Evaluation of Efficacy and Safety of Fostamatinib Monotherapy Compared With Adalimumab Monotherapy in Patients With Rheumatoid Arthritis (RA) (OSKIRA -4)

• DAS28 score change from baseline to week 6 compared to placebo (DAS28 = Disease Activity Score based on a 28 joint count) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
• DAS28 score change from baseline to week 24 compared to adalimumab [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

• Review of efficacy based on the following criteria: DAS28, DAS28 response criteria, ACR20, ACR50, ACR70, ACR-N [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  (ACR20 = American College of Rheumatology 20% response criteria) ACR50 = American College of Rheumatology 50% response criteria, ACR70 = American College of Rheumatology 70% response criteria, ACR N = numeric index of the ACR response)
• Health Assessment Questionnaire - Disability Index (HAQ-DI). [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• 36-item Short Form Health Survey (SF-36) questionnaire [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

The purpose of the study is to evaluate the improvements in signs and symptoms of rheumatoid arthritis (RA) for fostamatinib compared to placebo or adalimumab in patients who are Disease-Modifying anti-rheumatic drug (DMARD) naïve, DMARD intolerant or have had an inadequate response to DMARDs. The study will last for approximately six months

Sub-study:

Full title: Optional Genetic Research

Date: 10 September 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 adalimumab; and/or susceptibility to, progression of and prognosis of RA

The main study recruitment is complete, and sub study recruitment will continue until the target is reached, estimated to be June 2013

Sub-study:

Full title: (Sub-study to OSKIRA-4): A Phase IIB, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Fostamatinib Disodium Monotherapy Compared with Placebo or Adalimumab Monotherapy in Patients with Active Rheumatoid Arthritis: Magnetic Resonance Imaging Sub-Study

Date: 21 March 2011

Version: 1

Primary objective: Assess the efficacy of fostamatinib in reducing joint synovial disease activity as measured by:

• Change from baseline to Week 6 (versus placebo) in OMERACT RAMRIS synovitis score.

• Drug: Fostamatinib and placebo injections
  Fostamatinib 100mg twice daily and placebo injection once every two weeks
• Drug: Fostamatinib and placebo injections
  Fostamatinib 100mg twice daily / fostamatinib 150mg once daily and placebo injection once every two weeks
• Drug: Fostamatinib and placebo injections
  Fostamatinib 100mg twice daily / fostamatinib 100mg once daily and placebo injection once every two weeks.
• Drug: Adalimumab and placebo of fostamatinib
  Adalimumab 40mg injection once every two weeks and placebo to fostamatinib twice daily.
  Other Name: Humira®
• Drug: Placebo of fostamatinib, fostamatinib, and placebo injections
  Placebo to fostamatinib for six weeks, followed by fostamatinib 100mg twice daily / fostamatinib 150mg once daily. Placebo injection once every two weeks.

• Experimental: Dosing Group A
  Oral treatment and subcutaneous injection
  Intervention: Drug: Fostamatinib and placebo injections
• Experimental: Dosing Group B
  Oral treatment and subcutaneous injection
  Intervention: Drug: Fostamatinib and placebo injections
• Experimental: Dosing Group C
  Oral treatment and subcutaneous injection
  Intervention: Drug: Fostamatinib and placebo injections
• Active Comparator: Dosing Group D
  Oral treatment and subcutaneous injection
  Intervention: Drug: Adalimumab and placebo of fostamatinib
• Placebo Comparator: Dosing Group E
  Oral treatment and subcutaneous injection
  Intervention: Drug: Placebo of fostamatinib, fostamatinib, and placebo injections

Inclusion Criteria:

• Male or female aged 18 and over
• Active rheumatoid arthritis (RA) diagnosed after the age of 16 and diagnosis within 5 years prior to study visit 1 and inadequate response to treatment with a maximum 2 Disease-Modifying anti-rheumatic drug (DMARD) therapies, or diagnosis within 5 years prior to study visit 1 and intolerance to DMARD therapy, or diagnosis within 2 years prior to study visit 1 and no previous use of DMARDs
• 4 or more swollen joints and 4 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 2 of the following: documented history or current presence of positive 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
• Previously received treatment with a TNF alpha antagonist (including etanercept, certolizumab, adalimumab, infliximab, golimumab) or anakinra or previous treatment with other biological agent including rituximab, abatacept and tocilizumab
• Use of any DMARDs within 6 weeks before first study visit
• Severe renal impairment
• Neutropenia