A Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients with Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy

INTERVENTION:

Product Name: Sirukumab Product Code: CNTO136 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed

INN:

Sirukumab Current Sponsor code: CNTO 136 Other descriptive name: Human anti‐IL6 monoclonal antibody Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50 ‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Product Name: Sirukumab Product Code: CNTO136 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed

INN:

Sirukumab Current Sponsor code: CNTO136 Other descriptive name: Human anti‐IL6 monoclonal antibody Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use

CONDITION:

Rheumatoid Arthritis ; MedDRA version: 17.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20]

PRIMARY OUTCOME:

Main Objective: The primary objective is to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of RA in subjects with active RA who are refractory to an anti‐TNF alpha agent. Primary end point(s): Proportion of patients with an ACR 20 response Secondary Objective: The secondary objectives are to assess the following for sirukumab in subjects with active RA who are refractory to anti‐TNF alpha agents: ; ‐Safety ; ‐Physical function; ‐Population pharmacokinetics; ‐Immunogenicity; ‐Pharmacodynamics ; Timepoint(s) of evaluation of this end point: Week 16

SECONDARY OUTCOME:

Secondary end point(s): 1. Change from baseline in HAQ‐DI ; 2. Proportion of patients with an ACR 50 response ; 3. Proportion of patients with DAS28 (CRP) remission ; 4. Pharmacogenetics (deoxyribonucleic acid [DNA]) Evaluations ; 5. Health economics avaluations ; 6. Plasma concentrations of Sirukumab Timepoint(s) of evaluation of this end point: 1. Week 24 ; 2. Week 24 ; 3. Week 24 ; 4. Week 0 ; 5. 52 weeks ; 6. 52 weeks

INCLUSION CRITERIA:

‐ Have a diagnosis of rheumatoid arthritis (RA) for at least 3 months before screening ‐ Have moderately to severely active RA with at least 4 of 68 tender joints and 4 of 66 swollen joints, at screening and at baseline ‐ Have had anti‐tumor necrosis factor (TNF)‐alpha therapy and were unresponsive by 1 of the following 2 reasons: Lack of benefit to at least 1 anti‐TNF‐alpha biologic therapy, as assessed by the treating physician, after at least 12 weeks of etanercept, yisaipu, adalimumab, golimumab, or certolizumab pegol therapy and/or at least a 14‐week dosage regimen (ie, at least 4 doses) of infliximab; Intolerance to at least 2 anti‐TNF‐alpha biologic therapies, as assessed by the treating physician, to etanercept, yisaipu, adalimumab, golimumab, certolizumab pegol, or infliximab or have documented intolerance to an anti‐TNF‐alpha agent as described above that precludes further administration of anti‐TNF‐alpha agents ‐ If using oral corticostero