Long Term Evaluation of Sarilumab in Rheumatoid Arthritis Patients (SARIL-RA-EXTEND)

An adverse event (AE) was any untoward medical occurrence in a clinical study participant 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 hospitalization or prolongation of existing hospitalization, 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).

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 participant's failure to administer the full dose at a given attempt. A PTC was defined as any participant- 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. Participants who answered "no" for any of the questions of PTC, had PTF and/or FDD were reported in this outcome measure.

A PTF was defined as any PTC (defined as any participant- 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 participants enrolled in sub-study were reported in this outcome measure.

FDD was defined as participant's failure to administer the full dose at a given attempt. Number of FDD in the participants enrolled in sub-study were reported in this outcome measure.

A PTC was defined as any participant- 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 participant's answer to "no" for any of the questions of PTC) in the participants enrolled in sub-study were reported in this outcome measure.

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 the 5 remaining ACR core measures assessments: C-reactive protein [CRP] level (mg/liter [mg/L]); participant's assessment of pain (measured on 0 [no pain] to 100 mm [worst pain] visual analog scale [VAS]); participant'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); participant's assessment of physical function (measured by health assessment questionnaire disability index [HAQ-DI], with scoring range of 0 [better physical function] to 3 [worst physical function]). Higher score indicated worse outcomes.

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); participant's assessment of pain (measured on 0 [no pain] to 100 mm [worst pain] VAS); participant'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); participant'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.

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); participant's assessment of pain (measured on 0 [no pain] to 100 mm [worst pain] VAS); participant'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); participant'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.

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 participant using participant 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 participants with DAS28 remission were reported.

DAS28-based EULAR response criteria were used to measure individual response as none, good or moderate, depending on the extent of change from baseline and level of disease activity reached. The EULAR response criteria are defined as:

• Good response = change from baseline of >1.2 and a present DAS28-CRP score <=3.2.
• Moderate response = change from baseline of >0.6 to <=1.2 and a 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 were considered to indicate therapeutic response. 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 participant using participant global assessment (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS.

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 participant using participant global assessment (measured on 0 [no arthritis activity] to 100 mm [maximal arthritis activity] VAS). DAS28-CRP total score ranges from 0-10, where higher scores indicated greater disease activity. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752).

HAQ-DI is a standardized questionnaire used to assess the degree of difficulty a participant has experienced during the past week in 8 domains of daily living activities: dressing/grooming; arising; eating; walking; hygiene; reach; grip and activities. There were total of 30 items distributed in these 8 domains. Each item was scored on a 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 the sum of domain scores and divided by the number of domains answered. Total possible score range 0 (least difficulty in physical function) to 3 (extreme difficulty in physical function), where higher scores indicate more difficulty while performing daily living activities. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752).

Van der Heijde modified Sharp method is composite X-ray scoring system used to assess structural (joint) disease progression 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 outcome measure, change from initial study Baseline in 2 years X-ray data at Week 0 and 48 of LTS11210 were reported.

Van der Heijde modified Sharp method is composite X-ray scoring system used to assess structural (joint) disease progression in RA. The method evaluates both JE for 44 joints and 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 outcome measure, change from initial study (EFC11072 Part B) Baseline in 3 years X-ray data (participants with study duration of more than 48 weeks in LTS11210) at Week 48 and 96 of LTS11210 from Campaign 2 were reported.

Van der Heijde modified Sharp method is composite X-ray scoring system used to assess structural (joint) disease progression in RA. The method evaluates both JE for 44 joints and 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 outcome measure, change from initial study (EFC11072 Part B) Baseline in 5 years X-ray data (participants with study duration of more than 96 weeks in LTS11210) at Week 96, 144 and 192 of LTS11210 from Campaign 3 were reported.

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 used to assess structural (joint) disease progression in RA. The method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS was 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 represents progression of structural damage. In this outcome measure, percentage of participants with no radiographic progression at Week 48 of LTS11210 from Campaign 1 X-ray data were reported.

