Long-term Safety and Efficacy of Sirukumab in Participants With RA Completing Studies CNTO136ARA3002 or CNTO136ARA3003

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the long-term safety and efficacy of CNTO 136 (sirukumab) in participants with rheumatoid arthritis (RA) who are unresponsive to treatment with modifying antirheumatic drugs (DMARDs) or anti-TNF alpha agents.

Detailed Description
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This is a multicenter, long-term study of sirukumab (CNTO 136) that will be conducted in two groups of participants at the same time (parallel-group study). The maximum duration of participation in this study is 208 weeks, followed by approximately 16 weeks of safety and efficacy follow-up after the administration of the final study agent injection of sirukumab. Participant safety will be monitored throughout the study.

Official Title
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A Multicenter, Parallel-group Study of Long-term Safety and Efficacy of CNTO 136 (Sirukumab) for Rheumatoid Arthritis in Subjects Completing Treatment in Studies CNTO136ARA3002 (SIRROUND-D) and CNTO136ARA3003 (SIRROUND-T)

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Sirukumab 100 mg
* Drug: Sirukumab 50 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completed participation in Studies CNTO136ARA3002 or CNTO136ARA3003 Signed an informed consent form (ICF) indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study Signed an informed consent form (ICF) for pharmacogenetics research (how a person's genes may affect a drug's effects) in order to participate in the optional pharmacogenetics component of this study. Refusal to give consent for this component does not exclude a participant from participation in this clinical study Exclusion Criteria: Withdraws consent and/or discontinues participation in study CNTO136ARA3002 or CNTO136ARA3003 Is pregnant Has active diverticulitis Has any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the participant or that could prevent, limit, or confound the protocol-specified assessments

