A Study of Effectiveness and Safety of CNTO 136 in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness and safety of subcutaneous (under the skin) administration of anti-interleukin-6 monoclonal antibody (CNTO 136) in reducing signs and symptoms of participants with active rheumatoid arthritis (RA) with methotrexate (MTX) therapy.

Detailed Description
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This is a multicenter, double-blind (neither physician nor participants knows the treatment that the participant receives), randomized (study medication is assigned by chance), placebo-controlled (an inactive substance is compared with a medication to test whether the medication has a real effect in a clinical study) study. This study will be conducted in 2 parts (Part A and Part B). Each part consists of 3 phases: screening (approximately 1 month prior to the start of study medication), treatment phase (Part A: 22 weeks and Part B: 24 weeks), and follow-up phase (approximately 4 months after the last administration of study medication). In Part A, participants will be randomly assigned to 2 groups to receive CNTO 136 100 mg and placebo for 22 weeks. All participants in Part A, will be crossed over at Week 12 from placebo to CNTO 136 (for Group 1) and from CNTO 136 to placebo (for Group 2). In Part B, participants will be randomly assigned to 5 groups to receive placebo and/or 1 of 3 doses of CNTO 136 (100mg, 50mg or 25mg) for 24 weeks. Participants in Part B, Group 1 will be crossed over at Week 12 from placebo to CNTO 136. All participants should be maintained on a stable dose of MTX for at least 6 weeks prior to the start of study medication through Week 24. Safety will be evaluated by the assessment of adverse events, vital signs, clinical findings, 12-lead electrocardiogram, and clinical laboratory tests which will be monitored throughout the study. The total duration of study participation for a participant will be approximately 42 weeks.

Official Title
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A Phase 2, 2-Part, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Proof-of-concept, Dose-finding Study Evaluating the Efficacy and Safety of CNTO 136 Administered Subcutaneously in Subjects With Active Rheumatoid Arthritis Despite Methotrexate Therapy

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: CNTO 136 100 mg
* Drug: CNTO 136 50 mg
* Drug: CNTO 136 25 mg
* Drug: Placebo
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with rheumatoid arthritis (RA) for at least 4 months prior to screening Have been treated and having an inadequate response with the tolerated dose of methotrexate (MTX) (at least 15mg/week) for at least 4 months prior to screening. MTX doses of 10 or 12.5 mg/week are allowed if participant had intolerance of 15 mg/week MTX route of administration and dose (not to exceed 25 mg/week) should be stable for at least 6 weeks prior to the start of the study medication Have active RA as defined by persistent disease activity with at least 6 swollen and 6 tender joints, at the time of screening and baseline, and either anti-cyclic citrullinated peptide antibody-positive or rheumatoid factor positive at screening C-reactive protein greater than or equal to 1.0 mg/dL (10 mg/L) Agree to use one of the contraception methods defined in the protocol Exclusion Criteria: Have inflammatory diseases other than RA that might confound the evaluation of the benefit of CNTO 136 therapy in arthritis Family history of/ have long QT syndrome; or a history of second or third-degree heart block Received systemic immunosuppressives or disease modifying antirheumatic drug other than MTX, sulfasalazine, hydroxychloroquine or chloroquine within 4 weeks prior to the start of study medication Received intra articular (into joints), intramuscular, or intravenous corticosteroids within 4 weeks prior to the start of study medication Positive human immunodeficiency virus test, hepatitis B or hepatitis C History of / have chronic or recurrent infectious disease, history of / active tuberculosis Have serious infection within 2 months prior to start of study medication

