	99999 (99999 to 99999)
Week 408 (n=199, 0)	69.8 (63.0 to 76.1)	99999 (99999 to 99999)
Week 432 (n=106, 0)	76.4 (67.2 to 84.1)	99999 (99999 to 99999)
Week 456 (n=55, 0)	72.7 (59.0 to 83.9)	99999 (99999 to 99999)
Week 480 (n=39, 0)	76.9 (60.7 to 88.9)	99999 (99999 to 99999)
Week 504 (n=26, 0)	73.1 (52.2 to 88.4)	99999 (99999 to 99999)
Week 516 (n=2, 0)	50.0 (1.3 to 98.7)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects achieving Good Response, Moderate Response or Non-response Using the European League Against Rheumatism (EULAR) Response Criteria

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End point title

Percentage of Subjects achieving Good Response, Moderate Response or Non-response Using the European League Against Rheumatism (EULAR) Response Criteria

End point description

DAS28-based EULAR response criteria measured individual response as none, good or moderate, depending on extent of change from baseline and level of disease activity reached. EULAR response criteria were defined as: Good response=change from baseline of >1.2 and present DAS28-CRP score <=3.2. Moderate response=change from baseline of >0.6 to <=1.2 and present DAS28-CRP score <=5.1, or, change from baseline of >1.2 and present DAS28-CRP score >3.2. Non-response=change from baseline of <=0.6 or change from baseline of >0.6 to <=1.2 and present DAS28-CRP score >5.1. Scores of good and moderate=therapeutic response. DAS28-CRP: composite score which had 4 components: TJC with 28 joints assessed; SJC with 28 joints assessed; high-sensitivity CRP (in mg/L) and general health assessment by subject using subject global assessment (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS. Safety population. number of subjects=subjects evaluable and n=subjects with data.

End point type

Secondary

End point timeframe

At Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1872	110
Units: percentage of subjects
number (not applicable)
Week 0: Good response (n=1872,110)	44.7	60.9
Week 0: Moderate response (n=1872, 110)	40.3	30.9
Week 0: None response (n=1872, 110)	15.0	8.2
Week 4: Good response (n=1866,106)	57.2	69.8
Week 4: Moderate response (n=1866,106)	36.2	26.4
Week 4:None response (n=1866,106)	6.6	3.8
Week 8: Good response (n=1803, 105)	62.3	68.6
Week 8: Moderate response (n=1803, 105)	31.7	27.6
Week 8: None response (n=1803, 105)	6.0	3.8
Week 12: Good response (n=1818, 109)	64.1	74.3
Week 12: Moderate response (n=1818, 109)	30.6	22.9
Week 12: None response (n=1818, 109)	5.2	2.8
Week 24: Good response (n=1777, 109)	66.6	73.4
Week 24: Moderate response (n=1777, 109)	28.9	24.8
Week 24: None response (n=1777, 109)	4.5	1.8
Week 36: Good response (n=1720, 109)	67.9	71.6
Week 36: Moderate response (n=1720, 109)	27.0	24.8
Week 36: None response (n=1720, 109)	5.1	3.7
Week 48: Good response (n=1660, 107)	68.1	72.0
Week 48: Moderate response (n=1660, 107)	27.4	24.3
Week 48: None response (n=1660, 107)	4.5	3.7
Week 60: Good response (n=1607, 102)	71.1	68.6
Week 60: Moderate response (n=1607, 102)	24.6	29.4
Week 60: None response (n=1607, 102)	4.2	2.0
Week 72: Good response (n=1579, 101)	70.0	81.2
Week 72: Moderate response (n=1579, 101)	26.0	16.8
Week 72: None response (n=1579, 101)	4.0	2.0
Week 84: Good response (n=1536, 95)	71.3	84.2
Week 84: Moderate response (n=1536, 95)	24.2	14.7
Week 84: None response (n=1536, 95)	4.6	1.1
Week 96: Good response (n=1505, 92)	72.6	76.1
Week 96: Moderate response (n=1505, 92)	23.3	21.7
Week 96: None response (n=1505, 92)	4.1	2.2
Week 120: Good response (n=1443, 88)	73.5	80.7
Week 120: Moderate response (n=1443, 88)	22.3	17.0
Week 120: None response (n=1443, 88)	4.2	2.3
Week 144: Good response (n=1381, 83)	73.3	86.7
Week 144: Moderate response (n=1381, 83)	22.8	13.3
Week 144: None response (n=1381, 83)	3.9	0
Week 168: Good response (n=1309, 81)	74.5	84.0
Week 168: Moderate response (n=1309, 81)	20.6	16.0
Week 168: None response (n=1309, 81)	4.9	0
Week 192: Good response (n=1250, 76)	75.6	81.6
Week 192: Moderate response (n=1250, 76)	20.6	13.2
Week 192: None response (n=1250, 76)	3.8	5.3
Week 216: Good response (n=1175, 73)	75.9	80.8
Week 216: Moderate response (n=1175, 73)	20.5	17.8
Week 216: None response (n=1175, 73)	3.6	1.4
Week 240: Good response (n=1118, 73)	78.6	89.0
Week 240: Moderate response (n=1118, 73)	17.5	9.6
Week 240: None response (n=1118, 73)	3.8	1.4
Week 264: Good response (n=1036, 62)	76.7	83.9
Week 264: Moderate response (n=1036, 62)	20.2	16.1
Week 264: None response (n=1036, 62)	3.1	0
Week 288: Good response (n=715, 26)	82.4	80.8
Week 288: Moderate response (n=715, 26)	15.2	19.2
Week 288: None response (n=715, 26)	2.4	0
Week 312: Good response (n=655, 7)	81.5	100
Week 312: Moderate response (n=655, 7)	16.3	0
Week 312: None response (n=655, 7)	2.1	0
Week 336: Good response (n=540, 0)	83.0	99999
Week 336: Moderate response (n=540, 0)	14.6	99999
Week 336: None response (n=540, 0)	2.4	99999
Week 360: Good response (n=424, 0)	83.3	99999
Week 360: Moderate response (n=424, 0)	15.1	99999
Week 360: None response (n=424, 0)	1.7	99999
Week 384: Good response (n=334, 0)	86.2	99999
Week 384: Moderate response (n=334, 0)	12.9	99999
Week 384: None response (n=334, 0)	0.9	99999
Week 408: Good response (n=199, 0)	81.9	99999
Week 408: Moderate response (n=199, 0)	16.1	99999
Week 408: None response (n=199, 0)	2.0	99999
Week 432: Good response (n=106, 0)	85.8	99999
Week 432: Moderate response (n=106, 0)	14.2	99999
Week 432: None response (n=106, 0)	0	99999
Week 456: Good response (n=55, 0)	87.3	99999
Week 456: Moderate response (n=55, 0)	12.7	99999
Week 456: None response (n=55, 0)	0	99999
Week 480: Good response (n=39, 0)	79.5	99999
Week 480: Moderate response (n=39, 0)	17.9	99999
Week 480: None response (n=39, 0)	2.6	99999
Week 504: Good response (n=26, 0)	92.3	99999
Week 504: Moderate response (n=26, 0)	7.7	99999
Week 504: None response (n=26, 0)	0	99999
Week 516: Good response (n=2, 0)	100	99999
Week 516: Moderate response (n=2, 0)	0	99999
Week 516: None response (n=2, 0)	0	99999

No statistical analyses for this end point

Secondary: Change From Baseline in DAS28-CRP Score at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

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End point title

Change From Baseline in DAS28-CRP Score at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point description

DAS28-CRP is a composite score which included 4 components: TJC with 28 joints assessed; SJC with 28 joints assessed; high-sensitivity CRP (in mg/L) and general health assessment by the subject using subject global assessment (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS). DAS28-CRP total score ranges from 0 to 10, where higher scores indicated greater disease activity. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Analysis was performed on safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subjects with available data for each specified category and “99999” was used as space filler which indicates that data was not planned to be collected and analysed for the specified time-points in the respective groups.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1872	110
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=1872, 110)	-2.50 ± 1.52	-2.99 ± 1.42
Week 4 (n=1866, 106)	-2.98 ± 1.38	-3.18 ± 1.31
Week 8 (n=1803, 105)	-3.12 ± 1.41	-3.21 ± 1.26
Week 12 (n=1818, 109)	-3.19 ± 1.41	-3.28 ± 1.29
Week 24 (n=1777, 109)	-3.28 ± 1.41	-3.43 ± 1.21
Week 36 (n=1720, 109)	-3.31 ± 1.43	-3.35 ± 1.23
Week 48 (n=1660, 107)	-3.35 ± 1.42	-3.36 ± 1.35
Week 60 (n=1607, 102)	-3.41 ± 1.41	-3.50 ± 1.28
Week 72 (n=1579, 101)	-3.41 ± 1.42	-3.61 ± 1.24
Week 84 (n=1536, 95)	-3.40 ± 1.45	-3.70 ± 1.19
Week 96 (n=1505, 92)	-3.46 ± 1.43	-3.59 ± 1.32
Week 120 (n=1443, 88)	-3.49 ± 1.45	-3.72 ± 1.20
Week 144 (n=1381, 83)	-3.51 ± 1.41	-3.79 ± 1.29
Week 168 (n=1309, 81)	-3.52 ± 1.45	-3.66 ± 1.30
Week 192 (n=1250, 76)	-3.55 ± 1.43	-3.61 ± 1.48
Week 216 (n=1175, 73)	-3.59 ± 1.43	-3.71 ± 1.24
Week 240 (n=1118, 73)	-3.57 ± 1.44	-3.90 ± 1.35
Week 264 (n=1036, 62)	-3.64 ± 1.39	-3.92 ± 1.36
Week 288 (n=715, 26)	-3.80 ± 1.38	-4.38 ± 1.33
Week 312 (n=655, 7)	-3.86 ± 1.34	-5.62 ± 0.86
Week 336 (n=540, 0)	-3.86 ± 1.34	99999 ± 99999
Week 360 (n=424, 0)	-3.93 ± 1.34	99999 ± 99999
Week 384 (n=334, 0)	-3.99 ± 1.36	99999 ± 99999
Week 408 (n=199, 0)	-3.85 ± 1.44	99999 ± 99999
Week 432 (n=106, 0)	-4.11 ± 1.35	99999 ± 99999
Week 456 (n=55, 0)	-4.01 ± 1.14	99999 ± 99999
Week 480 (n=39, 0)	-3.69 ± 1.47	99999 ± 99999
Week 504 (n=26, 0)	-3.76 ± 1.24	99999 ± 99999
Week 516 (n=2, 0)	-3.76 ± 2.32	99999 ± 99999

No statistical analyses for this end point

Secondary: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Scores at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

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End point title

Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Scores at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point description

