Efficacy and Safety Study of R935788 Tablets to Treat Rheumatoid Arthritis (Taski-3)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the Spleen Tyrosine Kinase (Syk) Inhibitor, R935788 (R788) at a dose of 100 mg, tablet, orally, twice-a-day is effective in the treatment of Rheumatoid Arthritis in patients who have 'failed' a biologic therapy.

Official Title
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A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Dose Study of R935788 in Patients With Rheumatoid Arthritis Who Have Failed at Least One Biologic

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Fostamatinib disodium (R935788)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must give written informed consent by signing an IRB/EC-approved Informed Consent Form (ICF) prior to admission to this study. Males and females, 18 years of age or older, with active RA for at least 12 months prior to Day 1 dosing Are currently receiving or previously had received a biologic therapy with an inhibitor of TNF, rituximab, abatacept, or anakinra at an approved labeled dose for ≥3 months prior to Day 1 dosing and are designated as biologic therapy failures for lack of efficacy, safety, or tolerability. Patients may receive stable doses of methotrexate (MTX), azathioprine (not in combination with MTX), leflunomide (not in combination with MTX), sulfasalazine, chloroquine, hydroxychloroquine, gold, NSAIDs (including COX2 inhibitors), minocycline, or doxycycline. The dose must have been stable for at least 30 days prior to Day 1 dosing and must not be changed during the washout, screening and treatment periods, unless dictated by tolerability requirements. Patients who are taking MTX must have been receiving weekly MTX doses (7.5-25 mg/week) for a minimum of 3 months prior to Day 1 dosing and must be receiving a stable MTX dose, with no change in route, for the previous 6 weeks prior to Day 1 dosing. Patients who are receiving MTX must also be receiving folic or folinic acid supplementation at a stable dose for at least 6 weeks prior to Day 1 dosing. Females of childbearing potential must be fully informed of the potential for R788 to adversely affect the fetus and, if sexually active, must agree to use a well established method of birth control during the study (oral contraceptive, mechanical barrier, long acting hormonal agent). These patients must not be lactating and must have a negative urine pregnancy test at the time of randomization and at each laboratory determination. The patient must otherwise be in good health as determined by the Investigator on the basis of medical history, physical examination, and laboratory screening tests during the screening period. See exclusion criteria for specific exclusions. In the Investigator's opinion, the patient has the ability to understand the nature of the study and any hazards of participation, and to communicate satisfactorily with the Investigator and to participate in, and to comply with, the requirements of the entire protocol. Exclusion Criteria: The patient has a history of, or a concurrent, clinically significant illness, medical condition (other than arthritis) or laboratory abnormality that, in the Investigator's opinion, could affect the conduct of the study. Specifically, excluded are patients with the following: uncontrolled or poorly controlled hypertension; other autoimmune disease (psoriatic arthritis, lupus, mixed connective disorder) or arthritis syndromes (gout, Lyme disease, Reiter's syndrome); recent serious surgery or infectious disease; recent history ( of, or treatment for, a malignancy other than nonmelanomatous skin cancer, or any history of lymphoma; Hepatitis B; Hepatitis C; interstitial pneumonitis or active pulmonary infection on chest x-ray Tuberculosis (TB) known laboratory abnormalities The patient has a history of substance abuse, drug addiction or alcoholism. Patients may consume up to 4 units of alcohol per week; however, alcohol should be avoided in the 72 hours prior to lab assessments. Patients who cannot reliably comply with this should be excluded. A unit of alcohol is defined as the following: Beer=12 oz or 355 mL; wine = 5 oz or 148 mL; sweet dessert wine=3 oz or 89 mL; 80 proof distilled spirits= 1.5 oz or 44 mL. The patient has been treated previously treated with R788 under a different protocol. The patient has a pacemaker, aneurysm clip or other contraindication to MRI.