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirukumab 100 mg<br> | Drug: Sirukumab 100 mg<br>* Sirukumab 100 mg subcutaneously (SC) at Weeks 0 (administered as the last dose in CNTO136ARA3002 or CNTO136ARA3003), 2, and every 2 weeks through Week 156 for participants who completed CNTO136ARA3002 and through Week 208 for participants who completed CNTO136ARA3003.<br>|
| Experimental: Sirukumab 50 mg / placebo<br> | Drug: Sirukumab 50 mg<br>* Sirukumab 50 mg SC at Weeks 0 (administered as the last dose in CNTO136ARA3002 or CNTO136ARA3003), 4, and every 4 weeks through Week 156 for participants who completed CNTO136ARA3002 and through Week 208 for participants who completed CNTO136ARA3003.<br>Drug: Placebo<br>* Between sirukumab 50 mg injections, placebo SC injections will be administered at Weeks 2, 6, and every 4 weeks until the study becomes open-label, and placebo injections are discontinued.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | From baseline of this LTE study up to 4.3 years | 
| Percentage of Participants With Major Adverse Cardiovascular Events (MACE) | MACE was defined as a composite of Myocardial Infarction (MI), stroke, death, hospitalization for unstable angina, and hospitalization for Transient Ischemic Attack (TIA). Adjudication of these events by the Endpoint Adjudication Committee (EAC) was performed in a blinded fashion. | From baseline of this LTE study up to 4.3 years | 
| Percentage of Participants With Malignancies | Percentage of participants with one or more malignancy was reported. | From baseline of this LTE study up to 4.3 years | 
| Percentage of Participants With Serious Infections | Percentage of participants with one or more serious infections was reported. | From baseline of this LTE study up to 4.3 years | 
| Percentage of Participants With Gastrointestinal (GI) Perforations | Percentage of participants with one or more GI perforations was reported. GI perforation is a hole that develops through the entire wall of the stomach, small intestine, large bowel, or gallbladder. | From baseline of this LTE study up to 4.3 years | 
| Percentage of Participants With Hepatobiliary Abnormalities | Percentage of participants with hepatobiliary abnormalities was reported. | From baseline of this LTE study up to 4.3 years | 
| Percentage of Participants With Serious or Moderate/Severe Systemic Hypersensitivity Reactions, or Serum Sickness Adverse Events | Percentage of participants with serious or moderate/severe systemic hypersensitivity reactions, or serum sickness adverse events (AEs) was reported. | From baseline of this LTE study up to 4.3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Toxicity Grade 4 Decrease in Neutrophils | Percentage of participants with toxicity grade 4 decrease in neutrophils was reported. As per National Cancer Institute's Common Terminology Criteria for Adverse Events, toxicity grade 4 was defined as decrease in neutrophils less than (<) 500 per Cubic Millimeter (mm^3) or < 0.5 * 10^9 per liter. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With Toxicity Grade 4 Decrease in Platelets | Percentage of participants with toxicity grade 4 decrease in platelets was reported. As per National Cancer Institute's Common Terminology Criteria for Adverse Events, toxicity grade 4 was defined as decreased in platelets <25000/mm^3 or < 25.0 * 10^9 per liter. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With ALT >= 3*ULN, ALT >= 5*ULN and ALT >= 8*ULN | Percentage of participants with Alanine Aminotranserase (ALT) >= 3*Upper Limit of Normal (ULN), ALT >= 5*ULN or ALT >= 8*ULN was reported. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With AST >= 3*ULN, AST >= 5*ULN and AST >= 8*ULN | Percentage of participants with Aspartate Aminotransferase (AST) >= 3*ULN, AST >= 5*ULN and AST >= 8*ULN was reported. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With Either ALT >= 3*ULN or AST >= 3*ULN, and Total Bilirubin >= 2*ULN | Percentage of participants with either ALT >= 3*ULN or AST >= 3*ULN and total bilirubin >= 2*ULN was reported. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With Normal Total Cholesterol Value at Baseline and at Least 1 Abnormal Value Post-Baseline | Percentage of participants with normal total cholesterol value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal total cholesterol value was defined as total cholesterol value more than (>) 200 milligrams per deciliter (mg/dL). | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With Normal Low-Density Lipoprotein (LDL) Value at Baseline and at Least 1 Abnormal Value Post-Baseline | Percentage of participants with normal LDL value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal LDL value was defined as LDL value > 130 mg/dL. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With Normal High-Density Lipoprotein (HDL) Value at Baseline and at Least 1 Abnormal Value Post-Baseline | Percentage of participants with normal HDL value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal HDL value was defined as HDL value < 40 mg/dL. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants With Normal Triglyceride Value at Baseline and at Least 1 Abnormal Value Post-Baseline | Percentage of participants with normal triglyceride value at baseline and at least 1 abnormal value post-baseline was reported. Abnormal triglyceride value was defined as triglyceride value > 250 mg/dL. | From baseline of primary studies through end of this LTE study (Approximately 5.3 years) | 
| Percentage of Participants Who Achieved American College of Rheumatology (ACR) 50 Response Through Week 260 | ACR 50 response is greater than or equal to (>=) 50 percent (%) improvement in both tender joint count (68) and swollen joint count (66) and >= 50% 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 for efficacy according to assigned treatment groups from the primary studies, regardless of treatments actually received. | Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 
| Percentage of Participants With Boolean-Based American College of Rheumatology (ACR) or European League Against Rheumatism (EULAR) Remission Through Week 260 | Boolean based ACR/EULAR remission is achieved if all of the following 4 criteria at that visit are met: tender joint count (68 joints) <=1; swollen joint count (66 joints) <=1; CRP <=1 milligram per deciliter (mg/dL); and patient's global assessment of disease activity on visual analog scale (VAS) <=1 on a 0 (very well ) to 10 (extremely bad) scale. Higher scores indicates worst health condition. Participants were analyzed for efficacy according to the assigned treatment groups from the primary studies, regardless of the treatments they actually received. | Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 
| Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission Through Week 260 | The Disease Activity Index Score 28 (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. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of less than (<) 2.6 at any study visit. Participants were analyzed for efficacy according to the assigned treatment groups from the primary studies, regardless of the treatments they actually received. | Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 260 | 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 for efficacy according to the assigned treatment groups from the primary studies, regardless of the treatments they actually received. | Baseline (Week 0 of primary studies), Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 
| Percentage of Participants With Simplified Disease Activity Index Based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 260 | 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. Participants were analyzed for efficacy according to assigned treatment groups from the primary studies, regardless of treatments actually received. | Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 260 | 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 for efficacy according to assigned treatment groups from the primary studies, regardless of treatments actually received. | Baseline (Week 0 of primary studies), Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 
| Percentage of Participants With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 260 | 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 for efficacy according to assigned treatment groups from the primary studies, regardless of treatments actually received. | Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 80, 104, 128, 132, 156, 180, 208, 232 and 260 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Sirukumab, CNTO 136, CNTO136ARA3002, SIRROUND-D, CNTO136ARA3003, SIRROUND-T, SIRROUND-LTE