Trial Outcomes & Findings for A Study of CNTO 136 (Sirukumab), Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Disease-Modifying Antirheumatic Drug (DMARD) Therapy (SIRROUND-D) (NCT NCT01604343)

A total of 2746 participants were screened of which 1670 participants were randomized and received at least one administration of study treatment.

A Study of CNTO 136 (Sirukumab), Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Disease-Modifying Antirheumatic Drug (DMARD) Therapy (SIRROUND-D)

ACR 20 response is greater than or equal to (\>=) 20 percent (%) improvement in both tender joint count (68) and swollen joint count (66) and \>= 20% improvement in 3 of following 5 assessments:Participant's assessment of pain using visual analog scale (VAS) (0-10 scale, 0=no pain and 10=worst possible pain),Participant's global assessment of disease activity by using VAS (scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (scale ranges from 0= no difficulty to 3= inability to perform a task in that area), and Serum C-reactive protein (CRP). Participants were analyzed according to randomized treatment groups they were assigned, regardless of treatments they actually received. Here, TF= treatment failure.

The van der Heijde-modified Sharpe (vdH-S) score is defined as a measurement of progression in structural damage. It is the sum of joint erosion (32 joints of the hands and 12 joints of the feet) score and joint space narrowing (JSN) (30 joints of the hands and 12 joints of the feet) score. The joint erosion assessment is scored according to the surface area involved, from 0 to 5, with 0 indicating no erosion and 5 indicating complete collapse of bone whereas the JSN assessment including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received. Here, EE= early escape.

The Health Assessment Questionnaire-Disability Index (HAQ-DI) score is an evaluation of the functional status for a participant. The 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

An American College of Rheumatology (ACR) 50 response is defined as \>= 50 % improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and \>= 50% improvement in 3 of the following 5 assessments: Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. The Disease Activity Index Score 28 (DAS28) C-reactive protein (CRP) remission is defined as a DAS28 (CRP) value of less than 2.6 at a visit. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

MCR- participant achieving ACR 70 response for 6 continuous months (24 weeks) in the study period (i.e., through Week 52). An ACR 70 response is defined as \>= 70% improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and \>= 70% improvement in 3 of the following 5 assessments Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (scale ranges from 0 to 10, \[0=no arthritis to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by HAQ-DI (scale ranges from 0= no difficulty, to 3= inability to perform a task in that area) and Serum CRP. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

An ACR 20 response is defined as \>= 20 % improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and \>= 20% improvement in 3 of the following 5 assessments: Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

An ACR 50 response is defined as \>= 50 % improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and \>= 50% improvement in 3 of the following 5 assessments: Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

An ACR 70 response is defined as \>= 70 % improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and \>= 70% improvement in 3 of the following 5 assessments: Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

An ACR 90 response is defined as \>= 90 percent (%) improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and \>= 90% improvement in 3 of the following 5 assessments: Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

DAS28 based on C-Reactive Protein (CRP), a statistically derived index combining tender joints (28), swollen joints (28), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both upper right extremity and upper left extremity as well as knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. Good responders: improvement from baseline greater than (\>) 1.2 with DAS28 less than or equal to (\<=) 3.2; moderate responders: improvement from baseline \>1.2 with DAS28 \>3.2 to \<=5.1 or improvement from baseline \>0.6 to \<=1.2 with DAS28 \<=5.1; non-responders: improvement from baseline \<=0.6 or improvement from baseline \>0.6 and \<=1.2 with DAS28 \>5.1. Participants were analyzed according to randomized treatment groups they were assigned to, regardless of treatments they actually received.

The DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. A negative change from baseline in DAS28 (CRP) (that is, a decrease from baseline) indicates improvement from baseline. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. The Disease Activity Index Score 28 (DAS28) C-reactive protein (CRP) remission is defined as a DAS28 (CRP) value of less than 2.6 at a visit. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The SDAI score is a derived score combining tender joints (28 joints), swollen joints (28 joints), patient's global assessment of disease activity, physician's global assessments of disease activity, and CRP. The total score range is from 0 to 86 with a lower score indicating less disease activity. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The CDAI score is a derived score of 4 components: tender joints (28 joints), swollen joints (28 joints), patient's global assessment of disease activity, and physician's global assessments of disease activity. The total score ranges from 0 to 76 with a lower score indicating less disease activity. A negative change in CDAI score indicates an improvement in disease activity and a positive change in score indicates a worsening of disease activity. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

Participant having SDAI-based ACR/EULAR remission at a visit if SDAI score is of \<= 3.3. SDAI derived by combining 5 disease assessments: tender joint (28), swollen joint (28) counts, participants global assessment of disease activity using VAS (scale ranges from 0 to 10 \[0 =very well to 10 = very poor\]), physicians global assessment of disease activity using VAS (scale ranges from 0 to 10 \[0=no arthritis to 10=extremely active arthritis\]) and CRP. 28 joints evaluated for swelling and tenderness are same set of 28 joints used in DAS28 includes shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of upper right and left extremities and knee joints of lower right and left extremities. Change from baseline in SDAI score measures change in disease activity, where negative change= improvement and positive change= worsening. Participants were analyzed according to randomized treatment groups they were assigned regardless of treatments actually received.

