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Antibodies

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Abatacept

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Immunologic Factors

Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks

Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks

Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (\>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at week 24.

Participants received abatacept (from 500 to 1000 mg i.v. based on weight). Participants who did not respond to abatacept at Week 16 were re-randomized 1:1 to AIN457 75mg or 150mg at week 24 (after an 8 week washout period).

AIN457 (Secukinumab) is a human monoclonal antibody. Secukinumab binds and reduces the activity of Interleukin 17 (IL-17). AIN457 was given as i.v. (10mg/kg) at baseline, week 2 and week 4, and then s.c. (75 or 150mg) every 4 weeks starting at week 8.

AIN457

Placebo was given as i.v. at baseline, week 2 and week 4, and then s.c. every 4 weeks starting at week 8.

Placebo

Abatacept (from 500 to 1000 mg i.v. based on weight) was given as i.v. at baseline, weeks 2 and 4, and then every 4 weeks starting at week 8.

Novartis Pharmaceuticals

The core and extension studies assessed the safety and efficacy of secukinumab when added to a background therapy in patients with active rheumatoid arthritis who are intolerant to or have had an inadequate response to anti-TNF-α agents. Patients received either secukinumab, placebo or abatacept (active comparator). The core study was completed. However, the extension study was prematurely terminated after the primary endpoint analysis of the core study at week 24 had demonstrated numerically higher efficacy for the active comparator abatacept compared to secukinumab.

Efficacy at 24 Weeks and Safety, Tolerability and Long Term Efficacy of Secukinumab (AIN457) in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Anti-Tumor Necrosis Factor α (Anti-TNFα) Agents (CAIN457F2309 and CAIN457F2309E1)

A Randomized, Double-blind, Placebo- and Active-controlled Study of Secukinumab to Demonstrate the Efficacy at 24 Weeks and to Assess the Safety, Tolerability and Long Term Efficacy up to 1 Year in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Anti-TNFα Agents (CAIN457F2309) and A Four Year Extension Study to Evaluate the Long Term Efficacy, Safety and Tolerability of Secukinumab in Patients With Active Rheumatoid Arthritis (CAIN457F2309E1)

ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR20 response results at week 24 used non-responder imputation.

The DAS28 is a measure of disease activity in RA based on Swollen and Tender Joint Counts (out of a total of 28), hsCRP and the Patient's Global Assessment of Disease Activity. A DAS28 score greater than 5.1 implies active disease, equal to or less than 3.2 low disease activity, and less than 2.6 remission. A negative change from baseline indicates improvement.

The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, "are you able to..." perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement.

ACR50 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 50% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR50 response results at week 24 used non-responder imputation.

ACR20, ACR 50 and ACR 70 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20%, 50% and/or 70% improvement, respectively, in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR).

ACR20, ACR 50 and ACR 70 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20%, 50% and/or 70% improvement, respectively, in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR20, ACR50 and ACR70 response results from baseline up to week 52 were based on observed data, i.e. without imputation.

The HAQ-DI, assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, "are you able to..." perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement.

The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, "are you able to..." perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement. The HAQ-DI results from baseline up to week 52 were based on observed data, i.e. without imputation.

The DAS28 is a measure of disease activity in RA based on Swollen and Tender Joint Counts (out of a total of 28), hsCRP and the Patient's Global Assessment of Disease Activity. A DAS28 score greater than 5.1 implies active disease, equal to or less than 3.2 low disease activity, and less than 2.6 remission. A negative change from baseline indicates improvement. The DAS28-CRP results from baseline up to week 52 were based on observed data, i.e. without imputation.

Blood samples were obtained to identify the presence of inflammation, to determine its severity and to monitor response to treatment. A negative change from baseline indicates improvement. The hsCRP results from baseline up to week 52 were based on observed data, i.e. without imputation.

Blood samples were obtained to monitor disease activity and response to treatment. A negative change from baseline indicates improvement. The ESR results from baseline up to week 52 were based on observed data, i.e. without imputation.

Any AIN457 75 mg

Any AIN457 150 mg

Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks.

AIN457 10mg/kg - 75 mg

Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks.

AIN457 10mg/kg - 150 mg

Total

Age, Categorical

Sex: Female, Male

Study Director

Full analysis set: the full analysis set was comprised of all randomized participants (excluding mis-randomized participants) who were assigned to study treatment.

Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20).

Participants from the full analysis set were considered for the analysis. Participants with measurements at both baseline and week 24 were analyzed. The full analysis set was comprised of all randomized participants (excluding mis-randomized participants) who were assigned to study treatment.

Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP)

Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)

Percentage of Participants Achieving ACR50

ACR20, week 1

ACR20, week 2

ACR20, week 4

ACR20, week 8

ACR20, week 12

ACR20, week 16

ACR20, week 20

ACR20, week 24

ACR50, week 1

ACR50, week 2

ACR50, week 4

ACR50, week 8

ACR50, week 12

ACR50, week 16

ACR50, week 20

ACR50, week 24

ACR70, week 1

ACR70, week 2

ACR70, week 4

ACR70, week 8

ACR70, week 12

ACR70, week 16

ACR70, week 20

ACR70, week 24

Participants from the full analysis set were considered for the analysis. Participants with missing data were considered non-responders at the respective time point. Placebo and Abatacept participants were considered non-responders from the time of treatment switch.

Percentage of Participants Achieving ACR20, ACR 50 and ACR 70 - Using Non-responder Imputation

ACR20,wk 1,n=132,129,130,130,39,35,21,22,96,17,17

ACR20,wk 2,n=131,130,134,134,39,36,23,22,99,17,18

ACR20,wk 4,n=133,132,131,129,39,39,23,21,93,17,19

ACR20,wk 8,n=132,127,131,131,39,39,23,22,95,17,19

ACR20,wk 12,n=130,115,123,129,39,37,23,21,94,17,18

ACR20,wk 16,n=126,118,116,129,36,37,21,22,94,16,19

ACR20,wk 20,n=122,114,119,126,38,37,23,21,91,16,19

ACR20,wk 24,n=117,110,117,121,38,36,21,22,87,16,18

ACR20,wk28,n=115,103,na,na,33,35,21,21,86,17,19

ACR20,wk32,n=104,97,na,na,33,30,21,19,87,17,17

ACR20,wk36,n=102,93,na,na,30,30,21,20,85,18,16

ACR20,wk40,n=96,90,na,na,28,28,21,19,85,15,17

ACR20,wk44,n=97,90,na,na,28,27,20,18,84,15,16

ACR20,wk48,n=94,89,na,na,28,26,18,19,77,12,14

ACR20,wk52,n=92,88,na,na,28,26,20,18,79,15,15

ACR50,wk1,n=132,129,130,130,39,35,21,22,96,17,17

ACR50,wk2,n=131,130,134,134,39,36,23,22,99,17,18

ACR50,wk4,n=133,132,131,129,39,39,23,21,93,17,19

ACR50,wk8,n=132,127,131,131,39,39,23,22,95,17,19

ACR50,wk12,n=130,115,123,129,39,37,23,21,94,17,18

ACR50,wk16,n=126,118,116,129,36,37,21,22,94,16,19

ACR50,wk20,n=122,114,119,126,38,37,23,21,91,16,19

ACR50,wk24,n=117,110,117,121,38,36,21,22,87,16,18

ACR50,wk28,n=115,103,na,na,33,35,21,21,86,17,19

ACR50,wk32,n=104,97,na,na,33,30,21,19,87,17,17

ACR50,wk36,n=102,93,na,na,30,30,21,20,85,18,16

ACR50,wk40,n=96,90,na,na,28,28,21,19,85,15,17

ACR50,wk44,n=97,90,na,na,28,27,20,18,84,15,16

ACR50,wk48,n=94,89,na,na,28,26,18,19,77,12,14

ACR50,wk52,n=92,88,na,na,28,26,20,18,79,15,15

ACR70,wk1,n=132,129,130,130,39,35,21,22,96,17,17

ACR70,wk2,n=131,130,134,134,39,36,23,22,99,17,18

ACR70,wk4,n=133,132,131,129,39,39,23,21,93,17,19

ACR70,wk8,n=132,127,131,131,39,39,23,22,95,17,19

ACR70,wk12,n=130,115,123,129,39,37,23,21,94,17,18

ACR70,wk16,n=126,118,116,129,36,37,21,22,94,16,19

ACR70,wk20,n=122,114,119,126,38,37,23,21,91,16,19

ACR70,wk24,n=117,110,117,121,38,36,21,22,87,16,18

ACR70,wk28,n=115,103,na,na,33,35,21,21,86,17,19

ACR70,wk32,n=104,97,na,na,33,30,21,19,87,17,17

ACR70,wk36,n=102,93,na,na,30,30,21,20,85,18,16

ACR70,wk40,n=96,90,na,na,28,28,21,19,85,15,17

ACR70,wk44,n=97,90,na,na,28,27,20,18,84,15,16

ACR70,wk48,n=94,89,na,na,28,26,18,19,77,12,14

ACR70,wk52,n=92,88,na,na,28,26,20,18,79,15,15

Participants switched from placebo to AIN457 75 mg starting at week 16.

Placebo Non-responder - AIN457 75 mg

Participants switched from placebo to AIN457 150 mg starting at week 16.

Placebo Non-responder - AIN457 150 mg

Participants switched from placebo to AIN457 75 mg starting at week 24.

Placebo Responder - AIN457 75mg

Participants switched from placebo to AIN457 150 mg starting at week 24.

Placebo Responder - AIN457 150mg

Abatacept responders remained on abatacept (from 500 to 1000 mg iv based on weight).