HAQ-DI: standardised questionnaire used to assess degree of difficulty a subject has experienced during past week in 8 domains of daily living activities: dressing/grooming; arising; eating; walking; hygiene; reach; grip and activities. Total of 30 items distributed in these 8 domains. Each item was scored on 4-point scale from 0 to 3, where 0=no difficulty in physical function; 1=some difficulty in physical function; 2=much difficulty in physical function; 3=unable to do. Overall score was computed as sum of domain scores and divided by number of domains answered. Total possible score range 0 (least difficulty in physical function) to 3 (extreme difficulty in physical function), where higher scores=more difficulty while performing daily living activities. Baseline refers to Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subjects with available data.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1895	111
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=1895, 111)	-0.56 ± 0.63	-0.58 ± 0.59
Week 4 (n=1882, 109)	-0.59 ± 0.62	-0.57 ± 0.52
Week 8 (n=1858, 106)	-0.63 ± 0.63	-0.63 ± 0.53
Week 12 (n=1826, 109)	-0.65 ± 0.64	-0.65 ± 0.57
Week 24 (n=1787, 109)	-0.69 ± 0.65	-0.63 ± 0.60
Week 36 (n=1728, 109)	-0.70 ± 0.66	-0.67 ± 0.61
Week 48 (n=1667, 107)	-0.70 ± 0.66	-0.63 ± 0.60
Week 60 (n=1625, 103)	-0.70 ± 0.67	-0.67 ± 0.50
Week 72 (n=1586, 101)	-0.71 ± 0.66	-0.67 ± 0.59
Week 84 (n=1551, 95)	-0.71 ± 0.68	-0.68 ± 0.59
Week 96 (n=1509, 92)	-0.72 ± 0.67	-0.69 ± 0.58
Week 120 (n=1458, 89)	-0.74 ± 0.69	-0.67 ± 0.55
Week 144 (n=1386, 84)	-0.73 ± 0.70	-0.64 ± 0.61
Week 168 (n=1327, 81)	-0.74 ± 0.70	-0.61 ± 0.59
Week 192 (n=1268, 77)	-0.74 ± 0.71	-0.65 ± 0.65
Week 216 (n=1185, 70)	-0.75 ± 0.71	-0.62 ± 0.69
Week 240 (n=1127, 74)	-0.74 ± 0.72	-0.61 ± 0.64
Week 264 (n=998 , 57)	-0.76 ± 0.71	-0.54 ± 0.62

No statistical analyses for this end point

Secondary: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 0 and Week 48 of LTS11210: Campaign 1 X-ray Data - Subjects From EFC11072 Part B

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End point title

Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 0 and Week 48 of LTS11210: Campaign 1 X-ray Data - Subjects From EFC11072 Part B

End point description

Van der Heijde modified Sharp method is composite X-ray scoring system used to assess structural (joint) disease progression (DP) in RA. The method evaluates both joint erosions (JE) for 44 joints and joint space narrowing (JSN) for 42 joints in bilateral hand and foot joints. Total mTSS: sum of the scores from both erosion score and joint space narrowing score and ranged from 0 (normal, no progression) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Here, Baseline refers to the Baseline of initial study (EFC11072 Part B). In this endpoint, change from initial study baseline (CFISB) in 2 years X-ray data at Week 0 and 48 of LTS11210 were reported. Here, ‘number of subjects analysed’ = subjects from studies EFC11072 Part B evaluable for this endpoint and ‘n’=subjects with available data. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Week 0 and 48 of LTS11210

End point values	Sarilumab + DMARD: EFC11072 Part B
Number of subjects analysed	856
Units: score on scale
arithmetic mean (standard deviation)
Change at Week 0 (n=856)	1.05 ± 4.61
Change at Week 48 (n=848)	1.34 ± 5.31

No statistical analyses for this end point

Secondary: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 48 and Week 96 of LTS11210: Campaign 2 X-ray Data - Subjects From EFC11072 Part B

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End point title

Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 48 and Week 96 of LTS11210: Campaign 2 X-ray Data - Subjects From EFC11072 Part B

End point description

Van der Heijde modified Sharp method:composite X-ray scoring system to assess structural (joint) disease progression in RA. Method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS:sum of scores from both erosion score and joint space narrowing score and ranged from 0 (normal, no progression) to 448 (worst possible total score). Increase in total score=progression of structural damage. Baseline=Baseline of initial study (EFC11072 Part B). In this endpoint, CFISB in 3 years X-ray data (subjects with study duration of more than 48 weeks in LTS11210) at Week 48 and 96 from Campaign 2 were reported. Analysed on subset of subjects who previously completed study EFC11072, Part B with end of treatment X-ray evaluation. Number of subject analysed=subjects from study EFC11072 Part B evaluable for this endpoint and ‘n’=subjects with available data. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Week 48 and 96 of LTS11210

End point values	Sarilumab + DMARD: EFC11072 Part B
Number of subjects analysed	756
Units: score on scale
arithmetic mean (standard deviation)
Change at Week 48 (n=756)	1.60 ± 5.96
Change at Week 96 (n=755)	2.14 ± 7.20

No statistical analyses for this end point

Secondary: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 96, 144 and Week 192 of LTS11210: Campaign 3 X-ray Data - Subjects From EFC11072 Part B

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End point title

Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 96, 144 and Week 192 of LTS11210: Campaign 3 X-ray Data - Subjects From EFC11072 Part B

End point description

Van der Heijde modified Sharp method:composite X-ray scoring system to assess structural (joint) disease progression in RA. Method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS:sum of scores from both erosion score and joint space narrowing score and ranged from 0 (normal, no progression) to 448 (worst possible total score). Increase in total score=progression of structural damage. Baseline=Baseline of initial study (EFC11072 Part B). In this endpoint, CFISB in 5 years X-ray data (subjects with study duration of more than 96 weeks in LTS11210) at Week 96, 144 and 192 from Campaign 3 were reported. Analysed on subset of subjects who previously completed study EFC11072, Part B with end of treatment X-ray evaluation. Number of subjects analysed=subjects from studies EFC11072 Part B evaluable for this endpoint and ‘n’=subjects with data. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Week 96, 144 and 192 of LTS11210

End point values	Sarilumab + DMARD: EFC11072 Part B
Number of subjects analysed	699
Units: score on scale
arithmetic mean (standard deviation)
Change at Week 96 (n=699)	1.83 ± 7.76
Change at Week 144 (n=689)	2.24 ± 8.43
Change at Week 192 (n=656)	2.83 ± 9.42

No statistical analyses for this end point

Secondary: Percentage of Subjects With no Radiographic Progression of the Van Der Heijde Modified Total Sharp Score at Week 0 and 48 of LTS11210: Campaign 1 X-ray Data - Subjects From EFC11072 Part B

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End point title

Percentage of Subjects With no Radiographic Progression of the Van Der Heijde Modified Total Sharp Score at Week 0 and 48 of LTS11210: Campaign 1 X-ray Data - Subjects From EFC11072 Part B

End point description

Radiographic no progression: defined as a change from Baseline in Van der Heijde mTSS <= 0. Van der Heijde modified Sharp method is composite X-ray scoring system to assess structural (joint) disease progression in RA. Method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS = sum of scores from both erosion score and joint space narrowing score, ranged from 0 (normal, no progression) to 448 (worst possible total score). Increase in total score = progression of structural damage. In this endpoint, percentage (%) of subjects with no radiographic progression at Week 48 of LTS11210 from Campaign 1 X-ray data were reported. Analysed on subset of subjects who previously completed study EFC11072, Part B with end of treatment X-ray evaluation. Here, ‘number of subjects analysed’=subjects from studies EFC11072 Part B evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Week 0 (post-dose) and 48 of LTS11210

End point values	Sarilumab + DMARD: EFC11072 Part B
Number of subjects analysed	889
Units: percentage of subjects
number (not applicable)
Week 0	51.9
Week 48	51.2

No statistical analyses for this end point

Secondary: Percentage of Subjects With no Radiographic Progression of the Van Der Heijde Modified Total Sharp Score at Week 48 and 96 of LTS11210: Campaign 2 X-ray Data - Subjects From EFC11072 Part B

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End point title

Percentage of Subjects With no Radiographic Progression of the Van Der Heijde Modified Total Sharp Score at Week 48 and 96 of LTS11210: Campaign 2 X-ray Data - Subjects From EFC11072 Part B

End point description

Radiographic no progression:defined as change from Baseline in Van der Heijde mTSS <=0. Van der Heijde modified Sharp method:composite X-ray scoring system to assess structural (joint) DP in RA. Method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS=sum of scores from erosion score and joint space narrowing score, ranged from 0(normal, no progression) to 448(worst possible total score). Increase in total score=progression of structural damage. In this endpoint, % of subjects with no radiographic progression at Week 48 and 96 of LTS11210 from Campaign 2 X-ray data (subjects with study duration of more than 48 weeks in LTS11210) were reported. Analysed on subset of subjects who previously completed study EFC11072, Part B with end of treatment X-ray evaluation. Number of subjects analysed=subjects from study EFC11072 Part B evaluable for this endpoint. Data for this endpoint was not planned to be collected for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Week 48 and 96 of LTS11210

End point values	Sarilumab + DMARD: EFC11072 Part B
Number of subjects analysed	796
Units: percentage of subjects
number (not applicable)
Week 48	46.6
Week 96	44.2

No statistical analyses for this end point

Secondary: Percentage of Subjects With no Radiographic Progression of the Van Der Heijde Modified Total Sharp Score at Week 96, 144 and 192 of LTS11210: Campaign 3 X-ray Data - Subjects From EFC11072 Part B

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End point title

Percentage of Subjects With no Radiographic Progression of the Van Der Heijde Modified Total Sharp Score at Week 96, 144 and 192 of LTS11210: Campaign 3 X-ray Data - Subjects From EFC11072 Part B

End point description

Radiographic no progression:defined as change from Baseline in Van der Heijde mTSS <=0. Van der Heijde modified Sharp method:composite X-ray scoring system used to assess structural (joint) DP in RA. Method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS:sum of scores from erosion score and joint space narrowing score, ranged:0(normal, no progression) to 448(worst possible total score). Increase in total score=progression of structural damage. In this endpoint % of subjects with no radiographic progression at Week 96, 144 and 192 from Campaign 3 X-ray data (subjects with study duration more than 96 weeks in LTS11210) were reported. Analysed on subset of subjects who previously completed study EFC11072, Part B with end of treatment X-ray evaluation. Number of subjects analysed=subjects from studies EFC11072 Part B evaluable for endpoint. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Week 96, 144 and 192 of LTS11210

End point values	Sarilumab + DMARD: EFC11072 Part B
Number of subjects analysed	732
Units: percentage of subjects
number (not applicable)
Week 96	48.6
Week 144	46.0
Week 192	41.8

No statistical analyses for this end point

Secondary: Change From Baseline in Tender Joint Count (TJC) at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

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End point title

Change From Baseline in Tender Joint Count (TJC) at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point description

