Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Not Responding. (OSKIRA - 1)

• Proportion of patients with ACR20 compared to placebo (ACR20 = American College of Rheumatology 20% response criteria) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Change from baseline to week 24 in mTSS (mTSS = radiographic modified total Sharp score) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

• Proportion of patients with ACR20, ACR50, ACR70, ACR-N compared to placebo (ACR50 = American College of Rheumatology 50% response criteria, ACR70 = American College of Rheumatology 70% response criteria, [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with DAS28 and DAS28 EULAR response criteria compared to baseline (DAS28 = Disease Activity Score based on a 28 joint count; EULAR = European League Against Rheumatism) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Health Assessment Questionnaire - Disability Index (HAQ-DI). [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

• Proportion of patients with ACR20, ACR50, ACR70, ACR-N compared to placebo (ACR50 = American College of Rheumatology 50% response criteria, ACR70 = American College of Rheumatology 70% response criteria, ACR N = numeric index of the ACR response [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with DAS28 and DAS28 EULAR response criteria compared to baseline (DAS28 = Disease Activity Score based on a 28 joint count; EULAR = European League Against Rheumatism) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Health Assessment Questionnaire - Disability Index (HAQ-DI). [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

The purpose of the study is to evaluate the effectiveness of two dosing regimens of fostamatinib compared to placebo, in patients with rheumatoid arthritis (RA) who are taking methotrexate but not responding. The study will last for 1 year.

Sub-study:

Full title: Optional Genetic Research

Date: 18 June 2010

Version: 1

Objectives: To collect and store, with appropriate consent ,DNA samples for future exploratory research into genes/genetic variation that may influence response (ie, absorption, distribution, metabolism and excretion, safety, tolerability and efficacy) to fostamatinib disodium and/or methotrexate; and/or susceptibility to, progression of and prognosis of RA

• Drug: fostamatinib
  fostamatinib 100 mg twice daily
• Drug: fostamatinib
  fostamatinib 100 mg twice daily/150 mg once daily
• Drug: placebo, fostamatinib
  Placebo for 24 weeks followed by fostamatinib 100 mg twice daily

• Experimental: Dosing Regimen A
  Oral Treatment
  Intervention: Drug: fostamatinib
• Experimental: Dosing Regimen B
  Oral Treatment
  Intervention: Drug: fostamatinib
• Placebo Comparator: Dosing Regimen C
  Oral Treatment
  Intervention: Drug: placebo, fostamatinib

Inclusion Criteria:

• Active rheumatoid arthritis (RA) diagnosed after the age of 16
• Currently taking methotrexate
• 6 or more swollen joints and 6 or more tender/painful joints (from 28 joint count) and either Erythrocyte Sedimentation Rate (ESR) blood result of 28mm/h or more, or C-Reactive Protein (CRP) blood result of 10mg/L or more
• At least one of the following: documented history of positive rheumatoid factor (blood test), current presence of rheumatoid factor (blood test), radiographic erosion within 12 months prior to study enrolment, presence of serum anti-cyclic citrullinated peptide antibodies (blood test)

Exclusion Criteria:

• Females who are pregnant or breast feeding
• Poorly controlled hypertension
• Liver disease or significant liver function test abnormalities
• Certain inflammatory conditions (other than rheumatoid arthritis), connective tissue diseases or chronic pain disorders
• Recent or significant cardiovascular disease
• Significant active or recent infection including tuberculosis
• Previous failure to respond to a TNF alpha antagonist, anakinra or previous treatment with other biological agent
• Severe renal impairment
• Neutropenia