Abatacept Responders

Participants switched from abatacept to AIN457 75 mg starting at week 24.

Abatacept Non-respnders - AIN457 75mg

Participants switched from abatacept to AIN457 150 mg starting at week 24.

Abatacept Non-responders - AIN457 150mg

Participants from the full analysis set were considered for the analysis. Participants with measurements at both baseline and each post-baseline time point were analyzed for that post-baseline time point. The full analysis set was comprised of all randomized participants (excluding mis-randomized participants) who were assigned to study treatment.

Percentage of Participants Achieving ACR20, ACR 50 and ACR 70 - Observed Data

week 1, n=132,129,130,129

week 2, n=131,130,134,133

week 4, n=133,133,131,130

week 8, n=132,127,131,130

week 12, n=130,114,123,129

week 16, n=127,118,116,129

week 20, n=122,114,47,92

week 24, n=117,110,44,86

Participants from the full analysis set were considered for this analysis. For Placebo and Abatacept participants, data collected after treatment switch was treated as missing, as were missing values for all treatment groups.

Change From Baseline in HAQ-DI - Using Mixed Model Repeated Measures (MMRM)

wk1,n=132,129,130,129,39,35,21,22,95,17,17

Wk2,n=131,130,134,133,39,36,23,22,133,98,17,18

Wk4,n=133,133,131,130,39,39,23,21,94,17,19

Wk8,n=132,127,131,130,39,39,23,22,94,17,19

wk12,n=130,114,123,129,39,37,23,21,94,17,18

Wk16,n=127,118,116,129,36,37,21,22,94,16,19

Wk20,n=122,114,119,125,38,37,23,21,90,16,19

Wk24,n=117,110,117,120,38,36,21,22,86,16,18

Wk28,n=115,102,na,na,33,35,21,21,86,17,19

Wk32,n=104,97,na,na,33,30,21,19,87,17,17

Wk36,n=102,93,na,na,30,30,21,19,84,18,16,

Wk40,n=96,89,na,na,28,28,21,19,84,15,17

Wk44,n=97,90,na,na,28,27,20,18,84,15,16

Wk48,n-94,89,na,na,28,26,19,19,76,12,14

Wk52,n=92,87,na,na,28,26,20,18,79,15,15

Placebo Non-responder - AIN457 75mg

Placebo Non-responder - AIN457 150mg

Abatacept Non-responders - AIN457 75mg

Change From Baseline in HAQ-DI - Observed Data

week 1, n=131,129,130,129

week 2, n=131,127,132,133

week 4, n=130,131,138,138

week 8, n=130,126,130,130

week 12, n=130,114,123,128

week 16, n=126,116,114,127

week 20, n=121,114,47,92

week 24, n=116,108,44,84

Participants from the full analysis set were considered for the analysis. For Placebo and Abatacept participants, data collected after treatment switch was treated as missing, as were missing values for all treatment groups

Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) - Using MMRM

Wk1,n=131,129,130,129,39,35,21,22, 95,17,17

Wk2,n=131,127,132,133,39,36,23,21,98,17,18

Wk4,n=130,131,129,128,39,38,23,21,92,17,19

Wk8,n=130,126,130,130,39,39,23,22,94,17,19

Wk12,n=130,114,123,128,39,37,23,21,93,17,18

Wk16,n=126,116,114,128,36,36,21,21,94,15,19

Wk20,n=121,114,,119,125,38,37,23,21,90,16,19

Wk24,n=116,108,116,117,37,36,21,22,84,15,18

Wk28,n=115,103,na,na,33,35,21,21,86,17,18

Wk32,n=103,97,na,na,33,39,23,22,87,17,16

Wk36,n=101,92,na,na,30,30,21,20,84,18,15

Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) - Observed Data

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy at 24 Weeks and Safety, Tolerability and Long Term Efficacy of Secukinumab (AIN457) in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Anti-Tumor Necrosis Factor α (Anti-TNFα) Agents (CAIN457F2309 and CAIN457F2309E1)	NCT01350804	Rheumatoid Arth...	AIN457 Placebo Abatacept	18 Years -	Novartis
Efficacy at 24 Weeks and Safety, Tolerability and Long Term Efficacy of Secukinumab (AIN457) in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Anti-Tumor Necrosis Factor α (Anti-TNFα) Agents (CAIN457F2309 and CAIN457F2309E1)	NCT01350804	Rheumatoid Arth...	AIN457 Placebo Abatacept	18 Years -	Novartis
Efficacy at 24 Weeks and Safety, Tolerability and Long Term Efficacy of Secukinumab (AIN457) in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Anti-Tumor Necrosis Factor α (Anti-TNFα) Agents (CAIN457F2309 and CAIN457F2309E1)	NCT01350804	Rheumatoid Arth...	AIN457 Placebo Abatacept	18 Years -	Novartis

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