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 (OSKIRA - 3)

(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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: fostamatinib; Drug: fostamatinib; Drug: placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 323
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Research Site
  • Ciudad de Buenos Aires, Argentina
    • Research Site
  • Quilmes, Argentina
    • Research Site
  • Rosario, Argentina
    • Research Site
  • San Juan, Argentina
    • Research Site
  • San Miguel de Tucuman, Argentina
    • Research Site
  • CRD
    • Cordoba, CRD, Argentina
      • Research Site
  • Caba
    • Buenos Aires, Caba, Argentina
      • Research Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina
      • Research Site
  • TUC
    • San Miguel de Tucuman, TUC, Argentina
      • Research Site
• Belgium
  • Brussels, Belgium
    • Research Site
  • Gent, Belgium
    • Research Site
  • Liege, Belgium
    • Research Site
  • Yvoir, Belgium
    • Research Site
• Brazil
  • Brasil
    • Porto Alegre, Brasil, Brazil
      • Research Site
  • GO
    • Goiania, GO, Brazil
      • Research Site
  • PR
    • Curitiba, PR, Brazil
      • Research Site
  • SP
    • Sao Paulo, SP, Brazil
      • Research Site
• Canada
  • Newfoundland and Labrador
    • St John's, Newfoundland and Labrador, Canada
      • Research Site
  • Ontario
    • Mississauga, Ontario, Canada
      • Research Site
    • Toronto, Ontario, Canada
      • Research Site
  • Quebec
    • Pointe-claire, Quebec, Canada
      • Research Site
    • Rimouski, Quebec, Canada
      • Research Site
• Czech Republic
  • Bruntal, Czech Republic
    • Research Site
  • Ceske Budejovice, Czech Republic
    • Research Site
  • Hlucin, Czech Republic
    • Research Site
  • Ostrava-trebovice, Czech Republic
    • Research Site
  • Praha, Czech Republic
    • Research Site
  • Praha 2, Czech Republic
    • Research Site
  • Zlin, Czech Republic
    • Research Site
• France
  • Orleans Cedex 1, France
    • Research Site
• Germany
  • Erlangen, Germany
    • Research Site
  • Frankfurt, Germany
    • Research Site
  • Hamburg, Germany
    • Research Site
  • Heidelberg, Germany
    • Research Site
  • Muenchen, Germany
    • Research Site
  • HH
    • Hamburg, HH, Germany
      • Research Site
  • Nordrhein Westfalen
    • Aachen, Nordrhein Westfalen, Germany
      • Research Site
  • SN
    • Leipzig, SN, Germany
      • Research Site
• Hungary
  • Budapest, Hungary
    • Research Site
• Israel
  • Ashkelon, Israel
    • Research Site
  • Haifa, Israel
    • Research Site
  • Kfar Saba, Israel
    • Research Site
  • Ramat Gan, Israel
    • Research Site
  • Tel-hashomer, Israel
    • Research Site
• Italy
  • AN
    • Jesi, AN, Italy
      • Research Site
  • FE
    • Ferrara, FE, Italy
      • Research Site
• Mexico
  • Chihuahua, Mexico
    • Research Site
  • DF, Mexico
    • Research Site
  • Monterrey, Mexico
    • Research Site
  • Saltillo, Mexico
    • Research Site
  • SON
    • Obrergon, SON, Mexico
      • Research Site
• Portugal
  • Lisboa, Portugal
    • Research Site
  • Porto, Portugal
    • Research Site
• South Africa
  • Cape Town, South Africa
    • Research Site
  • Pretoria, South Africa
    • Research Site
  • Stellenbosch, South Africa
    • Research Site
• Spain
  • Barcelona, Spain
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom
    • Research Site
  • Christchurch, United Kingdom
    • Research Site
  • Ipswich, United Kingdom
    • Research Site
  • London, United Kingdom
    • Research Site
  • Nottingham, United Kingdom
    • Research Site
  • Westcliff-on-the Sea, United Kingdom
    • Research Site
  • Wirral, United Kingdom
    • Research Site
  • Berkshire
    • Reading, Berkshire, United Kingdom
      • Research Site
  • Cheshire
    • Warrington, Cheshire, United Kingdom
      • Research Site
  • Kent
    • Maidstone, Kent, United Kingdom
      • Research Site
  • Sussex
    • Eastbourne, Sussex, United Kingdom
      • Research Site
• United States
  • Alabama
    • Anniston, Alabama, United States
      • Research Site
    • Huntsville, Alabama, United States
      • Research Site
    • Tuscaloosa, Alabama, United States
      • Research Site
  • Arizona
    • Mesa, Arizona, United States
      • Research Site
    • Scottsdale, Arizona, United States
      • Research Site
  • Arkansas
    • Hot Springs, Arkansas, United States
      • Research Site
  • California
    • Glendale, California, United States
      • Research Site
    • La Jolla, California, United States
      • Research Site
    • Long Beach, California, United States
      • Research Site
    • Palo Alto, California, United States
      • Research Site
    • Santa Maria, California, United States
      • Research Site
