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)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: AIN457
* Biological: Placebo
* Biological: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant, non-lactating female patients Presence of RA classified by ACR 2010 revised criteria for at least 3 months before screening At Baseline: Disease activity criteria defined by >= 6 tender joints out of 68 and >= 6 swollen joints out of 66 WITH at least 1 of the following at screening: Anti-Cyclic Citrullinated Peptide (Anti-CCP) antibodies positive OR Rheumatoid Factor positive AND WITH at least 1 of the following at screening: High sensitivity C-Reactive Protein (hsCRP) >= 10 mg/L OR Erythrocyte Sedimentation Rate (ESR) >= 28 millimeter (mm)/1st hour Patients must have been taking at least one anti-TNF-α agent given at an approved dose for at least 3 months before randomization and have experienced an inadequate response to treatment or have been intolerant to at least one administration of an anti-TNF-α agent Patients must be taking MTX or any other DMARD (but not more than 1 DMARD) for at least 3 months before randomization and have to be on a stable dose at least 4 weeks before randomization (7.5 to 25 mg/week for MTX or other DMARD at maximum tolerated dose) Exclusion Criteria: Chest x-ray with evidence of ongoing infectious or malignant process, obtained within 3 months prior to screening and evaluated by a qualified physician RA patients functional status class IV according to the ACR 1991 revised criteria Patients who have ever received biologic immunomodulating agents except for those targeting TNFα Previous treatment with any cell-depleting therapies Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AIN457 10mg/kg - 75 mg<br>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 | Biological: AIN457<br>* 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.<br>* Other names: Secukinumab;|
| Experimental: AIN457 10mg/kg - 150 mg<br>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 | Biological: AIN457<br>* 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.<br>* Other names: Secukinumab;|
| Placebo Comparator: Placebo<br>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. | Biological: AIN457<br>* 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.<br>* Other names: Secukinumab;Biological: Placebo<br>* Placebo was given as i.v. at baseline, week 2 and week 4, and then s.c. every 4 weeks starting at week 8.<br>|
| Active Comparator: Abatacept<br>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). | Biological: AIN457<br>* 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.<br>* Other names: Secukinumab;Biological: Abatacept<br>* 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.<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20). | 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. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) | 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. | baseline, week 24 | 
| Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | 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. | baseline, week 24 | 
| Percentage of Participants Achieving ACR50 | 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. | week 24 | 
| Percentage of Participants Achieving ACR20, ACR 50 and ACR 70 - Using 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). | baseline, weeks 1, 2, 4, 8, 12, 16, 20 and 24 | 
| Percentage of Participants Achieving ACR20, ACR 50 and ACR 70 - Observed Data | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 | 
| Change From Baseline in HAQ-DI - Using Mixed Model Repeated Measures (MMRM) | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline in HAQ-DI - Observed Data | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 | 
| Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) - Using MMRM | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) - Observed Data | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 | 
| Change From Baseline in hsCRP - Observed Data | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) - Observed Data | 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. | baseline, weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RA, ACR, Rheumatoid Arthritis, inflammatory joints