TJC is the sum of all tender joints based on examination of the 68 joints of the fingers, elbows, hips, knees, ankles, and toes. Total TJC ranged from 0 (best) to 68 (worst), where higher score = more severity. Change from Baseline in TJC was reported in the endpoint. Here, Baseline refers to Baseline of initial study (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Analysis was performed on safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subjects with available data for each specified category and “99999” was used as space filler which indicates that data was not planned to be collected and analysed for the specified time-points in the respective groups.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1904	111
Units: joints
arithmetic mean (standard deviation)
Week 0 (n=1904, 111)	-16.67 ± 14.05	-19.86 ± 12.43
Week 4 (n=1891, 109)	-18.97 ± 13.81	-20.13 ± 12.64
Week 8 (n=1867, 106)	-19.72 ± 13.61	-20.09 ± 11.73
Week 12 (n=1837, 109)	-20.20 ± 13.89	-20.05 ± 12.99
Week 24 (n=1791, 109)	-20.67 ± 14.09	-21.19 ± 12.55
Week 36 (n=1733, 109)	-20.68 ± 14.39	-20.60 ± 12.19
Week 48 (n=1674, 107)	-20.95 ± 14.04	-20.27 ± 13.54
Week 60 (n=1625, 103)	-21.29 ± 14.06	-20.95 ± 12.66
Week 72 (n=1589, 101)	-21.41 ± 13.98	-21.67 ± 12.65
Week 84 (n=1553, 95)	-21.53 ± 14.17	-21.36 ± 13.04
Week 96 (n=1514, 92)	-21.65 ± 14.08	-20.89 ± 13.50
Week 120 (n=1459, 88)	-21.92 ± 14.20	-20.18 ± 12.73
Week 144 (n=1394, 83)	-22.13 ± 14.01	-22.52 ± 13.41
Week 168 (n=1331, 81)	-22.35 ± 14.26	-22.42 ± 13.34
Week 192 (n=1269, 78)	-22.62 ± 14.20	-21.83 ± 13.79
Week 216 (n=1211, 76)	-22.69 ± 14.28	-22.33 ± 13.29
Week 240 (n=1136, 74)	-22.89 ± 14.47	-23.07 ± 14.24
Week 264 (n=1072, 62)	-23.09 ± 14.08	-23.66 ± 15.02
Week 288 (n=788, 26)	-22.59 ± 15.70	-28.95 ± 14.79
Week 312 (n=713, 7)	-23.47 ± 15.23	-43.71 ± 12.12
Week 336 (n=556, 0)	-23.37 ± 15.24	99999 ± 99999
Week 360 (n=442, 0)	-24.12 ± 14.89	99999 ± 99999
Week 384 (n=358, 0)	-24.73 ± 15.14	99999 ± 99999
Week 408 (n=226, 0)	-24.58 ± 14.97	99999 ± 99999
Week 432 (n=109, 0)	-25.33 ± 15.05	99999 ± 99999
Week 456 (n=59, 0)	-24.21 ± 14.37	99999 ± 99999
Week 480 (n=45, 0)	-21.23 ± 14.66	99999 ± 99999
Week 504 (n=27, 0)	-23.62 ± 13.63	99999 ± 99999
Week 516 (n=2, 0)	-24.00 ± 12.73	99999 ± 99999

No statistical analyses for this end point

Secondary: Change From Baseline in Swollen Joint Count (SJC) at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

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End point title

Change From Baseline in Swollen Joint Count (SJC) at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point description

SJC is the sum of all swollen joints based on examination of the fingers, elbows, knees and toes. Total SJC ranged from 0 (best) to 66 (worst), where higher score = more severity. Change from Baseline in SJC was reported in the endpoint. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Analysis was performed on safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subject with available data for each specified category and “99999” was used as space filler which indicates that data was not planned to be collected and analysed for the specified time-points in the respective groups.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1904	111
Units: joints
arithmetic mean (standard deviation)
Week 0 (n=1904, 111)	-11.36 ± 9.96	-14.06 ± 9.65
Week 4 (n=1891, 109)	-12.81 ± 9.77	-14.55 ± 9.19
Week 8 (n=1867, 106)	-13.43 ± 9.82	-14.60 ± 9.30
Week 12 (n=1837, 109)	-13.77 ± 10.13	-14.58 ± 9.31
Week 24 (n=1791, 109)	-14.28 ± 10.09	-14.83 ± 9.64
Week 36 (n=1733, 109)	-14.37 ± 9.99	-14.51 ± 9.70
Week 48 (n=1674, 107)	-14.53 ± 9.97	-14.96 ± 9.22
Week 60 (n=1625, 103)	-14.75 ± 10.20	-15.54 ± 9.49
Week 72 (n=1589, 101)	-14.76 ± 10.12	-15.43 ± 9.67
Week 84 (n=1553, 95)	-14.84 ± 10.16	-15.83 ± 9.50
Week 96 (n=1514, 92)	-15.03 ± 10.20	-15.51 ± 10.24
Week 120 (n=1459, 88)	-15.09 ± 10.17	-15.77 ± 9.95
Week 144 (n=1394, 83)	-15.18 ± 10.20	-15.90 ± 8.57
Week 168 (n=1331, 81)	-15.16 ± 10.30	-15.47 ± 8.91
Week 192 (n=1269, 78)	-15.26 ± 10.09	-15.01 ± 9.17
Week 216 (n=1211, 76)	-15.25 ± 9.97	-15.72 ± 8.65
Week 240 (n=1135, 74)	-15.43 ± 10.34	-15.59 ± 9.08
Week 264 (n=1072, 62)	-15.50 ± 9.79	-16.59 ± 9.53
Week 288 (n=788, 26)	-14.67 ± 10.98	-18.65 ± 8.90
Week 312 (n=713, 7)	-15.38 ± 10.71	-23.57 ± 9.83
Week 336 (n=556, 0)	-15.51 ± 10.48	99999 ± 99999
Week 360 (n=442, 0)	-15.96 ± 10.76	99999 ± 99999
Week 384 (n=358, 0)	-16.42 ± 10.76	99999 ± 99999
Week 408 (n=226, 0)	-16.30 ± 11.47	99999 ± 99999
Week 432 (n=109, 0)	-16.62 ± 11.51	99999 ± 99999
Week 456 (n=59, 0)	-15.64 ± 10.65	99999 ± 99999
Week 480 (n=45, 0)	-15.43 ± 10.67	99999 ± 99999
Week 504 (n=27, 0)	-16.21 ± 10.94	99999 ± 99999
Week 516 (n=2, 0)	-13.00 ± 2.83	99999 ± 99999

No statistical analyses for this end point

Secondary: Change From Baseline in Physician’s Global Assessments of Disease Activity Visual Analogue Scale (VAS) Score at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, and 264 of LTS11210

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End point title

Change From Baseline in Physician’s Global Assessments of Disease Activity Visual Analogue Scale (VAS) Score at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, and 264 of LTS11210

End point description

Physician global assessment of disease activity was measured on a 100 millimetres (mm) horizontal VAS, ranging from 0 (best disease activity) to 100 (worst disease activity), where lower score = less disease activity and higher score = more disease activity. Here, Baseline refers to Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Analysis was performed on safety population. Here, 'number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, and 264 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1903	110
Units: millimetres
arithmetic mean (standard deviation)
Week 0 (n=1903, 110)	-40.51 ± 23.82	-46.38 ± 19.17
Week 4 (n=1888, 109)	-43.98 ± 22.03	-47.94 ± 19.16
Week 8 (n=1863, 106)	-45.79 ± 22.06	-49.27 ± 18.80
Week 12 (n=1832, 109)	-47.02 ± 22.03	-50.20 ± 19.74
Week 24 (n=1786, 109)	-48.39 ± 21.94	-50.82 ± 19.99
Week 36 (n=1730, 109)	-48.94 ± 21.72	-51.12 ± 19.87
Week 48 (n=1675, 107)	-49.36 ± 21.68	-50.58 ± 21.38
Week 60 (n=1624, 103)	-49.98 ± 21.62	-51.40 ± 20.51
Week 72 (n=1586, 101)	-49.91 ± 21.72	-52.90 ± 19.40
Week 84 (n=1551, 94)	-50.28 ± 21.42	-55.84 ± 17.39
Week 96 (n=1512, 92)	-50.73 ± 21.62	-54.14 ± 18.97
Week 120 (n=1458, 88)	-50.43 ± 21.39	-54.33 ± 19.41
Week 144 (n=1390, 84)	-50.84 ± 21.13	-55.73 ± 18.04
Week 168 (n=1329, 81)	-50.49 ± 21.65	-53.21 ± 21.36
Week 192 (n=1264, 78)	-50.32 ± 22.00	-52.22 ± 22.44
Week 216 (n=1209, 76)	-51.49 ± 21.57	-54.67 ± 18.30
Week 240 (n=1133, 74)	-51.00 ± 21.57	-55.16 ± 18.82
Week 264 (n=1055, 63)	-51.18 ± 21.24	-55.27 ± 21.70

No statistical analyses for this end point

Secondary: Change From Baseline in Subject Global Assessment of Disease Activity Visual Analogue Scale Score at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

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End point title

Change From Baseline in Subject Global Assessment of Disease Activity Visual Analogue Scale Score at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point description

Subject global assessment of disease activity was measured on a 100 mm horizontal VAS, ranging from 0 (best disease activity) to 100 (worst disease activity), where lower score = less disease activity and higher score = more disease activity. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Analysis was performed on safety population. Here, number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subject with available data for each specified category and “99999” was used as space filler which indicates that data was not planned to be collected and analysed for the specified time-points in the respective groups.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504 and 516 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1904	111
Units: millimetres
arithmetic mean (standard deviation)
Week 0 (n=1904, 111)	-30.51 ± 26.78	-32.30 ± 27.55
Week 4 (n=1887, 109)	-32.87 ± 25.60	-33.63 ± 25.86
Week 8 (n=1863, 106)	-34.65 ± 26.25	-34.25 ± 25.90
Week 12 (n=1830, 109)	-35.60 ± 26.77	-34.24 ± 28.38
Week 24 (n=1785, 109)	-36.91 ± 26.50	-36.12 ± 27.82
Week 36 (n=1729, 109)	-37.08 ± 27.18	-37.13 ± 24.73
Week 48 (n=1674, 107)	-37.28 ± 26.93	-35.98 ± 28.18
Week 60 (n=1622, 103)	-37.79 ± 27.38	-37.82 ± 25.40
Week 72 (n=1589, 101)	-37.90 ± 27.26	-37.95 ± 26.53
Week 84 (n=1552, 95)	-37.45 ± 27.82	-40.52 ± 26.69
Week 96 (n=1512, 92)	-38.34 ± 27.34	-41.46 ± 26.57
Week 120 (n=1459, 89)	-38.41 ± 27.43	-41.67 ± 26.43
Week 144 (n=1394, 84)	-38.91 ± 27.52	-38.52 ± 26.40
Week 168 (n=1328, 81)	-38.22 ± 28.26	-37.27 ± 27.46
Week 192 (n=1267, 76)	-39.26 ± 28.16	-37.79 ± 32.12
Week 216 (n=1191, 74)	-39.96 ± 27.72	-38.72 ± 32.76
Week 240 (n=1133, 74)	-39.54 ± 27.79	-41.64 ± 30.13
Week 264 (n=1061, 62)	-39.87 ± 27.31	-37.84 ± 32.94
Week 288 (n=727, 26)	-43.68 ± 25.55	-48.00 ± 33.87
Week 312 (n=671, 7)	-44.05 ± 26.40	-65.71 ± 21.40
Week 336 (n=543, 0)	-43.42 ± 26.95	99999 ± 99999
Week 360 (n=445, 0)	-44.56 ± 26.59	99999 ± 99999
Week 384 (n=349, 0)	-47.19 ± 26.25	99999 ± 99999
Week 408 (n=214, 0)	-44.97 ± 29.16	99999 ± 99999
Week 432 (n=109, 0)	-49.77 ± 25.95	99999 ± 99999
Week 456 (n=58, 0)	-50.40 ± 24.27	99999 ± 99999
Week 480 (n=43, 0)	-46.65 ± 29.66	99999 ± 99999
Week 504 (n=27, 0)	-48.89 ± 28.83	99999 ± 99999
Week 516 (n=2,0)	-40.50 ± 36.06	99999 ± 99999