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: Arm 1<br>Fostamatinib disodium (R935788) 100 mg tablet, orally, twice-a-day | Drug: Fostamatinib disodium (R935788)<br>* R935788 100 mg tablet, orally, twice-a-day<br>|
| Placebo Comparator: Arm 2<br>Placebo, orally, twice-a-day | Drug: Placebo<br>* Placebo, orally, twice-a-day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American College of Rheumatology 20 (ACR20) Response at 3 Months | The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI); and CRP or ESR, after 3 months | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American College of Rheumatology 50 (ACR50) Response at 3 Months | The number of participants with greater than or equal to 50% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 3 months | 3 months | 
| American College of Rheumatology 70 (ACR70) Response at 3 Months | The number of participants with greater than or equal to 70% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 3 months | 3 months | 
| American College of Rheumatology Index of Improvement (ACRn) at 3 Months | The index of improvement in RA, where 0 indicates no improvement and 100 indicates a 100% improvement across all signs and symptoms of RA after 3 months of treatment | 3 months | 
| Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 3 Months | Number of participants with DAS28-CRP (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and CRP in patients with high CRP at baseline), of less than 2.6. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 2.6 indicates remission of RA symptoms | 3 months | 
| Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 3 Months | Number of participants with DAS28-CRP (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and CRP in patients with high CRP at baseline), of less than 3.2. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 3.2 indicates low disease activity. | 3 months | 
| Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 3 Months | Number of participants with DAS28-ESR (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and ESR in patients with high ESR at baseline), of less than 2.6. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 2.6 indicates remission of RA symptoms | 3 months | 
| Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 3 Months | Number of participants with DAS28-ESR (measuring RA symptoms including: tender joint count, swollen joint count, patient's assessment of disease activity, and ESR in patients with high ESR at baseline), of less than 3.2. The DAS runs from 0 to 10 - higher scores indicate worse symptoms. A score of less than 3.2 indicates low disease activity. | 3 months | 
| American College of Rheumatology 20 (ACR20) Response at Week 1 | The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 1 week. | 1 week | 
| American College of Rheumatology 20 (ACR20) Response at Week 2 | The number of participants with greater than or equal to 20% improvement in tender and swollen joint counts, AND in any 3 of the following: physician's assessment of disease activity, patient's assessment of disease activity, patient's assessment of pain, HAQ-DI; and CRP or ESR, whichever was elevated at baseline, after 2 weeks | 2 weeks | 
| Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) Erosion Score at 3 Months | Change from baseline in RAMRIS erosion score (a measure of bone erosion in the hands and wrists), calculated as the score at 3 months minus the score at baseline. The erosion score runs from 0 to 250 with lower values indicating a better clinical condition. A negative change indicates an improvement in symptoms. | Baseline to 3 months | 
| Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) Osteitis Score at 3 Months | Change from baseline in RAMRIS osteitis score (a measure of bone inflammation in the hands and wrists), calculated as the score at 3 months minus the score at baseline. The osteitis score runs from 0 to 75 with lower values indicating a better clinical condition. A negative change indicates an improvement in symptoms. | Baseline to 3 months | 
| Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) Synovitis Score at 3 Months | Change from baseline in RAMRIS synovitis score (a measure of inflammation in the joints of the hands and wrists), calculated as the score at 3 months minus the score at baseline. The synovitis score runs from 0 to 24 with lower values indicating a better clinical condition. A negative change indicates an improvement in symptoms. | Baseline to 3 months | 
| Alanine Aminotransferase (ALT) >1.5x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 1.5 times the ULN | Any time between baseline and 3 months | 
| Alanine Aminotransferase (ALT) >1.5-2x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 1.5 to 2 times the ULN | Any time between baseline and 3 months | 
| Alanine Aminotransferase (ALT) >2-3x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 2 to 3 times the ULN | Any time between baseline and 3 months | 
| Alanine Aminotransferase (ALT) >3x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 3 times the ULN | Any time between baseline and 3 months | 
| Alanine Aminotransferase (ALT) >3-5x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 3 to 5 times the ULN | Any time between baseline and 3 months | 
| Alanine Aminotransferase (ALT) >5-10x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 5 to 10 times the ULN | Any time between baseline and 3 months | 
| Alanine Aminotransferase (ALT) >10x Upper Limit of Normal (ULN) | The number of participants with ALT (a test of liver function) values greater than 10 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >1.5x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 1.5 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >1.5-2x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 1.5 to 2 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >2-3x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 2 to 3 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >3x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 3 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >3-5x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 3 to 5 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >5-10x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 5 to 10 times the ULN | Any time between baseline and 3 months | 
| Aspartate Aminotransferase (AST) >10x Upper Limit of Normal (ULN) | The number of participants with AST (a test of liver function) values greater than 10 times the ULN | Any time between baseline and 3 months | 
| Alkaline Phosphatase >1.5x Upper Limit of Normal (ULN) and >1.5x Baseline | The number of participants with alkaline phosphatase (a test of liver function) values greater than 1.5 times the ULN and greater than 1.5 times baseline | Any time between baseline and 3 months | 
| Bilirubin >1.5x Upper Limit of Normal (ULN) | The number of participants with bilirubin (a test of liver function) values greater than 1.5 times the ULN | Any time between baseline and 3 months | 
| Bilirubin >2x Upper Limit of Normal (ULN) | The number of participants with bilirubin (a test of liver function) values greater than 2 times the ULN | Any time between baseline and 3 months | 
| Absolute Neutrophil Count (ANC) <1500/mm3 | The number of participants with ANC values less than 1500/mm3 | Any time between baseline and 3 months |