Evaluation of Effectiveness of Two Dosing Regimens of Fostamatinib Compared to Placebo in Patients With Rheumatoid Arthritis (RA) Who Are Taking Disease Modifying Anti-rheumatic Drug (DMARD) But Not Responding. (OSKIRA - 2)

(OSKIRA-2): 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 an Inadequate Response to DMARDs

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 disease modifying anti-rheumatic drug (DMARD) but not responding. The study will last for 1 year.

Study Overview

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

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): 913
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada
    • Research Site
  • Reading, Canada
    • Research Site
  • Alberta
    • Edmonton, Alberta, Canada
      • Research Site
  • Manitoba
    • Winnipeg, Manitoba, Canada
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  • Ontario
    • Bowmanville, Ontario, Canada
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    • Hamilton, Ontario, Canada
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    • Mississauga, Ontario, Canada
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    • Ottawa, Ontario, Canada
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    • Toronto, Ontario, Canada
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  • Quebec
    • Montreal, Quebec, Canada
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    • Trois-rivieres, Quebec, Canada
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• Czech Republic
  • Brno, Czech Republic
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  • Bruntal, Czech Republic
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  • Ceska Lipa, Czech Republic
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  • Ceske Budejovice, Czech Republic
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  • Hlucin, Czech Republic
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  • Liberec, Czech Republic
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  • Ostrava - Trebovice, Czech Republic
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  • Praha, Czech Republic
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  • Praha 11, Czech Republic
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  • Praha 2, Czech Republic
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  • Praha 4, Czech Republic
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  • Sokolov, Czech Republic
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  • Terezin, Czech Republic
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  • Zlin, Czech Republic
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• Germany
  • Erlangen, Germany
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  • Hamburg, Germany
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  • Muenchen, Germany
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• India
  • Lucknow, India
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  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India
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  • Gujarat
    • Ahmedabad, Gujarat, India
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    • Gandhinagar, Gujarat, India
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    • Vadodara, Gujarat, India
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  • Karnataka
    • Bangalore, Karnataka, India
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    • Mangalore, Karnataka, India
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  • Maharashtra
    • Mumbai, Maharashtra, India
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    • Pune, Maharashtra, India
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  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India
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    • Madurai, Tamil Nadu, India
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• Israel
  • Ashkelon, Israel
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  • Beer Yaakov, Israel
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  • Haifa, Israel
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  • Kfar-saba, Israel
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  • Petah-tikva, Israel
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  • Ramat Gan, Israel
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  • Ramat-gan, Israel
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  • Rehovot, Israel
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  • Tel Aviv, Israel
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• Italy
  • AN
    • Jesi, AN, Italy
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  • MI
    • Legnano, MI, Italy
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  • UD
    • Udine, UD, Italy
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  • VA
    • Varese, VA, Italy
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• Latvia
  • Liepaja, Latvia
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  • Riga, Latvia
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  • Valmiera, Latvia
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• Lithuania
  • Kaunas, Lithuania
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  • Klaipeda, Lithuania
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  • Siauliai, Lithuania
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• Portugal
  • Aveiro, Portugal
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  • Lisboa, Portugal
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  • Porto, Portugal
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• Romania
  • Baia Mare, Romania
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  • Brailari, Romania
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  • Bucharest, Romania
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  • Bucuresti, Romania
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  • Ploiesti, Romania
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• Serbia
  • Belgrade, Serbia
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  • Kragujevac, Serbia
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  • Niska Banja, Serbia
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  • Novi Sad, Serbia
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• South Africa
  • Port Elizabeth, South Africa
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  • Stellenbosch, South Africa
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  • Gauteng
    • Kempron Park, Gauteng, South Africa
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    • Pretoria, Gauteng, South Africa
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  • Kz-natal
    • Durban, Kz-natal, South Africa
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  • W Cape
    • Cape Town, W Cape, South Africa
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• Spain
  • Barcelona, Spain
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  • Getafe, Spain
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  • Canarias
    • La Laguna (tenerife), Canarias, Spain
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  • Extremadura
    • Merida, Extremadura, Spain
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• Ukraine
  • Kharkiv, Ukraine
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  • Kyiv, Ukraine
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  • Lutsk, Ukraine
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  • Lviv, Ukraine
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  • Simferopol, Ukraine
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  • Vinnytsia, Ukraine
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  • Zaporizhzhya, Ukraine
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  • Zaporyzhzhya, Ukraine
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• United Kingdom
  • Basingstoke, United Kingdom
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  • Cambridge, United Kingdom
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  • London, United Kingdom
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  • Newcastle Upon Tyne, United Kingdom
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  • Stoke on Trent, United Kingdom
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  • Swindon, United Kingdom
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  • Kent
    • Maidstone, Kent, United Kingdom
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  • Sussex
    • Eastbourne, Sussex, United Kingdom
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  • West Midlands
    • Solihull, West Midlands, United Kingdom
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• United States
  • Alabama
    • Birmingham, Alabama, United States
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  • Arizona
    • Glendale, Arizona, United States
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    • Mesa, Arizona, United States
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    • Phoenix, Arizona, United States
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    • Scottsdale, Arizona, United States
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    • Tucson, Arizona, United States
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  • Arkansas
    • Hot Springs, Arkansas, United States