No statistical analyses for this end point

Secondary: Change From Baseline in Subject's Assessment of Pain Visual Analogue Scale Score at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, and 264 of LTS11210

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End point title

Change From Baseline in Subject's Assessment of Pain Visual Analogue Scale Score at Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, and 264 of LTS11210

End point description

Subjects were requested to indicate their pain intensity due to their RA on a 100 mm horizontal VAS, ranging from 0 (no pain) to 100 (worst pain), where a higher score represented more pain due to RA. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects evaluable for endpoint and ‘n’ = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, and 264 of LTS11210

End point values	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Number of subjects analysed	1897	111
Units: millimetres
arithmetic mean (standard deviation)
Week 0 (n=1897, 111)	-31.08 ± 27.45	-37.01 ± 28.73
Week 4 (n=1885, 109)	-34.04 ± 26.52	-37.53 ± 27.28
Week 8 (n=1859, 106)	-35.79 ± 26.88	-38.14 ± 27.16
Week 12 (n=1827, 109)	-36.46 ± 27.46	-39.08 ± 26.79
Week 24 (n=1784, 109)	-37.87 ± 27.07	-38.75 ± 28.12
Week 36 (n=1725, 109)	-37.60 ± 27.97	-39.56 ± 25.72
Week 48 (n=1671, 107)	-38.07 ± 28.33	-39.41 ± 30.12
Week 60 (n=1621, 103)	-38.46 ± 28.18	-40.79 ± 26.20
Week 72 (n=1587, 101)	-38.00 ± 28.54	-42.62 ± 27.33
Week 84 (n=1547, 95)	-38.37 ± 28.79	-42.38 ± 28.69
Week 96 (n=1510, 92)	-38.62 ± 28.57	-43.73 ± 27.59
Week 120 (n=1457, 89)	-39.29 ± 28.44	-44.11 ± 25.69
Week 144 (n=1392, 84)	-39.19 ± 28.21	-41.42 ± 27.31
Week 168 (n=1325, 81)	-39.47 ± 28.84	-38.86 ± 29.46
Week 192 (n=1266, 76)	-40.17 ± 28.98	-41.25 ± 30.44
Week 216 (n=1185, 70)	-40.25 ± 28.56	-44.01 ± 30.27
Week 240 (n=1129, 74)	-40.28 ± 28.44	-43.59 ± 29.22
Week 264 (n=1044, 62)	-41.02 ± 28.09	-40.71 ± 29.79

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 (SF-36; Version 2) Physical Component Summary (PCS) Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, ACT11575 and EFC10832 Only

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End point title

Change From Baseline in Short Form 36 (SF-36; Version 2) Physical Component Summary (PCS) Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, ACT11575 and EFC10832 Only

End point description

SF-36 is a generic 36-item questionnaire consisting of 8 domains, measuring quality of life (QoL) covering 2 summary measures: PCS and mental component summary (MCS). PCS with 4 domains: physical functioning, role limitations due to physical problems, bodily pain, and general health; and MCS with 4 domains: vitality, social functioning, role limitations due to emotional problems, and mental health. Each domain is scored by summing individual items, which are transformed into a score range from 0 to 100; where 0=worst QoL to 100=best QoL. PCS total score ranged from 0 to 100 with higher scores = better physical health. Here, Baseline refers to Baseline of initial studies (EFC11072, ACT11575 and EFC10832). Here, ‘number of subjects analysed’=subjects from studies EFC11072, ACT11575 and EFC10832 evaluable for this endpoint and ‘n’=subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, ACT11575 and EFC10832
Number of subjects analysed	1367
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=1301)	7.95 ± 8.29
Week 12 (n=1367)	8.84 ± 8.45
Week 24 (n=1339)	9.25 ± 8.59
Week 36 (n=1303)	9.72 ± 8.85
Week 48 (n=1269)	9.43 ± 8.89
Week 60 (n=1231)	9.64 ± 8.53
Week 72 (n=1213)	9.62 ± 8.78
Week 84 (n=1179)	9.95 ± 8.97
Week 96 (n=1143)	9.90 ± 8.90
Week 120 (n=1111)	10.18 ± 9.12
Week 144 (n=1065)	10.15 ± 9.18
Week 168 (n=1018)	10.24 ± 9.24
Week 192 (n=967)	10.34 ± 9.52
Week 216 (n=908)	10.15 ± 9.45
Week 240 (n=848)	10.38 ± 9.21
Week 264 (n=754)	10.32 ± 9.38

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 (SF-36; Version 2) Mental Component Summary Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, ACT11575 and EFC10832 Only

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End point title

Change From Baseline in Short Form 36 (SF-36; Version 2) Mental Component Summary Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, ACT11575 and EFC10832 Only

End point description

SF-36 is a generic 36-item questionnaire consisting of 8 domains, measuring QoL covering 2 summary measures: PCS and MCS. PCS with 4 domains: physical functioning, role limitations due to physical problems, bodily pain and general health; and MCS with 4 domains: vitality, social functioning, role limitations due to emotional problems and mental health. Each domain is scored by summing the individual items, which are transformed into a score range from 0 to 100; 0 = worst QoL to 100 = best QoL. MCS total score ranged from 0 to 100 with higher scores = better physical and mental health. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575 and EFC10832). Analysed on safety population. Here, ‘number of subjects analysed’=subjects from studies EFC11072, ACT11575 and EFC10832 evaluable for this endpoint and ‘n’=subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, ACT11575 and EFC10832
Number of subjects analysed	1367
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=1301)	6.43 ± 10.80
Week 12 (n=1367)	7.15 ± 11.03
Week 24 (n=1339)	7.43 ± 11.15
Week 36 (n=1303)	7.20 ± 11.31
Week 48 (n=1269)	7.48 ± 11.15
Week 60 (n=1231)	7.43 ± 11.21
Week 72 (n=1213)	7.25 ± 11.24
Week 84 (n=1179)	7.29 ± 11.20
Week 96 (n=1143)	7.47 ± 11.52
Week 120 (n=1111)	7.69 ± 11.62
Week 144 (n=1065)	7.22 ± 11.60
Week 168 (n=1018)	7.29 ± 11.52
Week 192 (n=967)	7.10 ± 11.51
Week 216 (n=908)	7.20 ± 11.91
Week 240 (n=848)	7.23 ± 12.03
Week 264 (n=754)	7.32 ± 12.08

No statistical analyses for this end point

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-fatigue) Total Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, ACT11575 and EFC10832 only

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-fatigue) Total Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, ACT11575 and EFC10832 only

End point description

The FACIT-F is a 13-item questionnaire assessing fatigue where subjects scored each item on a 5-point scale (0 to 4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. The sum of all responses resulted in the FACIT-Fatigue total score ranged from 0 to 52, where higher score = lower level of fatigue and indicates better QoL. A positive change from baseline score indicates an improvement. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, and EFC10832). Here, ‘number of subjects analysed’ = subjects from studies EFC11072, ACT11575 and EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, ACT11575 and EFC10832
Number of subjects analysed	1651
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=1342)	9.20 ± 10.05
Week 12 (n=1651)	10.26 ± 10.10
Week 24 (n=1621)	10.94 ± 10.31
Week 36 (n=1570)	10.91 ± 10.67
Week 48 (n=1520)	10.86 ± 10.64
Week 60 (n=1474)	10.97 ± 10.50
Week 72 (n=1444)	10.84 ± 10.68
Week 84 (n=1411)	10.75 ± 10.88
Week 96 (n=1372)	11.09 ± 10.85
Week 120 (n=1323)	11.18 ± 10.74
Week 144 (n=1262)	11.14 ± 10.86
Week 168 (n=1197)	11.00 ± 11.27
Week 192 (n=1141)	10.80 ± 11.10
Week 216 (n=1062)	11.12 ± 11.25
Week 240 (n=1013)	11.15 ± 11.21
Week 264 (n=910)	10.99 ± 11.19

No statistical analyses for this end point

Secondary: Change From Baseline in Sleep Visual Analogue Scale Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

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End point title

Change From Baseline in Sleep Visual Analogue Scale Score at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

End point description

Rheumatoid arthritis (RA), like other chronic illness, is associated with sleep disturbances and is linked to pain, mood, and disease activity. The effect of sarilumab on sleep was assessed on a on 100 mm horizontal VAS scale, ranging from 0 (sleep is not a problem) to 100 (sleep is a major problem), where higher score = more sleep disturbances. Here, Baseline refers to the Baseline of initial studies (EFC11072, and ACT11575). Analysis was performed on safety population. Here, ‘number of subjects analyed’ = subjects from studies EFC11072, and ACT11575 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, and ACT11575
Number of subjects analysed	1231
Units: millimetres
arithmetic mean (standard deviation)
Week 0 (n=894)	-24.58 ± 30.96
Week 12 (n=1231)	-26.11 ± 30.59
Week 24 (n=1206)	-26.44 ± 30.94
Week 36 (n=1164)	-27.37 ± 31.52
Week 48 (n=1132)	-26.15 ± 31.37
Week 60 (n=1098)	-26.98 ± 31.24
Week 72 (n=1075)	-26.85 ± 32.16
Week 84 (n=1051)	-25.81 ± 31.90
Week 96 (n=1024)	-26.91 ± 31.63
Week 120 (n=983)	-27.63 ± 32.26
Week 144 (n=940)	-26.90 ± 31.54
Week 168 (n=892)	-27.33 ± 33.25
Week 192 (n=853)	-26.87 ± 32.03
Week 216 (n=802)	-28.58 ± 31.46
Week 240 (n=755)	-27.72 ± 33.07
Week 264 (n=705)	-27.71 ± 32.08

No statistical analyses for this end point

Secondary: Change From Baseline in Work Productivity and Activity Impairment (WPAI): Percent Work Time Missed due to RA at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072 and ACT11575 only

