A Study of the Safety and Efficacy of Golimumab (CNTO 148) in Subjects With Active Rheumatoid Arthritis Previously Treated With Biologic Anti-TNFa Agent(s)

• American College of Rheumatology 50 Response at Week 14 [ Time Frame: Week 14 ] [ Designated as safety issue: No ]
  Number of patients who achieved an American College of Rheumatology (ACR) 50 response at Week (Wk) 14. ACR 50 response is an improvement of >= 50% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessemnt of disease activity VAS scale, Physician's global assessment of disease activity VAS scale,HAQ and CRP)
• Disease Activity Index Score 28 (Using C-reactive Protein) Response at Week 14 [ Time Frame: Week 14 ] [ Designated as safety issue: No ]
  Number of patients who achieved Disease Activity Index Score 28 (DAS28) (using C-reactive protein CRP) response at Week (Wk) 14. DAS has a low value of about 1; if the CRP is 10, indicating a very serious condition, all 28 joints are swollen and tender and the disease activity index is the maximum score of 100, DAS is about 8.4.
• American College of Rheumatology 20 at Week 24 [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
  Number of patients who achieved American College of Rheumatology (ACR) 20 response at Week (Wk) 24. ACR 20 response is an improvement of >= 20% from baseline in both the tender and swollen joint count and in at least 3 of the 5 assessments ( patient's assessment of pain visual analog scale (VAS), patient's global assessemnt of disease activity VAS scale, Physician's global assessment of disease activity VAS scale,HAQ and CRP)
• Health Assessment Questionnaire Score at Week 24 [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
  Improvement from baseline in Health Assessment Questionnaire (HAQ) score at Week (Wk) 24. This 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 based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores; HAQ ranges from 0 to 3.

The purpose of this study is to evaluate the efficacy and safety of golimumab (CNTO 148) in subjects who have active rheumatoid arthritis and have been treated previously with at least 1 dose of a biologic anti-TNFa agent (etanercept, adalimumab or infliximab).

At this time, Centocor is resuming enrollment in this trial. Individual site recruitment will resume on an ongoing basis as clinical supplies are available.

Golimumab is a fully human protein (antibody) which binds to tumor necrosis factor-alpha (TNFa). TNFa is increased in patients with rheumatoid arthritis (RA), and plays a major role in causing the joint pain, swelling and damage from RA. Other marketed drugs that target TNFa (anti-TNFa drugs) have been shown to be effective in reducing the symptoms, signs and joint damage of RA, but have limitations with respect to safety and ease of use. This is a randomized, double-blind, placebo-controlled trial of the efficacy and safety of a new anti-TNFa drug, golimumab, at 2 doses, injected under the skin every 4 weeks in subjects with active RA previously treated with at least 1 dose of a biologic anti-TNFa agent (etanercept, adalimumab or infliximab). Concomitant therapy with methotrexate, sulfasalazine and/or hydroxychloroquine is permitted if the subject has tolerated these medications for at least 12 weeks prior to the first administration of study drug and is on a stable dose for at least 4 weeks prior to the first administration of study agent. The study hypothesis is that golimumab will be a safe and effective treatment for RA in subjects with active RA previously treated with at least one biologic anti-TNFa agent as measured by the American College of Rheumatology (ACR) response criteria, the Disease Activity Score 28 (DAS28) responses and the change from baseline in Health Assessment Questionnaire (HAQ), without causing unacceptable significant adverse effects. The ACR response criteria were designed to assess the level of improvement in the signs and symptoms of RA. The DAS28 responses also measure improvement in the signs and symptoms of RA using the joint examination and laboratory testing. The HAQ is a series of questions that measure a subject's impairment in physical function caused by RA. Patients will receive golimumab 50 mg or 100 mg or placebo injections under the skin every 4 weeks until Week 24. After Week 24, all subjects receive golimumab 50 mg or 100 mg injections, and golimumab continues for all groups every 4 weeks for about 4 and a half more years.

• Drug: placebo; golimumab
  SC injections every 4 wks thru wk 20 (unless early escape at wk 16).;golimumab - if early escape, 50 mg sc injections from wk 16 up 5 yrs ; golimumab - 50 mg sc injections beginning wk 24 up to 5yrs (unless early escape); golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg
• Biological: golimumab
  50 mg sc injs every 4 wks from Wk 0 thru 5 yrs(unless early escape at wk 16) ;golimumab - if early escape, 100 mg sc injs every 4 weeks beginning wk 16 up to 5 yrs ; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg
• Biological: golimumab
  100 mg sc injections every 4 weeks from weeks 0 up to 5 yrs

• Experimental: 003
  golimumab 100 mg sc injections every 4 weeks from weeks 0 up to 5 yrs
  Intervention: Biological: golimumab
• Placebo Comparator: 001
  placebo; golimumab SC injections every 4 wks thru wk 20 (unless early escape at wk 16).;golimumab - if early escape, 50 mg sc injections from wk 16 up 5 yrs ; golimumab - 50 mg sc injections beginning wk 24 up to 5yrs (unless early escape); golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg
  Intervention: Drug: placebo; golimumab
• Experimental: 002
  golimumab 50 mg sc injs every 4 wks from Wk 0 thru 5 yrs(unless early escape at wk 16) ;golimumab - if early escape, 100 mg sc injs every 4 weeks beginning wk 16 up to 5 yrs ; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100mg
  Intervention: Biological: golimumab

Inclusion Criteria:

• Patients have a diagnosis of rheumatoid arthritis (RA) (according to the revised 1987 criteria of the ACR) for at least 3 months prior to screening
• Have active RA as defined by persistent disease activity with at least 4 swollen and 4 tender joints, at the time of screening and baseline
• Must have been previously treated with at least one dose of etanercept, adalimumab, or infliximab
• If currently using methotrexate, sulfasalazine and/or hydroxychloroquine must have tolerated these agents for at least 12 weeks and be on a stable dose for at least 4 weeks prior to the first administration of study agent
• If using NSAIDs or other analgesics must be on a stable dose for at least 2 weeks prior to the first administration of study agent
• If using oral corticosteroids must be on a stable dose equivalent to <= 10 mg of prednisone/day for at least 2 weeks prior to first administration of study agent
• Are considered eligible according to specified tuberculosis (TB) screening criteria.

Exclusion Criteria:

• Patients cannot have other inflammatory diseases other than RA that might interfere with the evaluation of the benefit of golimumab therapy
• No history of treatment with natalizumab, rituximab or cytotoxic agents
• No history of demyelinating diseases such as multiple sclerosis or optic neuritis or of concurrent congestive heart failure (CHF), lymphoproliferative disease, known malignancy or history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence of recurrence)
• No history of, or ongoing, chronic or recurrent infectious disease
• No serious infection within 2 months prior to first administration of study agent.