A participant was considered as having achieved the Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) remission at a visit if all of the following 4 criteria were met at that visit: Tender joint count (68 joints) less than or equal to (\<=) 1; Swollen joint count (66 joints) \<=1; CRP \<=1 milligram per deciliter (mg/dL); Patient's Global Assessment of Disease Activity \<=1 on a 0 (very well) to 10 (very poor) VAS. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The Health Assessment Questionnaire-Disability Index (HAQ-DI) score is an evaluation of the functional status for a participant. The 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Negative change reflects an improvement and a positive change reflects a worsening. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

HAQ-DI has 20-question in 8 functional areas: dressing, arising, eating, walking, hygiene, reaching, gripping, and daily living activities, scored from 0=no difficulty to 3=inability to perform task in that area. Overall score computed as sum of domain score divided by number of domains answered. Total possible score range 0= least difficulty to 3= extreme difficulty. AUC of change from baseline in HAQ-DI score is AUC of change from baseline in HAQ-DI score versus time. AUC was calculated based on measurement (observed HAQ-DI score change from baseline) at scheduled visits using trapezoidal rule.Functional status was determined as cumulative measure of HAQ-DI over 1 year by using AUC of change from baseline in HAQ-DI score through week 52. Decreases in AUC of change from baseline in HAQ-DI means greater average improvement in physical function over time. Participants analyzed according to randomized treatment groups they were assigned, regardless of treatments they actually received.

HAQ-DI response was defined as change of less than -0.22 from baseline in HAQ-DI score. The HAQ-DI score is an evaluation of the functional status for a participant. The 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

HAQ-DI score is an evaluation of the functional status for a participant. The 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

vdH-S score is defined as a measurement of progression in structural damage. It is the sum of joint erosion (32 joints of the hands and 12 joints of the feet) score and joint space narrowing (JSN) (30 joints of the hands and 12 joints of the feet) score. The joint erosion assessment is scored according to the surface area involved, from 0 to 5, with 0 indicating no erosion and 5 indicating complete collapse of bone whereas the JSN assessment including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

vdH-S score measures structural damage progression as sum of joint erosion(JE) and joint space narrowing(JSN) scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints, scored as per surface area- from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32\*5) and MAX JES for F- 120 (12\*10 \[5\*2 sides of foot\]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30\*4), and MAX JSS for F-48(12\*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS (i.e., JE score + JSN score) of 448. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

vdH-S score measures structural damage progression as sum of joint erosion(JE) and joint space narrowing(JSN) scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints, scored as per surface area- from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32\*5) and MAX JES for F- 120 (12\*10 \[5\*2 sides of foot\]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30\*4), and MAX JSS for F-48(12\*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS (i.e., erosion score + JSN score) of 448. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

vdH-S score measures structural damage progression as sum of joint erosion(JE) and joint space narrowing(JSN) scores(S). JE is summary of erosion severity in 32 of hand and 12 of feet joints, scored according to the surface area, from 0 (no erosion) to 5 (complete collapse of bone) whereas the JSN is summary of severity of 30 of hand and 12 of feet joints, scored according to the subluxation from 0 (normal) to 4 (bony ankylosis or complete luxation). The SDC is smallest change in score that is considered to be assessed correctly based on limits of agreement (that is., above the measurement error). The SDC for change from baseline in vdH-S Score is determined as: SDC=1.96 \* SD / (root 2 \* root k), where SD is the standard deviation of the difference between 2 readers in change from baseline in vdH-S score; k is the number of readers. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

vdH-S score measures structural damage progression as sum of joint erosion(JE) and joint space narrowing(JSN) scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints, scored as per surface area- from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32\*5) and MAX JES for F- 120 (12\*10 \[5\*2 sides of foot\]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30\*4), and MAX JSS for F-48(12\*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of (i.e., erosion score + JSN score) 448. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

vdH-S score measures structural damage progression as sum of joint erosion(JE) and joint space narrowing(JSN) scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints, scored as per surface area- from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32\*5) and MAX JES for F- 120 (12\*10 \[5\*2 sides of foot\]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30\*4), and MAX JSS for F-48(12\*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS (i.e., JE score + JSN score) of 448. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

Serum CRP is a marker of systemic inflammation. A negative change from baseline in CRP represents improvement. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

Duration of morning stiffness was defined as the time elapsed when participant woke up in the morning and was able to resume normal activities without stiffness in minutes (If none was present = 0; If morning stiffness was continuing at the time of assessment or was unusual compared to the recent past, average of duration of stiffness over the past 3 days was reported; If stiffness persisted the entire day, 1440 minutes was recorded). Negative values for this outcome measure represent improvement, i.e. shortening of duration of morning stiffness. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

SF-36 questionnaire is health related quality of life (QOL) instrument with 36 questions with 8 multi-item scales (evaluated limitations in): physical functioning due to health problems; usual role activities due to physical health problems; Bodily pain; General mental health (psychological distress and well-being); usual role activities due to personal or emotional problems; social functioning due to physical or mental health problems; Vitality (energy and fatigue); General health perception. Each 8 scales scored from 0 to 100 with higher scores= better health. Based on scale scores, summary scores, physical component score (PCS) and mental component score (MCS) will be derived. Scoring is derived based on algorithm developed in software provided by developer. Summary MCS and PCS score is also scaled from 0 to 100 with higher scores= better health. Participants were analyzed according to randomized treatment groups they were assigned regardless of treatments they actually received.

The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The questionnaire consists of 13 questions that assess a participant's level of fatigue and tiredness over the last 7 days. Each question is graded on a 5-point scale (0 - 4); and accordingly, the total FACIT-Fatigue scores can range from 0 to 52, with lower score reflecting more fatigue and higher scores reflecting less fatigue. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The Work Limitations Questionnaire (WLQ) was used to measure the impairment in work-related productivity, with reference to the previous two weeks. Each work-related question is scored from 0 to 4 and the total score ranges from 0-100, with lower scores signifying fewer limitations at work. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The EuroQol Health State Visual Analogue Scale (EQ VAS) records the respondent's self-rated health on a vertical line, VAS where the endpoints are labeled as 0= 'Worst imaginable health state' and 100= 'Best imaginable health state'. The EQ VAS can be used as a quantitative measure of health outcome as judged by the individual respondents. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

The EQ-5D-3L Descriptive System comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.