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End point title

Change From Baseline in Work Productivity and Activity Impairment (WPAI): Percent Work Time Missed due to RA at Week 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072 and ACT11575 only

End point description

WPAI assesses work productivity and impairment. It is 6-item questionnaire to assess degree to which RA affected work productivity and regular activities over past 7 days. Questions were: Q1=currently employed; Q2=hours missed due to RA; Q3=hours missed due to other reasons; Q4=hours actually worked; Q5=RA affected productivity while working (0-10 scale, with higher numbers=less productivity); Q6=RA affected regular activities (0-10 scale, higher numbers=greater impairment). Percent work time missed due to RA was subscale and calculated: 100*Q2/(Q2+Q4) for those who were currently employed. Subscale score was expressed as impairment percentage (range:0 to 100%) where higher numbers=greater impairment and less productivity. Baseline=Baseline of initial studies (EFC11072 and ACT11575). Safety population. Number of subjects analysed=subjects from studies EFC11072 and ACT11575 evaluable for this endpoint & 'n'=with data. Data was not planned to be collected for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Week 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, and ACT11575
Number of subjects analysed	267
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=191)	-10.82 ± 30.64
Week 12 (n=267)	-8.62 ± 28.67
Week 24 (n=255)	-11.92 ± 29.33
Week 36 (n=251)	-9.62 ± 30.08
Week 48 (n=243)	-11.39 ± 29.92
Week 60 (n=236)	-10.03 ± 25.74
Week 72 (n=216)	-9.10 ± 28.14
Week 84 (n=206)	-8.20 ± 27.06
Week 96 (n=209)	-11.32 ± 30.28
Week 120 (n=189)	-8.62 ± 32.95
Week 144 (n=183)	-9.01 ± 30.16
Week 168 (n=176)	-10.38 ± 31.48
Week 192 (n=166)	-8.99 ± 29.24
Week 216 (n=147)	-11.17 ± 29.35
Week 240 (n=147)	-8.57 ± 26.11
Week 264 (n=133)	-13.40 ± 30.57

No statistical analyses for this end point

Secondary: Change From Baseline in Work Productivity and Activity Impairment: Percent Impairment While Working due to RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

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End point title

Change From Baseline in Work Productivity and Activity Impairment: Percent Impairment While Working due to RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

End point description

WPAI assesses work productivity & impairment. It is 6-item questionnaire to assess degree to which RA affected work productivity & regular activities over past 7 days. Questions: Q1=currently employed; Q2=hours(hrs) missed due to RA; Q3=hrs missed due to other reasons; Q4=hrs actually worked; Q5=RA affected productivity while working (0-10 scale, higher numbers=less productivity); Q6=RA affected regular activities (0-10 scale, higher numbers=greater impairment). Percent impairment while working was subscale and calculated: 10*Q5 for those who were currently employed & actually worked in past 7 days. Subscale score=expressed as impairment percentage (range:0-100%), where higher numbers=greater impairment and less productivity. Baseline:Baseline of initial studies (EFC11072 & ACT11575). Safety population. Number of subjects analysed=subjects from studies EFC11072 & ACT11575 evaluable for this endpoint and 'n'=with data. Data was not planned to be collected for Sarilumab monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, and ACT11575
Number of subjects analysed	273
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=194)	-21.65 ± 27.74
Week 12 (n=273)	-22.16 ± 26.53
Week 24 (n=258)	-23.45 ± 26.70
Week 36 (n=254)	-27.01 ± 27.11
Week 48 (n=252)	-24.76 ± 26.05
Week 60 (n=240)	-25.17 ± 25.12
Week 72 (n=224)	-24.33 ± 27.57
Week 84 (n=214)	-24.02 ± 27.09
Week 96 (n=212)	-26.42 ± 27.11
Week 120 (n=189)	-24.02 ± 27.63
Week 144 (n=184)	-24.67 ± 28.20
Week 168 (n=181)	-24.25 ± 28.46
Week 192 (n=168)	-25.24 ± 26.60
Week 216 (n=147)	-24.56 ± 27.28
Week 240 (n=155)	-24.39 ± 26.48
Week 264 (n=135)	-25.26 ± 27.40

No statistical analyses for this end point

Secondary: Change From Baseline in Work Productivity and Activity Impairment: Percent Overall Work Impairment due to RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

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End point title

Change From Baseline in Work Productivity and Activity Impairment: Percent Overall Work Impairment due to RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

End point description

WPAI assesses work productivity and impairment. It is 6-item questionnaire to assess degree to which RA affected work productivity & regular activities over past 7 days. Questions were: Q1=currently employed; Q2=hrs missed due to RA; Q3=hrs missed due to other reasons;Q4=hrs actually worked; Q5=RA affected productivity while working (0-10 scale, higher numbers=less productivity); Q6=RA affected regular activities (0-10 scale, higher numbers=greater impairment). Percent overall work impairment due to RA was subscale and calculated: 100*Q2/(Q2+Q4)+100*[(1- Q2/(Q2+Q4))*(Q5/10)] for those who were currently employed . Subscale score=expressed as impairment percentage (range:0-100%) where higher numbers=greater impairment. Baseline: Baseline of initial studies (EFC11072 and ACT11575). Safety population. Number of subjects analysed=subjects from studies EFC11072, and ACT11575 evaluable for this endpoint and 'n'=with data. Data was not planned to be collected for Sarilumab monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, and ACT11575
Number of subjects analysed	246
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=172)	-22.84 ± 30.73
Week 12 (n=246)	-23.13 ± 27.98
Week 24 (n=232)	-25.39 ± 28.84
Week 36 (n=230)	-28.13 ± 29.01
Week 48 (n=223)	-24.72 ± 29.38
Week 60 (n=222)	-26.44 ± 28.03
Week 72 (n=200)	-25.06 ± 29.84
Week 84 (n=193)	-23.62 ± 29.25
Week 96 (n=193)	-27.06 ± 30.60
Week 120 (n=172)	-24.15 ± 31.14
Week 144 (n=168)	-23.97 ± 32.05
Week 168 (n=162)	-24.59 ± 31.16
Week 192 (n=155)	-24.77 ± 29.63
Week 216 (n=136)	-24.54 ± 31.55
Week 240 (n=140)	-25.05 ± 29.26
Week 264 (n=122)	-27.10 ± 28.75

No statistical analyses for this end point

Secondary: Change From Baseline in Work Productivity and Activity Impairment: Percent Activity Impairment due to RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

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End point title

Change From Baseline in Work Productivity and Activity Impairment: Percent Activity Impairment due to RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210 - Subjects From EFC11072, and ACT11575 only

End point description

WPAI assesses work productivity and impairment. It is 6-item questionnaire to assess degree to which RA affected work productivity & regular activities over past 7 days. Questions: Q1=currently employed; Q2=hrs missed due to RA; Q3=hrs missed due to other reasons; Q4=hrs actually worked; Q5=RA affected productivity while working (0 to 10 scale, with higher numbers indicated less productivity); Q6 = RA affected regular activities (0-10 scale, with higher numbers=greater impairment). Percent activity impairment due to RA was a subscale and calculated as: 10*Q6 for all respondents. Subscale score=expressed as impairment percentage (range: 0-100%) where higher numbers indicate greater impairment. Here, Baseline: Baseline of initial studies (EFC11072 and ACT11575). Safety population. Here, ‘number of subjects analysed’=subjects from studies EFC11072, and ACT11575 evaluable for this endpoint and ‘n'=subjects with data. Data was not planned to be collected for Sarilumab Monotherapy arm.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC11072, and ACT11575
Number of subjects analysed	1157
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=846)	-26.47 ± 29.30
Week 12 (n=1157)	-28.02 ± 27.44
Week 24 (n=1121)	-28.76 ± 27.62
Week 36 (n=1095)	-29.71 ± 28.03
Week 48 (n=1061)	-29.11 ± 28.28
Week 60 (n=1034)	-29.81 ± 27.78
Week 72 (n=1013)	-29.61 ± 29.02
Week 84 (n=985)	-30.28 ± 29.53
Week 96 (n=954)	-30.28 ± 28.32
Week 120 (n=924)	-30.42 ± 28.78
Week 144 (n=883)	-30.29 ± 28.90
Week 168 (n=840)	-30.64 ± 29.30
Week 192 (n=804)	-30.88 ± 29.36
Week 216 (n=753)	-30.36 ± 29.34
Week 240 0 (n=722)	-31.12 ± 29.63
Week 264 (n=645)	-31.97 ± 28.77

No statistical analyses for this end point

Secondary: Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Work Days Missed Due to Arthritis - Subjects From EFC10832 Only

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End point title

Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Work Days Missed Due to Arthritis - Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with arthritis over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Change from Baseline in number of work days missed in the last month due to arthritis by the subject was reported in the endpoint. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	145
Units: days
arithmetic mean (standard deviation)
Week 0 (n=145)	-2.72 ± 6.38
Week 12 (n=127)	-3.66 ± 6.80
Week 24 (n=125)	-3.70 ± 6.85
Week 36 (n=121)	-3.73 ± 7.08
Week 48 (n=116)	-3.37 ± 7.18
Week 60 (n=114)	-3.55 ± 6.93
Week 72 (n=111)	-3.58 ± 7.07
Week 84 (n=106)	-3.11 ± 8.49
Week 96 (n=101)	-3.47 ± 7.57
Week 120 (n=101)	-3.54 ± 7.56
Week 144 (n=94)	-3.51 ± 6.84
Week 168 (n=88)	-3.73 ± 7.37
Week 192 (n=80)	-3.76 ± 7.21
Week 216 (n=74)	-3.51 ± 7.30
Week 240 (n=73)	-2.44 ± 6.70
Week 264 (n=66)	-2.86 ± 5.83

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Work Productivity Reduced by >=50% Due to Arthritis - Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Work Productivity Reduced by >=50% Due to Arthritis - Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subjects self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Change from Baseline in number of work days with work productivity reduced by >= 50% by the subjects was reported in the endpoint. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	145
Units: days
arithmetic mean (standard deviation)
Week 0 (n=145)	-3.47 ± 7.64
Week 12 (n=126)	-4.93 ± 9.22
Week 24 (n=123)	-5.14 ± 7.67
Week 36 (n=122)	-5.47 ± 8.41
Week 48 (n=115)	-5.75 ± 8.14
Week 60 (n=114)	-5.16 ± 7.96
Week 72 (n=110)	-5.21 ± 7.74
Week 84 (n=105)	-4.40 ± 8.27
Week 96 (n=101)	-5.03 ± 6.91
Week 120 (n=101)	-4.63 ± 7.47
Week 144 (n=94)	-4.88 ± 7.53
Week 168 (n=88)	-4.67 ± 7.06
Week 192 (n=80)	-4.55 ± 7.25
Week 216 (n=74)	-4.42 ± 8.01
Week 240 (n=73)	-3.48 ± 7.56
Week 264 (n=66)	-3.97 ± 5.02