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  • California
    • Huntington Beach, California, United States
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    • Torrance, California, United States
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  • Connecticut
    • Trumbull, Connecticut, United States
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  • District of Columbia
    • Washington, District of Columbia, United States
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  • Florida
    • Boca Raton, Florida, United States
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    • Brandon, Florida, United States
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    • Jacksonville, Florida, United States
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    • Miami, Florida, United States
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    • Orlando, Florida, United States
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    • Tampa, Florida, United States
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    • Venice, Florida, United States
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    • Zephyr Hills, Florida, United States
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  • Georgia
    • Canton, Georgia, United States
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    • Decatur, Georgia, United States
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    • Macon, Georgia, United States
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  • Idaho
    • Boise, Idaho, United States
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  • Indiana
    • South Bend, Indiana, United States
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  • Kentucky
    • Elizabethtown, Kentucky, United States
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  • Maryland
    • Crofton, Maryland, United States
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    • Cumberland, Maryland, United States
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    • Hagerstown, Maryland, United States
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  • Michigan
    • Kalamazoo, Michigan, United States
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  • Mississippi
    • Flowood, Mississippi, United States
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  • Missouri
    • St. Louis, Missouri, United States
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  • Montana
    • Kalispell, Montana, United States
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  • Nebraska
    • Omaha, Nebraska, United States
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  • New Jersey
    • Manalapan, New Jersey, United States
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  • New Mexico
    • Las Cruces, New Mexico, United States
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  • New York
    • Brooklyn, New York, United States
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    • Rochester, New York, United States
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    • Roslyn, New York, United States
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    • Syracuse, New York, United States
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  • North Carolina
    • Charlotte, North Carolina, United States
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    • Durham, North Carolina, United States
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  • Ohio
    • Dayton, Ohio, United States
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  • Pennsylvania
    • Duncansville, Pennsylvania, United States
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    • Philadelphia, Pennsylvania, United States
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    • West Reading, Pennsylvania, United States
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  • South Carolina
    • Greenville, South Carolina, United States
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    • Orangeburg, South Carolina, United States
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  • Tennessee
    • Memphis, Tennessee, United States
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  • Texas
    • Amarillo, Texas, United States
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    • Austin, Texas, United States
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    • Dallas, Texas, United States
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    • Houston, Texas, United States
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    • Lubbock, Texas, United States
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    • Mesquite, Texas, United States
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    • San Antonio, Texas, United States
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  • Virginia
    • Chesapeake, Virginia, United States
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  • Washington
    • Tacoma, Washington, United States
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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
• Treatment with one the following disease modifying anti-rheumatic drug: methotrexate, sulfasalazine, hydroxychloroquine or chloroquine
• 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 one of the following: documented history of positive rheumatoid factor (blood test), current presence of 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
• Previous failure to respond to a TNF alpha antagonist, anakinra or previous treatment with other biological agent
• 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, fostamatinib; Placebo for 24 weeks followed by fostamatinib 100 mg twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With 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 CRP) and the physician and patient's own assessments of disease activity, pain and physical function. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Achieving ACR20, Comparison Between Fostamatinib and Placebo at Week 1	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. BID = twice daily, CRP = C-reactive protein, DMARD = Disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.	1 week
Proportion of Patients Achieving ACR50, Comparison Between Fostamatinib and Placebo at 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. BID = twice daily, CRP = C-reactive protein, DMARD = Disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.	24 weeks
Proportion of Patients Achieving ACR70, Comparison Between Fostamatinib and Placebo at 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. BID = twice daily, CRP = C-reactive protein, DMARD = Disease-modifying anti-rheumatic drug, PO = orally, QD = once a day.	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 CRP) 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. BID = twice daily, CI = confidence interval, CRP = C-reactive protein, DMARD = Disease-modifying anti-rheumatic drug, PO = orally, QD = once a day. Mean refers to change at Week 24.	Baseline and 24 weeks
Proportion of Patients Achieving DAS28-CRP <2.6 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 patient's 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 a day.	12 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 patient's 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 a day.	24 weeks
Proportion of Patients Achieving 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. 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.	24 weeks
HAQ-DI Response - Comparison of the Change(>=0.22) From Baseline Between Fostamatinib and Placebo at Week 24	HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is then 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. The HAQ-DI response is a reduction from baseline in HAQ-DI score 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.	Baseline and 24 weeks
Change From Baseline to Week 24 in mTSS, 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 erosions and joint space narrowing and the results summed to give a value between 0 and 448. A higher value represents more serious progression of the disease. After disregarding ineligible records, patients with 2 or more non-missing values have 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, 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, 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 0-100. 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 mean of 50+/- 10. Higher scores represent 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. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once a day.	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, 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 0-100. 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 mean of 50+/- 10. Higher scores represent 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. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once a day.	Baseline and 24 weeks

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

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Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 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 17, 2014
• Last Update Submitted That Met QC Criteria: March 13, 2014
• Last Verified: March 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: D4300C00002; 2010-020744-35 (EudraCT Number)