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

(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 Adalimumab Monotherapy in Patients With Active Rheumatoid Arthritis

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

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Fostamatinib and placebo injections; Drug: Fostamatinib and placebo injections; Drug: Fostamatinib and placebo injections; Drug: Adalimumab and placebo of fostamatinib; Drug: Placebo of fostamatinib, fostamatinib, and placebo injections

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 644
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Pleven, Bulgaria
    • Research Site
  • Plovdiv, Bulgaria
    • Research Site
  • Ruse, Bulgaria
    • Research Site
  • Sevlievo, Bulgaria
    • Research Site
  • Sofia, Bulgaria
    • Research Site
  • Veliko Tarnovo, Bulgaria
    • Research Site
• Canada
  • Ontario
    • Mississauga, Ontario, Canada
      • Research Site
• Czech Republic
  • Brno, Czech Republic
    • Research Site
  • Bruntal, Czech Republic
    • Research Site
  • Hlucin, Czech Republic
    • Research Site
  • Liberec, Czech Republic
    • Research Site
  • Ostrava, Czech Republic
    • Research Site
  • Ostrava - Poruba, Czech Republic
    • Research Site
  • Ostrava - Trebovice, Czech Republic
    • Research Site
  • Praha, Czech Republic
    • Research Site
  • Praha 11, Czech Republic
    • Research Site
  • Praha 2, Czech Republic
    • Research Site
  • Praha 4, Czech Republic
    • Research Site
  • Zlin, Czech Republic
    • Research Site
• Germany
  • Dresden, Germany
    • Research Site
  • Hamburg, Germany
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  • Muenchen, Germany
    • Research Site
• Hungary
  • Balatonfured, Hungary
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  • Balatonfüred, Hungary
    • Research Site
  • Budapest, Hungary
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  • Debrecen, Hungary
    • Research Site
  • Zalaegerszeg, Hungary
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• Netherlands
  • Amsterdam, Netherlands
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• Poland
  • Bytom, Poland
    • Research Site
  • Chelm Slaski, Poland
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  • Grodzisk Mazowiecki, Poland
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  • Sroda Wielkopolska, Poland
    • Research Site
  • Warszawa, Poland
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  • Wroclaw, Poland
    • Research Site
  • Zyrardow, Poland
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  • Łódź, Poland
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• Russian Federation
  • Moscow, Russian Federation
    • Research Site
  • Nizhny Novgorod, Russian Federation
    • Research Site
  • Petrozavodsk, Russian Federation
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  • Ryazan, Russian Federation
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  • St. Petersburg, Russian Federation
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  • Voronezh, Russian Federation
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  • Yaroslavl, Russian Federation
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• Slovakia
  • Trebisov, Slovakia
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  • Trnava, Slovakia
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• South Africa
  • Cape Town, South Africa
    • Research Site
  • Durban, South Africa
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  • Pretoria, South Africa
    • Research Site
  • Stellenbosch, South Africa
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  • Gauteng
    • Pretoria, Gauteng, South Africa
      • Research Site
  • Kwazulu Natal
    • Durban, Kwazulu Natal, South Africa
      • Research Site
  • Western Cape
    • Cape Town, Western Cape, South Africa
      • Research Site
• Ukraine
  • Donetsk, Ukraine
    • Research Site
  • Ivano-frankivsk, Ukraine
    • Research Site
  • Kharkiv, Ukraine
    • Research Site
  • Kyiv, Ukraine
    • Research Site
  • Lutsk, Ukraine
    • Research Site
  • Lviv, Ukraine
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  • Odessa, Ukraine
    • Research Site
  • Simferopol, Ukraine
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  • Zaporyzhzhya, Ukraine
    • Research Site
• United Kingdom
  • Basingstoke, United Kingdom
    • Research Site
  • Eastbourne, United Kingdom
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  • London, United Kingdom
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  • Manchester, United Kingdom
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  • Wolverhampton, United Kingdom
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  • Berkshire
    • Reading, Berkshire, United Kingdom
      • Research Site
  • Greater London
    • London, Greater London, United Kingdom
      • Research Site
  • Sussex
    • Eastbourne, Sussex, United Kingdom
      • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Research Site
  • Arizona
    • Glendale, Arizona, United States
      • Research Site
    • Mesa, Arizona, United States
      • Research Site
    • Phoenix, Arizona, United States
      • Research Site
    • Scottsdale, Arizona, United States
      • Research Site
  • California
    • Huntington Beach, California, United States
      • Research Site
    • Long Beach, California, United States
      • Research Site
  • Colorado
    • Colorado Springs, Colorado, United States
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  • Connecticut
    • Bridgeport, Connecticut, United States
      • Research Site
  • Florida
    • Daytona Beach, Florida, United States
      • Research Site
    • Jacksonville, Florida, United States
      • Research Site
    • Miami, Florida, United States
      • Research Site
    • Ocala, Florida, United States
      • Research Site
    • Palm Harbor, Florida, United States
      • Research Site
    • Pinellas Park, Florida, United States
      • Research Site
    • Venice, Florida, United States
      • Research Site
  • Illinois
    • Chicago, Illinois, United States
      • Research Site
  • Indiana
    • South Bend, Indiana, United States
      • Research Site
  • Kentucky
    • Bowling Green, Kentucky, United States
      • Research Site
    • Elizabethtown, Kentucky, United States
      • Research Site
  • Maryland
    • Oxon Hill, Maryland, United States
      • Research Site
  • Michigan
    • Kalamazoo, Michigan, United States
      • Research Site
  • Missouri
    • Richmond Heights, Missouri, United States
      • Research Site
  • Montana
    • Kalispell, Montana, United States
      • Research Site
  • New Hampshire
    • Nashua, New Hampshire, United States
      • Research Site
  • New Mexico
    • Albuquerque, New Mexico, United States
      • Research Site
    • Las Cruces, New Mexico, United States
      • Research Site
  • New York
    • Brooklyn, New York, United States
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States
      • Research Site
  • Ohio
    • Perrysburg, Ohio, United States
      • Research Site
  • Pennsylvania
    • Duncansville, Pennsylvania, United States