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Arthritis Interference With Work Productivity - Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Arthritis Interference With Work Productivity - Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subejct self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Interference in the last month with work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference), where higher scores indicated more interference. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	144
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=144)	-20.83 ± 30.51
Week 12 (n=127)	-27.95 ± 58.67
Week 24 (n=124)	-35.16 ± 31.45
Week 36 (n=123)	-37.48 ± 33.72
Week 48 (n=115)	-36.78 ± 31.58
Week 60 (n=115)	-40.35 ± 33.19
Week 72 (n=111)	-38.74 ± 32.73
Week 84 (n=106)	-39.62 ± 41.56
Week 96 (n=102)	-42.35 ± 32.19
Week 120 (n=102)	-37.84 ± 32.32
Week 144 (n=95)	-39.16 ± 32.28
Week 168 (n=90)	-38.11 ± 32.25
Week 192 (n=81)	-40.74 ± 34.96
Week 216 (n=74)	-39.19 ± 37.00
Week 240 0 (n=73)	-38.22 ± 38.24
Week 264 (n=66)	-39.24 ± 36.09

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: House Work Days Missed due to Arthritis - Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: House Work Days Missed due to Arthritis - Subjects From EFC10832 Only

End point description

'The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Change from baseline in number of days with no household work//household work missed in the last month by the subjects was reported. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol. '

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	446
Units: days
arithmetic mean (standard deviation)
Week 0 (n=446)	-4.65 ± 9.44
Week 12 (n=401)	-6.17 ± 10.29
Week 24 4 (n=397)	-6.55 ± 9.92
Week 36 (n=388)	-6.65 ± 10.36
Week 48 (n=373)	-6.61 ± 10.57
Week 60 (n=364)	-6.84 ± 10.47
Week 72 (n=355)	-6.50 ± 10.72
Week 84 (n=343)	-6.56 ± 10.63
Week 96 (n=336)	-6.80 ± 10.32
Week 120 (n=323)	-6.81 ± 10.31
Week 144 (n=309)	-6.78 ± 10.67
Week 168 (n=283)	-7.04 ± 10.13
Week 192 (n=274)	-6.74 ± 10.51
Week 216 (n=261)	-6.78 ± 10.07
Week 240 (n=243)	-6.82 ± 10.02
Week 264 (n=230)	-6.95 ± 10.16

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Household Work Productivity Reduced by >=50% Due to Arthritis - Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Household Work Productivity Reduced by >=50% Due to Arthritis - Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Change from baseline in number of days with reduced household work productivity by >= 50% in the last month by the subjects was reported. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n' = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	445
Units: days
arithmetic mean (standard deviation)
Week 0 (n=445)	-4.08 ± 10.24
Week 12 (n=402)	-5.64 ± 10.93
Week 24 (n=395)	-6.01 ± 10.40
Week 36 (n=387)	-6.57 ± 10.29
Week 48 (n=372)	-7.06 ± 10.13
Week 60 (n=363)	-7.01 ± 10.30
Week 72 (n=353)	-6.70 ± 10.72
Week 84 (n=342)	-6.38 ± 10.79
Week 96 (n=334)	-7.05 ± 10.62
Week 120 (n=322)	-7.12 ± 10.37
Week 144 (n=308)	-6.58 ± 10.59
Week 168 (n=284)	-6.39 ± 10.28
Week 192 (n=274)	-6.01 ± 10.07
Week 216 (n=259)	-6.27 ± 10.30
Week 240 (n=241)	-6.31 ± 9.99
Week 264 (n=229)	-6.93 ± 9.43

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Family/Social/Leisure Activities Missed Due to Arthritis - Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Family/Social/Leisure Activities Missed Due to Arthritis - Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Change from baseline in number of days missed of family/social/leisure activities in the last month by the subjects was reported. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	447
Units: days
arithmetic mean (standard deviation)
Week 0 (n=447)	-2.94 ± 8.34
Week 12 (n=401)	-4.16 ± 8.38
Week 24 (n=397)	-4.50 ± 8.42
Week 36 (n=388)	-4.38 ± 8.88
Week 48 (n=373)	-4.44 ± 8.51
Week 60 (n=364)	-4.46 ± 8.31
Week 72 (n=354)	-4.20 ± 8.52
Week 84 (n=343)	-4.31 ± 8.30
Week 96 (n=335)	-4.38 ± 8.03
Week 120 (n=323)	-4.43 ± 8.01
Week 144 (n=309)	-4.17 ± 7.90
Week 168 (n=285)	-4.12 ± 8.16
Week 192 (n=272)	-4.23 ± 8.17
Week 216 (n=261)	-3.93 ± 8.03
Week 240 (n=242)	-4.03 ± 8.26
Week 264 (n=230)	-3.85 ± 7.65

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Outside Help Hired Due to Arthritis- Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Days With Outside Help Hired Due to Arthritis- Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Change from baseline in number of days with outside help hired in the last month by the subject was reported. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	446
Units: days
arithmetic mean (standard deviation)
Week 0 (n=446)	-2.92 ± 10.14
Week 12 (n=401)	-4.24 ± 10.16
Week 24 (n=397)	-4.12 ± 10.47
Week 36 (n=388)	-4.28 ± 10.27
Week 48 (n=373)	-4.58 ± 10.12
Week 60 (n=364)	-4.21 ± 10.16
Week 72 (n=354)	-4.00 ± 9.52
Week 84 (n=343)	-3.81 ± 9.67
Week 96 (n=335)	-3.90 ± 10.11
Week 120 (n=323)	-3.90 ± 9.62
Week 144 (n=309)	-3.91 ± 9.73
Week 168 (n=285)	-4.14 ± 10.00
Week 192 (n=273)	-3.93 ± 10.14
Week 216 (n=261)	-4.19 ± 9.84
Week 240 (n=242)	-4.12 ± 10.43
Week 264 (n=230)	-4.05 ± 9.67

No statistical analyses for this end point

Secondary: Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Arthritis Interference With Household Work Productivity - Subjects From EFC10832 Only

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End point title

Change From Baseline in WPS-RA at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210: Arthritis Interference With Household Work Productivity - Subjects From EFC10832 Only

End point description

The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire was interviewer-administered and was based on subject self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). The RA interference in the last month with household work productivity was measured on a scale that ranged from 0 (no interference) to 10 (complete interference), where higher scores indicated more interference. Here, Baseline refers to the Baseline of initial study (EFC10832). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects from study EFC10832 evaluable for this endpoint and ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for Sarilumab Monotherapy arm, as pre-specified in the protocol.

End point type

Secondary

End point timeframe

Baseline, Weeks 0 (post-dose), 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240 and 264 of LTS11210

End point values	Sarilumab + DMARD: EFC10832
Number of subjects analysed	444
Units: units on a scale
arithmetic mean (standard deviation)
Week 0 (n=444)	-23.24 ± 35.09
Week 12 (n=401)	-33.49 ± 35.76
Week 24 (n=399)	-36.94 ± 36.75
Week 36 (n=388)	-36.42 ± 39.35
Week 48 (n=373)	-37.45 ± 34.85
Week 60 (n=365)	-38.19 ± 34.55
Week 72 (n=355)	-36.48 ± 35.37
Week 84 (n=344)	-35.61 ± 39.69
Week 96 (n=335)	-36.81 ± 36.04
Week 120 (n=324)	-38.86 ± 35.22
Week 144 (n=310)	-36.23 ± 37.52
Week 168 (n=286)	-36.01 ± 39.84
Week 192 (n=274)	-35.80 ± 40.99
Week 216 (n=260)	-38.54 ± 39.81
Week 240 (n=240)	-40.08 ± 35.68
Week 264 (n=228)	-38.07 ± 42.39

No statistical analyses for this end point

Secondary: Sub-study: Number of subjects who Reported Adverse Events Related to Pre-filled Syringe With Safety System

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End point title

Sub-study: Number of subjects who Reported Adverse Events Related to Pre-filled Syringe With Safety System

End point description

AEs related to PFS-S included PTC-related AEs, device-related AEs, or AEs of injection site reaction. In this endpoint, only PTC-related AEs, device-related AEs, or AEs of injection site reaction assessed during the sub-study were reported. TEAEs and SAEs reported during the sub-study were included in the main study data and no separate data collection and analysis was performed, as pre-planned in the protocol. Analysis was performed on all subjects who were enrolled in the sub-study.

End point type

Secondary

End point timeframe

From Week 24 to 36

End point values	PFS-S Sarilumab 150 mg q2w	PFS-S Sarilumab 200 mg q2w	PFS-S Sarilumab 200 to 150 mg q2w
Number of subjects analysed	25	98	1
Units: subejcts
PTC-related AEs	0	0	0
Device-related AEs	0	0	0
AEs of injection site reaction	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose (i.e., Day 1 of study LTS11210) of IMP to last dose of IMP + 60 days (maximum duration: up to 523 weeks)

Adverse event reporting additional description

Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as time from 1st dose of IMP to last dose of IMP + 60 days). As pre-specified and initially planned, TEAEs and SAEs reported during sub-study were included in the main study data and no separate analysis was done. Safety population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)

Reporting group description

Subjects who completed any of initial studies:Part A or B of EFC11072, ACT11575, EFC10832 or SFY13370 were enrolled in LTS11210 and received sarilumab 150 milligrams (mg) subcutaneously (SC) once weekly (qw). Dose could be reduced to 150 mg every 2 weeks (q2w) due to neutropenia, thrombocytopenia or increase in liver enzymes (alanine aminotransferase [ALT]). After dose regimens selection for Phase 3 studies (150 mg q2w and 200 mg q2w), subjects already receiving 150 mg qw were switched to sarilumab 200 mg q2w. Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks). Subjects who were already taking concomitant non-biologic DMARDs in initial study continued stable dose of one or combination of conventional synthetic DMARDs they were taking.

Reporting group title

Sarilumab monotherapy

Reporting group description

Subjects who completed study EFC13752 were enrolled in LTS11210 and received sarilumab 200 mg q2w. Dose could be reduced to 150 mg q2w due to neutropenia, thrombocytopenia or increase in liver enzymes (ALT). Treatment duration per subject was at least 264 weeks from first study drug administration in LTS11210. Subjects continued to be treated beyond 264 weeks until sarilumab was commercially available in their respective countries or until 2020, at the latest (maximum duration: 523 weeks).

