Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate and Have Had Inadequate Response to Single TNF-alpha Antagonist

Study Overview
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Brief Summary
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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 and have had an inadequate response to a single TNF-alpha antagonist. The study will last for approximately six months.

Detailed Description
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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

Official Title
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(OSKIRA-3): A Phase III, Multi-centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of Two Dosing Regimens of Fostamatinib Disodium in Rheumatoid Arthritis Patients With Inadequate Response to a TNF-alpha Antagonist

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: fostamatinib
* Drug: fostamatinib
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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 12months 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 anakinra or previous treatment with biological agent (other than TNF alpha antagonists including rituximab, abatacept and tocilizumab) Severe renal impairment Neutropenia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosing Regimen A<br>Oral Treatment | Drug: fostamatinib<br>* fostamatinib 100 mg twice daily<br>|
| Experimental: Dosing Regimen B<br>Oral Treatment | Drug: fostamatinib<br>* fostamatinib 100 mg twice daily/150 mg once daily<br>|
| Placebo Comparator: Dosing Regimen C<br>Oral Treatment | Drug: placebo<br>* Placebo twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving ACR20 at Week 24, Comparison Between Fostamatinib and Placebo | ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving ACR20 at Week 1, Comparison Between Fostamatinib and Placebo | ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily. | 1 week | 
| Proportion of Patients Achieving ACR50 at Week 24, Comparison Between Fostamatinib and Placebo | ACR50: American College of Rheumatology 50% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily. | 24 weeks | 
| Proportion of Patients Achieving ACR70 at Week 24, Comparison Between Fostamatinib and Placebo | ACR70: American College of Rheumatology 70% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as C-Reactive Protein) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once daily. | 24 weeks | 
| ACRn - Comparison Between Fostamatinib and Placebo at Week 24 | ACRn: American College of Rheumatology index of RA improvement, based on smallest percentage improvement in the count of swollen joints (out of 28 joints), count of tender joints (out of 28 joints), or in blood test measures of inflammation (such as C-Reactive Protein) or the physician or patient's own assessments of disease activity, pain and physical function. Scores are reported as a percentage improvement on a scale of -100 to +100, with larger values representing a better clinical outcome. Mean refers to change at Week 24. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day. | Baseline and 24 weeks | 
| Proportion of Patients Achieving DAS28-CRP <2.6 at Week 24, Comparison Between Fostamatinib and Placebo | DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patients' own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. A DAS28-CRP score of <2.6 is indicative of remission of RA symptoms. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once daily. | 24 weeks | 
| Proportion of Patients Achieving DAS28-CRP <=3.2 at Week 12, Comparison Between Fostamatinib and Placebo | DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patients' own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. A DAS28-CRP score of <=3.2 indicates low disease activity. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once daily. | 12 weeks | 
| Proportion of Patients Achieving DAS28-CRP EULAR Response at Week 24, Comparison Between Fostamatinib and Placebo | Change from baseline in DAS28-CRP at Week 24 was categorised using the European League Against Rheumatism (EULAR) response criteria. BID = twice daily, CRP = C-reactive protein, DAS28 = Disease Activity Score based on a 28-joint count, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day. | 24 weeks | 
| Proportion of Patients With a HAQ-DI Response at Week 24 - Comparison Between Fostamatinib and Placebo | HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygeine, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. A HAQ-DI response is a reduction from baseline in HAQ-DI greater than or equal to the minimally important difference (0.22). BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, QD = once a day. | 24 weeks | 
| Change From Baseline to Week 24 in mTSS Score, Comparison Between Fostamatinib and Placebo | mTSS: modified total sharp score, a measure of structural progression based upon X-rays. Hand and foot joints are scored for eroisions and joint space narrowing and the results summed to give a value between 0 and 488. A higher value represents more serious progression of the disease. After disregarding ineligible records, patients with 2 or more non-missing values had missing data imputed via linear extrapolation/interpolation methods. Patients with only 1 result were excluded from the analysis. ANCOVA = Analysis of covariance, BID = twice daily, IP = investigational product, PO = orally, QD = once a day. | Baseline and 24 weeks | 
| SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Placebo at Week 24 | SF-36: 36 item short form health survey, as a measure of health-related quality of life. Scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in scores at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily | Baseline and 24 weeks | 
| SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Placebo at Week 24 | SF-36: 36 item short form health survey, as a measure of health-related quality of life. The SF-36 scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in score at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily. | Baseline and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis