A Study to Assess the Effect of Tocilizumab + Methotrexate on Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis

• Percentage of patients ACR 50/70 responses; change from baseline in ACR core set components. [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
• AEs, laboratory parameters, vital signs [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

This 3 arm study will compare the safety and efficacy, with regard to reduction of signs and symptoms, of tocilizumab versus placebo, both in combination with methotrexate (MTX). in patients with moderate to severe active rheumatoid arthritis (RA) who currently have an inadequate response to MTX. Patients wil be randomized to receive tocilizumab 4mg/kg iv, tocilizumab 8mg/mg iv, or placebo iv, every 4 weeks; all patients will also receive methotrexate 10-25mg weekly. The anticipated time on study treatment is 3-12 months, and the target sample size is 500+ individuals.

• Drug: tocilizumab [RoActemra/Actemra]
  4mg/kg iv / month
• Drug: tocilizumab [RoActemra/Actemra]
  8mg/kg iv / month
• Drug: Placebo
  iv / month
• Drug: Methotrexate
  10-25mg/week

• Experimental: 1
  Interventions:

  • Drug: tocilizumab [RoActemra/Actemra]
  • Drug: Methotrexate
• Experimental: 2
  Interventions:

  • Drug: tocilizumab [RoActemra/Actemra]
  • Drug: Methotrexate
• Placebo Comparator: 3
  Interventions:

  • Drug: Placebo
  • Drug: Methotrexate

• Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum. 2010 Jan;62(1):33-43.
• Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R; OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008 Mar 22;371(9617):987-97.

Inclusion Criteria:

• adult patients at least 18 years of age with moderate to severe active RA for at least 6 months;
• inadequate response to a stable dose of MTX;
• patients of reproductive potential must be using reliable methods of contraception.

Exclusion Criteria:

• major surgery (including joint surgery) within 8 weeks before entering study, or planned surgery within 6 months after entering study;
• prior treatment failure with an anti-tumor necrosis factor agent;
• women who are pregnant or breast-feeding.