Serious adverse events	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	617 / 1910 (32.30%)	27 / 111 (24.32%)
number of deaths (all causes)	49	3
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Of Colon
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ameloblastoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal Squamous Cell Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
B-Cell Lymphoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basal Cell Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Benign Neoplasm Of Thyroid Gland
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder Cancer Stage Ii
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast Cancer Stage Ii
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervix Cancer Metastatic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Cholesteatoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clear Cell Renal Cell Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal Adenocarcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal Cancer Metastatic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Eye Naevus
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fibroadenoma Of Breast
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fibroma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder Cancer Metastatic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Invasive Ductal Breast Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung Adenocarcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Lung Cancer Metastatic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung Carcinoma Cell Type Unspecified Stage Iii
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung Neoplasm Malignant
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant Melanoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic Renal Cell Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neoplasm Malignant
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Non-Small Cell Lung Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ovarian Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian Germ Cell Teratoma Benign
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Papillary Thyroid Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parathyroid Tumour Benign
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pituitary Tumour Benign
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleomorphic Adenoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatic Adenoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Refractory Anaemia With An Excess Of Blasts
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal Cell Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Serous Cystadenocarcinoma Ovary
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin Cancer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small Intestine Carcinoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous Cell Carcinoma Of Skin
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous Cell Carcinoma Of The Cervix
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine Leiomyoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	7 / 1910 (0.37%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Accelerated Hypertension
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic Embolus
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep Vein Thrombosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	8 / 1910 (0.42%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive Crisis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic Shock
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Iliac Artery Embolism
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic Venous Thrombosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral Artery Occlusion
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral Embolism
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral Ischaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral Venous Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicose Vein
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous Thrombosis Limb
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion Missed
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion Spontaneous
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Cardiac Death
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chills
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Multiple Organ Dysfunction Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Non-Cardiac Chest Pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden Death
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyrexia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Social circumstances
Pregnancy Of Partner
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Acquired Hydrocele
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adnexa Uteri Cyst
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Benign Prostatic Hyperplasia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast Enlargement
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast Hyperplasia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical Dysplasia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical Polyp
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial Hyperplasia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometriosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Menometrorrhagia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Menorrhagia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian Cyst
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic Prolapse
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine Prolapse
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute Respiratory Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Asthma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial Hyperreactivity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic Obstructive Pulmonary Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diaphragmatic Abnormal Relaxation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Emphysema
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Epistaxis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Idiopathic Pulmonary Fibrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial Lung Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung Infiltration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural Effusion
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia Aspiration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax Spontaneous
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary Embolism
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	10 / 1910 (0.52%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	1 / 10	0 / 3
deaths causally related to treatment / all	1 / 2	0 / 0
Pulmonary Fibrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary Hypertension
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary Mass
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sleep Apnoea Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Acute Psychosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol Abuse
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bipolar Disorder
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Conversion Disorder
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Major Depression
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mixed Anxiety And Depressive Disorder
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Paranoia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal Ideation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide Attempt
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device Breakage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device Dislocation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device Loosening
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device Malfunction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine Aminotransferase Increased
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	9 / 1910 (0.47%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	7 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal Test Positive
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hiv Test False Positive
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil Count Decreased
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oxygen Saturation Decreased
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases Increased
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal Injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Accidental Overdose
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol Poisoning
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Anaemia Postoperative
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bite
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Comminuted Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral Injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dislocation Of Vertebra
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral Neck Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	8 / 1910 (0.42%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	7 / 1910 (0.37%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foot Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fractured Sacrum
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal Stoma Complication
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gun Shot Wound
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incision Site Fibrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incisional Hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint Dislocation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament Sprain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower Limb Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple Injuries
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Patella Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital Haematoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periprosthetic Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periprosthetic Osteolysis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post Procedural Fistula
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post Procedural Haematoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post Procedural Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural Pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural Shock
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radius Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Compression Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural Haematoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon Rupture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal Burn
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity To Various Agents
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ulna Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute Coronary Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute Left Ventricular Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute Myocardial Infarction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	11 / 1910 (0.58%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	3 / 11	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina Pectoris
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina Unstable
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial Fibrillation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	9 / 1910 (0.47%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	2 / 11	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial Flutter
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial Tachycardia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular Block Complete
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiac Failure Acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac Failure Congestive
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac Tamponade
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-Respiratory Arrest
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiogenic Shock
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiomyopathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Congestive Cardiomyopathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary Artery Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary Artery Perforation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary Artery Stenosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Left Ventricular Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Microvascular Coronary Artery Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial Infarction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial Ischaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus Node Dysfunction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular Tachycardia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular Asystole
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular Fibrillation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Amnesia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Carpal Tunnel Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar Stroke
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral Haematoma
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral Infarction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular Accident
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebrovascular Insufficiency
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed Level Of Consciousness
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage Intracranial
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haemorrhagic Stroke
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic Transformation Stroke
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intraventricular Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ischaemic Stroke
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar Radiculopathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multifocal Motor Neuropathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myelopathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Partial Seizures
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral Sensory Neuropathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiculopathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ruptured Cerebral Aneurysm
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Sciatica
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Syncope
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient Global Amnesia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient Ischaemic Attack
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular Headache
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Anaemia Megaloblastic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood Loss Anaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone Marrow Failure
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile Neutropenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Iron Deficiency Anaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphatic Insufficiency
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	11 / 1910 (0.58%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	12 / 12	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spontaneous Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Eye disorders
Cataract
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Central Vision Loss
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Choroiditis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dry Age-Related Macular Degeneration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Macular Hole
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neovascular Age-Related Macular Degeneration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Optic Ischaemic Neuropathy
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal Vascular Thrombosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicolith
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic Gastritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Crohn's Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticular Perforation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum Intestinal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum Intestinal Haemorrhagic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal Perforation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterovesical Fistula
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral Hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric Ulcer Perforation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal Inflammation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal Reflux Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoidal Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hernial Eventration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hiatus Hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileal Perforation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated Umbilical Hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inflammatory Bowel Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal Hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal Dilatation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal Obstruction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Irritable Bowel Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large Intestine Perforation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Noninfectious Peritonitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic Necrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic Pseudocyst Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis Acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis Necrotising
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal Adhesions
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small Intestinal Obstruction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Rectal Prolapse
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Umbilical Hernia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper Gastrointestinal Haemorrhage
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile Duct Stone
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	9 / 1910 (0.47%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis Acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	24 / 1910 (1.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 24	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis Chronic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis Obstructive
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Portosplenomesenteric Venous Thrombosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Cutaneous Lupus Erythematosus
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decubitus Ulcer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dermatomyositis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema Multiforme
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin Necrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin Ulcer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous Emphysema
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic Skin Eruption
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus Urinary
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis Haemorrhagic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hydronephrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	7 / 1910 (0.37%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal Colic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral Stenosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary Incontinence
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Goitre
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroiditis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroiditis Subacute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Ankle Deformity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atlantoaxial Subluxation
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back Pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone Cyst
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bursitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Costochondritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fasciitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Flank Pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Foot Deformity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	14 / 1910 (0.73%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 19	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hand Deformity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral Disc Degeneration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral Disc Disorder
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral Disc Protrusion
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint Destruction
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Knee Deformity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar Spinal Stenosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	45 / 1910 (2.36%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 52	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoporotic Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological Fracture
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid Arthritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	32 / 1910 (1.68%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	3 / 33	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid Nodule
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator Cuff Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Osteoarthritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Stenosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spondylolisthesis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Synovitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist Deformity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess Limb
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess Neck
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess Oral
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess Soft Tissue
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute Sinusitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous Graft Site Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis Bacterial
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	5 / 7	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis Infective
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical Pneumonia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial Dacryocystitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bartholin's Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone Tuberculosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis Fungal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bullous Erysipelas
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bursitis Infective
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Covid-19 Pneumonia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Carbuncle
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	21 / 1910 (1.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	15 / 24	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis Staphylococcal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis Infective
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium Difficile Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	2 / 111 (1.80%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Coccidioidomycosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colonic Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dengue Fever
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device Related Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea Infectious
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	7 / 1910 (0.37%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	2 / 7	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis Infectious
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epiglottitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	0 / 1910 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia Urinary Tract Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extradural Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gas Gangrene
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis Bacterial
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis Salmonella
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis Viral
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes Ophthalmic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes Zoster
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	5 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Histoplasmosis Disseminated
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Infected Bite
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected Skin Ulcer
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	5 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious Pleural Effusion
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Infective Exacerbation Of Bronchiectasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infective Exacerbation Of Chronic Obstructive Airways Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large Intestine Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leptospirosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Localised Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lyme Disease
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Medical Device Site Joint Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis Viral
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningoencephalitis Herpetic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Necrotising Fasciitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Necrotising Soft Tissue Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ophthalmic Herpes Zoster
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral Candidiasis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	3 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis Acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreas Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Perineal Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	7 / 1910 (0.37%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	3 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	52 / 1910 (2.72%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	25 / 55	0 / 1
deaths causally related to treatment / all	1 / 5	0 / 0
Pneumonia Chlamydial
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia Pneumococcal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia Streptococcal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia Viral
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Post Procedural Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative Wound Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psoas Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary Tuberculosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis Acute
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	4 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis Chronic
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Relapsing Fever
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory Tract Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salpingitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Salpingo-Oophoritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	3 / 6	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Septic Arthritis Neisserial
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic Shock
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	6 / 1910 (0.31%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0
Sialoadenitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft Tissue Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal Bacteraemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal Skin Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	5 / 1910 (0.26%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tubo-Ovarian Abscess
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper Respiratory Tract Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary Tract Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	4 / 1910 (0.21%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral Myositis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound Infection Staphylococcal
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound Sepsis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes Mellitus
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes Mellitus Inadequate Control
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic Ketoacidosis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemic Hyperosmolar Nonketotic Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertriglyceridaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	2 / 1910 (0.10%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Latent Autoimmune Diabetes In Adults
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obesity
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	3 / 1910 (0.16%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour Lysis Syndrome
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	1 / 1910 (0.05%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Sarilumab + Disease Modifying Anti-Rheumatic Drugs (DMARD)	Sarilumab monotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	1444 / 1910 (75.60%)	82 / 111 (73.87%)
Investigations
Alanine Aminotransferase Increased
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	201 / 1910 (10.52%)	4 / 111 (3.60%)
occurrences all number	287	4
Injury, poisoning and procedural complications
Accidental Overdose
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	330 / 1910 (17.28%)	20 / 111 (18.02%)
occurrences all number	496	22
Fall
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	109 / 1910 (5.71%)	3 / 111 (2.70%)
occurrences all number	122	3
Vascular disorders
Hypertension
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	235 / 1910 (12.30%)	4 / 111 (3.60%)
occurrences all number	271	5
Blood and lymphatic system disorders
Leukopenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	101 / 1910 (5.29%)	4 / 111 (3.60%)
occurrences all number	181	5
Neutropenia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	348 / 1910 (18.22%)	18 / 111 (16.22%)
occurrences all number	786	64
General disorders and administration site conditions
Injection Site Erythema
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	111 / 1910 (5.81%)	0 / 111 (0.00%)
occurrences all number	751	0
Gastrointestinal disorders
Diarrhoea
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	122 / 1910 (6.39%)	2 / 111 (1.80%)
occurrences all number	153	2
Respiratory, thoracic and mediastinal disorders
Cough
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	62 / 1910 (3.25%)	7 / 111 (6.31%)
occurrences all number	70	7
Musculoskeletal and connective tissue disorders
Arthralgia
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	87 / 1910 (4.55%)	9 / 111 (8.11%)
occurrences all number	109	11
Rheumatoid Arthritis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	227 / 1910 (11.88%)	16 / 111 (14.41%)
occurrences all number	357	31
Back Pain
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	122 / 1910 (6.39%)	6 / 111 (5.41%)
occurrences all number	141	6
Infections and infestations
Bronchitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	215 / 1910 (11.26%)	12 / 111 (10.81%)
occurrences all number	301	19
Influenza
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	124 / 1910 (6.49%)	3 / 111 (2.70%)
occurrences all number	160	4
Pharyngitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	110 / 1910 (5.76%)	4 / 111 (3.60%)
occurrences all number	129	4
Nasopharyngitis
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	249 / 1910 (13.04%)	14 / 111 (12.61%)
occurrences all number	390	26
Upper Respiratory Tract Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	303 / 1910 (15.86%)	16 / 111 (14.41%)
occurrences all number	574	21
Urinary Tract Infection
alternative dictionary used: MedDRA 23.1
subjects affected / exposed	264 / 1910 (13.82%)	14 / 111 (12.61%)
occurrences all number	428	22