    • Torrance, California, United States
      • Research Site
    • Tustin, California, United States
      • Research Site
    • Upland, California, United States
      • Research Site
  • Colorado
    • Colorado Springs, Colorado, United States
      • Research Site
  • Connecticut
    • Bridgeport, Connecticut, United States
      • Research Site
    • Trumbull, Connecticut, United States
      • Research Site
  • Delaware
    • Lewes, Delaware, United States
      • Research Site
  • Florida
    • Brandon, Florida, United States
      • Research Site
    • Jacksonville, Florida, United States
      • Research Site
    • Ocala, Florida, United States
      • Research Site
    • Orlando, Florida, United States
      • Research Site
    • Tampa, Florida, United States
      • Research Site
    • Venice, Florida, United States
      • Research Site
    • Zephyr Hills, Florida, United States
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States
      • Research Site
    • Canton, Georgia, United States
      • Research Site
  • Idaho
    • Idaho Falls, Idaho, United States
      • Research Site
  • Illinois
    • Decatur, Illinois, United States
      • Research Site
  • Iowa
    • Cedar Rapids, Iowa, United States
      • Research Site
  • Kentucky
    • Bowling Green, Kentucky, United States
      • Research Site
    • Elizabethtown, Kentucky, United States
      • Research Site
  • Maryland
    • Crofton, Maryland, United States
      • Research Site
  • Massachusetts
    • Fall River, Massachusetts, United States
      • Research Site
    • Worcester, Massachusetts, United States
      • Research Site
  • Michigan
    • Lansing, Michigan, United States
      • Research Site
  • Mississippi
    • Flowood, Mississippi, United States
      • Research Site
  • Missouri
    • Florissant, Missouri, United States
      • Research Site
    • Richmond Heights, Missouri, United States
      • Research Site
  • New Mexico
    • Las Cruces, New Mexico, United States
      • Research Site
  • New York
    • Albany, New York, United States
      • Research Site
    • Brooklyn, New York, United States
      • Research Site
    • Olean, New York, United States
      • Research Site
    • Rochester, New York, United States
      • Research Site
    • Roslyn, New York, United States
      • Research Site
    • Smithtown, New York, United States
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States
      • Research Site
    • Durham, North Carolina, United States
      • Research Site
    • Greensboro, North Carolina, United States
      • Research Site
  • Ohio
    • Dayton, Ohio, United States
      • Research Site
    • Mayfield Village, Ohio, United States
      • Research Site
  • Oregon
    • Lake Oswego, Oregon, United States
      • Research Site
  • Pennsylvania
    • Duncansville, Pennsylvania, United States
      • Research Site
    • Philadelphia, Pennsylvania, United States
      • Research Site
    • Pittsburgh, Pennsylvania, United States
      • Research Site
    • West Reading, Pennsylvania, United States
      • Research Site
  • South Carolina
    • Charleston, South Carolina, United States
      • Research Site
    • Greenville, South Carolina, United States
      • Research Site
  • Tennessee
    • Hixson, Tennessee, United States
      • Research Site
    • Memphis, Tennessee, United States
      • Research Site
    • Nashville, Tennessee, United States
      • Research Site
  • Texas
    • Amarillo, Texas, United States
      • Research Site
    • Austin, Texas, United States
      • Research Site
    • Dallas, Texas, United States
      • Research Site
    • Houston, Texas, United States
      • Research Site
    • San Antonio, Texas, United States
      • Research Site
  • Washington
    • Tacoma, Washington, 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:

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dosing Regimen A; Oral Treatment	Drug: fostamatinib; fostamatinib 100 mg twice daily; Drug: fostamatinib; fostamatinib 100 mg twice daily/150 mg once daily
Experimental: Dosing Regimen B; Oral Treatment	Drug: fostamatinib; fostamatinib 100 mg twice daily; Drug: fostamatinib; fostamatinib 100 mg twice daily/150 mg once daily
Placebo Comparator: Dosing Regimen C; Oral Treatment	Drug: placebo; Placebo twice daily

What is the study measuring?

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

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: September 8, 2010
• First Submitted That Met QC Criteria: September 8, 2010
• First Posted (Estimate): September 9, 2010

Study Record Updates

• Last Update Posted (Estimate): April 7, 2014
• Last Update Submitted That Met QC Criteria: February 27, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: D4300C00003; 2010-020745-27 (EudraCT Number)