      • Research Site
  • South Carolina
    • Greenville, South Carolina, United States
      • Research Site
  • Tennessee
    • Jackson, Tennessee, United States
      • Research Site
    • Knoxville, Tennessee, United States
      • Research Site
    • Memphis, Tennessee, United States
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  • Texas
    • Austin, Texas, United States
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    • Houston, Texas, United States
      • Research Site
    • Mesquite, Texas, United States
      • Research Site
    • Plano, Texas, United States
      • Research Site
    • San Antonio, Texas, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dosing Group A; Oral treatment and subcutaneous injection	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.
Experimental: Dosing Group B; Oral treatment and subcutaneous injection	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.
Experimental: Dosing Group C; Oral treatment and subcutaneous injection	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.
Active Comparator: Dosing Group D; Oral treatment and subcutaneous injection	Drug: Adalimumab and placebo of fostamatinib; Adalimumab 40mg injection once every two weeks and placebo to fostamatinib twice daily.; Other Names: Humira®
Placebo Comparator: Dosing Group E; Oral treatment and subcutaneous injection	Drug: Placebo of fostamatinib, fostamatinib, and placebo injections; Placebo injection once every two weeks. Placebo to fostamatinib for six weeks, followed by fostamatinib 100mg twice daily (Group F) / fostamatinib 100mg twice daily then 150mg once daily (Group G).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DAS28-CRP Score - Change From Baseline to Week 6 Compared to 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 patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, QD = once a day, SC = subcutaneous.	Baseline and 6 weeks
DAS28-CRP Score - Change From Baseline to Week 24 Compared to Adalimumab	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 patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, QD = once a day, SC = subcutaneous.	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DAS28 EULAR Response at Week 6	Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. Non-responder imputation has been applied by carrying the baseline observation forward. bid = twice daily, 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, SC = subcutaneous.	6 weeks
DAS28 EULAR Response at Week 24	Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. Non-responder imputation has been applied by carrying the baseline observation forward. bid = twice daily, 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, SC = subcutaneous.	24 weeks
Proportion of Patients Achieving ACR20 up to Week 24	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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	6 and 24 weeks
Proportion of Patients Achieving ACR50 up to Week 24	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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	6 and 24 weeks
Proportion of Patients Achieving ACR70 up to Week 24	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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	6 and 24 weeks
ACRn - Comparison Between Fostamatinib and Placebo at Week 6	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 CRP) or the physician and patient's own asessment 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. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous. Mean refers to change at Week 6. Treatment difference: difference between fostamatinib and placebo groups.	Baseline and 6 weeks
ACRn - Comparison Between Fostamatinib and Adalimumab 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 CRP) or the physician and patient's own asessment 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. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous. Mean refers to change at Week 24. Treatment difference: difference between fostamatinib and adalimumab groups.	Baseline and 24 weeks
HAQ-DI - Comparison of the Change From Baseline Between Fostamatinib and Placebo at Week 6	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, hygiene, 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. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	Baseline and 6 weeks
HAQ-DI - Comparison of the Change From Baseline Between Fostamatinib and Adalimumab at Week 24	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, hygiene, 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. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.	Baseline and 24 weeks
SF-36 - Comparison of the Change in PCS From Baseline Between Fostamatinib and Adalimumab at Week 24	SF-36: 36-item Short Form Health Survey, a measure of health-related QoL. Scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional & Mental Health) are derived & normalised to a scale of 0-100. Physical & Mental Component Scores (PCS & MCS) are derived by multiplying each of these 8 scores by a constant, summing them & standardising against a population with mean of 50, standard deviation of 10. Higher scores represent a better QoL. Mean changes from baseline score are presented at each visit as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Non-responder imputation applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, PO = orally, QD = once a day, QoL = quality of life, SC = subcutaneous.	Baseline and 24 weeks
SF-36 - Comparison of the Change in MCS From Baseline Between Fostamatinib and Adalimumab at Week 24	SF-36: 36-item Short Form Health Survey, a measure of health-related QoL. Scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional & Mental Health) are derived & normalised to a scale of 0-100. Physical & Mental Component Scores (PCS & MCS) are derived by multiplying each of these 8 scores by a constant, summing them & standardising against a population with mean of 50, standard deviation of 10. Higher scores represent a better QoL. Mean changes from baseline score are presented at each visit as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Non-responder imputation applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, PO = orally, QD = once a day, QoL = quality of life, SC = subcutaneous.	Baseline and 24 weeks

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Neil MacKillop, MD PhD, AstraZeneca

Publications and helpful links

General Publications

• Taylor PC, Genovese MC, Greenwood M, Ho M, Nasonov E, Oemar B, Stoilov R, Vencovsky J, Weinblatt M. OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy. Ann Rheum Dis. 2015 Dec;74(12):2123-9. doi: 10.1136/annrheumdis-2014-205361. Epub 2014 Jul 29.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: December 17, 2010
• First Submitted That Met QC Criteria: December 21, 2010
• First Posted (Estimate): December 22, 2010

Study Record Updates

• Last Update Posted (Estimate): May 6, 2014
• Last Update Submitted That Met QC Criteria: April 3, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis; fostamatinib; OSKIRA
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: D4300C00004; 2010-023692-26 (EudraCT Number)