More information

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Were there any global substantial amendments to the protocol? Yes

10 Jan 2011

Following changes were performed: • Included subjects in LTS11210 study population who were randomised into and completed treatment period of ACT11575. • Indicated that study name of LTS11210 is ABILITY (Monoclonal AntiBody anti-IL-6R extensiontrial in RA for safety purposes). • Added a section that described assessment of following subject-reported outcomes health questionnaires: Functional Assessment of Chronic Illness Therapy Fatigue (FACITFatigue), Work Productivity and Activities Impairment (WPAI), Sleep Visual Analog Scale (VAS), and the SF-36 Health Survey. • Clarified that an independent joint assessor (ie, a third party who is not involved in the conduct of the study at the investigational site) was not required to carry out efficacy assessments in LTS11210 study. • Clarified hypersensitivity reactions, referred to throughout protocol as systemic hypersensitivity reactions rather than local reactions. • Specified that thrombocytopenia was an indication to decrease study drug dose regimen from 150 mg SAR153191 (subcutaneous) weekly to 150 mg SAR153191 every other week. • Indicated that prior ACT11575 subject(s) enrolled in LTS11210 study were allowed to continue use of rescue treatment, for example, sulfasalazine or leflunomide, if use was ongoing at ACT11575 end-of-treatment visit. • Deleted sIL-6Rα measurements in LTS11210 study. • Revised exclusion criterion from female of childbearing potential with a positive pregnancy test to pregnant or breastfeeding women. • Deleted exclusion criterion - Men who were unwilling to utilise 2 forms of contraception: a condom and spermicidal agent. • Indicated that absolute neutrophil count of <500/mm3, lasting more than 5 days, was reported as serious adverse event. • Clarified within statistical section of LTS11210 study protocol. • Added RNA sample collection time points and modified biomarker collection time points in LTS11210 study protocol. • Provided minor clarifications to protocol.

26 May 2011

• Indicated that investigational drug product administered to subjects enrolled in LTS11210 was to be switched to new drug product, which consisted of new formulation made with different cell line, and with different drug concentrations compared to drug product that was currently in use in study. New drug product was to be packaged in prefilled syringe, compared to former drug product packaged in vial. • Clarified that after selection of Phase 3 pivotal dose(s) for program, it was intention of sponsor to switch currently enrolled subjects to highest of available selected dose regimens. All new subjects, subsequently enrolled were to be assigned to highest available selected dose regimen. Dosage switch procedure was instituted so that all enrolled subjects (preceding and proceeding pivotal dose selection) were on dose regimen with same benefit: risk ratio. • Clarified that step-down dose (due to safety issue) after selection of Phase 3 pivotal dose(s) was to be lowest available selected dose regimen. • Indicated that additional pharmaceutical form of SAR153191 (sarilumab) in amber glass vial at concentration of 100 mg/mL was to be administered to subjects enrolled into LTS11210. Use of this drug product was to be implemented, if at time of dose selection decision, selected pivotal dose regimen(s) included 200 mg dose, and/or 100 mg every other week dose. • Excluded subjects with latex hypersensitivity from enrolment because needle cap on prefilled syringe contained dry natural rubber latex particles that might cause allergic reactions. • Incorporated recently assigned International Non-proprietary Name of sarilumab. • Provided Sponsor’s guidance for medical follow-up of laboratory abnormality, by adding “Thrombocytopenia” appendix. • Removed text related to nonclinical studies of embryo-fetal development, pre-/postnatal development and fertility since final study results were now formally presented in updated Investigator’s Brochure. • Provided minor clarifications

24 Jan 2012

• Indicated that all enrolled subjects in LTS11210 were to be assigned to highest available sarilumab dose, 200 mg q2w dose and step-down dose (in case of specified safety issue) was to be 150 mg q2w. 150 mg and 200 mg q2w doses were selected based on analysis of completed and locked Part A study results. • Included subjects in LTS11210 population who were randomised into and completed treatment period of EFC10832. • Removed 7-day screening period from design and flowchart for subjects rolling over into LTS11210 that were previously randomised into EFC11072 Part B, Cohort 2 and EFC10832 and successfully completed treatment period. • Revised study name from ABILITY to SARIL-RA-EXTEND. • Added Week 10 visit blood samples for hematology and liver function tests (LFTs) to insure collection of hematology and LFTs every 2 weeks for initial 12 weeks of LTS11210, which mirrors schedule in EFC11072. • Provided summary of EFC11072, Part A results. • Indicated that Cardiovascular Adjudication Committee was to be established for LTS11210 to ensure that cardiovascular events were evaluated with consistent criteria and in unbiased manner. • Modified Exclusion criterion to bring consistency between exclusion criteria applied to study populations across all preceding study protocols (EFC11072, ACT11575 and EFC10832). • Added Permitted Concomitant Treatment list that needed dose adjustment following initiation of sarilumab. • Updated description of endpoints and statistical methodology for clarification purposes. • WPS-RA was added in LTS11210 because WPS-RA was included in EFC10832. • Added Subject Safety guidelines for reporting adverse events with prespecified monitoring to be consistent with guidance provided in upcoming Phase 3 sarilumab study protocols. • Provided Investigators set of clinical criteria for diagnosing anaphylaxis and Web link to National Heart, Lung and Blood Institute for reference to clinical management of lipid disorders. • Provided minor clarifications.

08 Aug 2012

The following changes were made: • Implemented new safety precautions to prevent administration of sarilumab to subjects at risk for thrombocytopenia <100 000/mm3 and/or grade 3/grade 4 neutropenia. These changes were to be implemented immediately • Provided additional safety information related to thrombocytopenia and neutropenia, and to infections.

31 Oct 2012

The following changes were made: • Modified to allow rollover of subjects from study SFY13370. • Modified the assessment schedule starting at 2 years from 12-week to 24-week intervals, with intervening 12-week IMP supply visits • Added yearly HIV testing starting at Week 48. • Revised scheduling of X-rays of hands and feet at EOT visit to have 14-day windows except Week 260. • Added DMARD concomitant medication restrictions. • Added FM30 latex-free formulation. • Updated IMP administration language. • Updated urine analysis language. • Updated safety language related to neurological event, anti-DNA antibodies, platelets, pregnancy and infections • Added chronic neurodegenerative disease to list of medically important events • Updated database lock language • Updated Appendix L language

17 Jul 2014

• Included subjects in LTS11210 who were randomised and completed monotherapy treatment period of EFC13752; sarilumab in LTS11210 was not administered with concomitant DMARDs in subjects of EFC13752. • Modified protocol title to remove 'on top of DMARDs' and modified other sections. • Modified Exclusion Criteria: - Deleted history of latex allergy (systemic hypersensitivity reaction to latex) except for subjects coming from EFC10832 or SFY13370'. - Women of childbearing potential was modified to be part of local informed consent in order to follow local guidelines - Deleted “Subjects with active or latent tuberculosis at last treatment visit in EFC11072, ACT11575, SFY13370 or EFC10832' as these subjects were to be permanently discontinued in initial studies. - Added “Subjects with temporary IMP discontinuation lasting >31 days at time of planned first dose in LTS11210 ' and “Subjects fulfilling protocol-defined criteria for permanent treatment discontinuation'. • Removed Phase 2 results and added Phase 3 results of EFC11072 Part B. • Conditions for any change in concomitant treatments including nonbiologic DMARDs, steroids, and nonsteroidal anti-inflammatory drugs and analgesics were adapted. • Modified temporary treatment discontinuation up to 3 missed doses (<=59 days). • 2 local amendments were incorporated in this global amendment. • Other minor changes: - Removed tuberculin skin test and serum QuantiFERON test at Week 260. - Replaced HIV yearly testing with HIV testing anytime during study when subject was at risk for this infection. - Added pharmacokinetic sampling to sampling time points for ADA beyond 2 years of study treatment to facilitate appropriate interpretation of the results. - Removed X-rays performed at Week 192 visit. - Updated total number of subjects and sites. - Improved wording throughout protocol and removed superseded text. - Modified safety section to harmonise with other ongoing sarilumab studies. - Corrected schedule inconsistencies.

31 Aug 2015

• Sarilumab treatment in LTS11210 was extended to 264 weeks in order to allow all subjects to be treated for approximately 5 calendar years from 1st sarilumab administration. • Subjects continued to be treated beyond 264 weeks if sarilumab was not commercially available in their country at Week 264.. • In the UK, duration of treatment was 264 weeks from 1st study drug administration in LTS11210 to provide finite duration of study treatment in accordance with local requirements. • Some assessments were not performed after Week 264 as per flowcharts, including health economics assessments, 12-lead ECG, and some DAS28 components of ACR core set (after Week 264, only TJC& SJC for 28 joints, subject´s global assessment of disease activity) • Week 192 X-ray was deleted in Amendment 8 and reinstated with Amendment 9. • PFS-S syringe was modified version of prefilled syringe that included needle safety shield to prevent needle stick injury. •12-week substudy was optional and was to be conducted at limited sites in selected countries. • Prior to this amendment, the protocol required permanent discontinuation of subject from study treatment in case of opportunistic infection or possible opportunistic infection per protocol. Definition of opportunistic infection had been modified. • To ensure continuity of treatment between last administration of IMP and 1st dose of commercial sarilumab, • PK: clarified analysis of bound sarilumab concentrations. After completion of EFC11072 Part B study, decision was made to only analyse functional sarilumab concentrations. • Deatiled Serum and RNA biomarkers samples long-term storage. • Corrected 2 secondary efficacy endpoints inconsistency. • Replaced “initial study” with “LTS11210”, where applicable, to clarify that treatment period of 264 weeks begins day of 1st dose of sarilumab in LTS11210. • Added active comparator to list of drugs subject might had been exposed to in prior study • Corrected minor grammatical errors.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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