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 used to assess structural (joint) disease progression in RA. The method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS was 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 represents progression of structural damage. In this outcome measure, percentage of participants with no radiographic progression at Week 48 and 96 of LTS11210 from Campaign 2 X-ray data (participants with study duration of more than 48 weeks in LTS11210) were reported.

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 used to assess structural (joint) disease progression in RA. The method evaluates both JE for 44 joints and JSN for 42 joints in bilateral hand and foot joints. Total mTSS was 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 represents progression of structural damage. In this outcome measure, percentage of participants with no radiographic progression at Week 96, 144 and 192 of LTS11210 from Campaign 3 X-ray data (participants with study duration more than 96 weeks in LTS11210) were reported.

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 outcome measure. Here, Baseline refers to Baseline of initial study (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752).

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 outcome measure. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, EFC10832, SFY13370 and EFC13752).

Physician global assessment of disease activity was measured on a 100 millimeters (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).

Participant 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).

Participants 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).

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 the 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 indicating better physical health. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, and EFC10832).

SF-36 is a generic 36-item questionnaire consisting of 8 domains, measuring quality of life (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 indicating better physical and mental health. Here, Baseline refers to the Baseline of initial studies (EFC11072, ACT11575, and EFC10832).

The FACIT-F is a 13-item questionnaire assessing fatigue where participants 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).

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).

WPAI assesses work productivity and impairment. It is 6-item questionnaire used 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 = degree problem affected productivity while working (0 to 10 scale, with higher numbers indicated less productivity); Q6 = degree problem affected regular activities (0 to 10 scale, with higher numbers indicated greater impairment). The percent work time missed due to RA was a subscale and calculated as: 100*Q2/(Q2+Q4) for those who were currently employed. Subscale score was expressed as impairment percentage (range:0 to 100%) where higher numbers indicate greater impairment and less productivity. Here, Baseline refers to Baseline of initial studies (EFC11072 and ACT11575).

WPAI assesses work productivity and impairment. It is 6-item questionnaire used 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 = degree problem affected productivity while working (0 to 10 scale, with higher numbers = less productivity); Q6 = degree problem affected regular activities (0 to 10 scale, with higher numbers = greater impairment). Percentage impairment while working due to RA was subscale and calculated as: 10*Q5 for those who were currently employed and actually worked in past 7 days. Subscale score=expressed as impairment percentage (range:0 to 100%), where higher numbers=greater impairment and less productivity. Here, Baseline refers to the Baseline of initial studies (EFC11072 and ACT11575).

WPAI assesses work productivity and impairment. It is 6-item questionnaire used 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 = degree problem affected productivity while working (0 to 10 scale, with higher numbers indicated less productivity); Q6 = degree problem affected regular activities (0 10 scale, with higher numbers indicated greater impairment). Percent overall work impairment due to RA was subscale and calculated as: 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 to 100%) where higher numbers indicate greater impairment. Here, Baseline refers to Baseline of initial studies (EFC11072 and ACT11575).

WPAI assesses work productivity and impairment. It is 6-item questionnaire used 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 = degree problem affected productivity while working (0 to 10 scale, with higher numbers indicated less productivity); Q6 = degree problem affected regular activities (0 10 scale, with higher numbers indicated 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 to 100%) where higher numbers indicate greater impairment. Here, Baseline refers to Baseline of initial studies (EFC11072 and ACT11575).

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 participant 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 participant was reported in the outcome measure. Here, Baseline refers to the Baseline of initial study (EFC10832).

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 participant 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 reduced productivity by >= 50% in the last month by the participant was reported in the outcome measure. Here, Baseline refers to the Baseline of initial study (EFC10832).

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 participant 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 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).

'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 participant 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 participants was reported. Here, Baseline refers to the Baseline of initial study (EFC10832).

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 participant 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 participants was reported. Here, Baseline refers to the Baseline of initial study (EFC10832).

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 participant 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 participants was reported. Here, Baseline refers to the Baseline of initial study (EFC10832).

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 participant 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 participant was reported. Here, Baseline refers to the Baseline of initial study (EFC10832).

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 participant 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).

AEs related to PFS-S included PTC-related AEs, device-related AEs, or AEs of injection site reaction. In this outcome measure, 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 .