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Group 1<br>Participants will receive placebo (Week 0 to Week 10) and later CNTO 136 100 mg (Week 12 to Week 22) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 100 mg<br>* CNTO 136 100 mg will be administered subcutaneously (under the skin) every 2 or 4 weeks as per the appropriate randomized arm.<br>* Other names: Sirukumab;Drug: Placebo<br>* Placebo will be adminstered subcutaneously as per the appropriate randomized arm.<br>Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|
| Experimental: Part A, Group 2<br>Participants will receive CNTO 136 100 mg (Week 0 to Week 10) and later placebo (Week 12 to Week 22) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 100 mg<br>* CNTO 136 100 mg will be administered subcutaneously (under the skin) every 2 or 4 weeks as per the appropriate randomized arm.<br>* Other names: Sirukumab;Drug: Placebo<br>* Placebo will be adminstered subcutaneously as per the appropriate randomized arm.<br>Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|
| Experimental: Part B, Group 1<br>Participants will receive placebo (Week 0 to Week 10) and later CNTO 136 100 mg (Week 12 to Week 24) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 100 mg<br>* CNTO 136 100 mg will be administered subcutaneously (under the skin) every 2 or 4 weeks as per the appropriate randomized arm.<br>* Other names: Sirukumab;Drug: Placebo<br>* Placebo will be adminstered subcutaneously as per the appropriate randomized arm.<br>Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|
| Experimental: Part B, Group 2<br>Participants will receive CNTO 136 100 mg (Week 0 to Week 24) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 100 mg<br>* CNTO 136 100 mg will be administered subcutaneously (under the skin) every 2 or 4 weeks as per the appropriate randomized arm.<br>* Other names: Sirukumab;Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|
| Experimental: Part B, Group 3<br>Participants will receive CNTO 136 100 mg (Week 0 to Week 24) every 4 weeks and placebo at interim visits (Weeks 2, 6, 10, 14, 18, and 22). Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 100 mg<br>* CNTO 136 100 mg will be administered subcutaneously (under the skin) every 2 or 4 weeks as per the appropriate randomized arm.<br>* Other names: Sirukumab;Drug: Placebo<br>* Placebo will be adminstered subcutaneously as per the appropriate randomized arm.<br>Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|
| Experimental: Part B, Group 4<br>Participants will receive CNTO 136 50 mg (Week 0 to Week 24) every 4 weeks and placebo at interim visits (Weeks 2, 6,10, 14, 18, and 22). Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 50 mg<br>* CNTO 136 50 mg will be administered subcutaneously every 4 weeks from Week 0 to Week 24.<br>* Other names: Sirukumab;Drug: Placebo<br>* Placebo will be adminstered subcutaneously as per the appropriate randomized arm.<br>Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|
| Experimental: Part B, Group 5<br>Participants will receive CNTO 136 25 mg (Week 0 to Week 24) every 4 weeks and placebo at interim visits (Weeks 2, 6,10, 14, 18, and 22). Stable dose of methotrexate will be maintained through Week 24. | Drug: CNTO 136 25 mg<br>* CNTO 136 25 mg will be administered subcutaneously every 4 weeks from Week 0 to Week 24.<br>* Other names: Sirukumab;Drug: Placebo<br>* Placebo will be adminstered subcutaneously as per the appropriate randomized arm.<br>Drug: Methotrexate<br>* Stable dose of methotrexate will be maintained through Week 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 12 (Part B) | An American College of Rheumatology (ACR) 50 response is defined as greater than or equal to (>=) 50 percent (%) 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 Visual Analogue Scale (Score) 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 Health Assessment Questionnaire-Disability Index (HAQ-DI, the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and serum C-reactive protein (CRP). | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Index Score 28 (DAS28) Based on C-reactive Protein (CRP) at Week 12 (Part A and Part B) | 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. | Baseline, Week 12 | 
| Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 12 (Part A) | 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. | Week 12 | 
| Serum Sirukumab Concentrations Through Week 38 (Part A) | Sirukumab Concentrations in serum were measured. | Week 0, Day 2, Day 5, Day 8, Day 11, Week 2, Week 4, Week 8, Week 10, Week 10 Day 4, Week 10 Day 7, Week 12, Week 14, Week 18, Week 22, Week 24, and Week 38 | 
| Serum Sirukumab Concentrations Through Week 38 (Part B) | Sirukumab Concentrations in serum were measured. | Week 0, Day 5, Day 8, Day 11, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 24 Day4, Week 24 Day7, Week 26, Week 28, Week 30, Week 34 and Week 38 | 
| Percent Improvement From Baseline in Serum C-Reactive Protein (CRP) At Week 2 (Part A and Part B) | Serum CRP is a marker of systemic inflammation. A negative change from baseline in CRP represents improvement. | Baseline, Week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis, Rheumatoid, Rheumatoid Arthritis, Active Rheumatoid Arthritis, CNTO 136, Interleukin-6, Anti-interleukin-6 monoclonal antibody, Methotrexate, Placebo