Randomised Double-Blind, Placebo-Controlled, Parallel Group Study in Patients With Active Rheumatoid Arthritis:Magnetic Resonance Imaging Sub-Study (OSKIRA 4 SS)

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

This is a sub-study of the OSKIRA-4 study, (D4300C0004, NCT01264770) to explore alternative and more sensitive modalities for measuring the beneficial effects of syk inhibition with fostamatinib in patients with active RA. This MRI sub-study was reported later than the main study due to recruitment delays at specialist imaging sites and so is registered and presented entirely separately to the main study results.

This study will investigate the impact of treatment on joint activity and damage by assessing synovitis, osteitis, bone erosions and joint space narrowing.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Fostamatinib; Drug: Placebo of Adalimumab; Drug: Adalimumab; Drug: Placebo of Fostamatinib

Detailed Description

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): 198
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Pleven, Bulgaria
    • Research Site
• Canada
  • Ontario
    • Mississauga, Ontario, Canada
      • Research Site
• Czech Republic
  • Prague, Czech Republic
    • Research Site
• Germany
  • Hamburg, Germany
    • Research Site
  • Munich, Germany
    • Research Site
• Hungary
  • Balatonfüred, Hungary
    • Research Site
  • Budapest, Hungary
    • Research Site
• Netherlands
  • Amsterdam, Netherlands
    • Research Site
• Poland
  • Warsaw, Poland
    • Research Site
• Russian Federation
  • Yaroslavl, Russian Federation
    • Research Site
• South Africa
  • Durban, South Africa
    • Research Site
  • Pretoria, South Africa
    • Research Site
  • Stellenbosch, South Africa
    • Research Site
• United Kingdom
  • Manchester, United Kingdom
    • Research Site
  • Oxford, United Kingdom
    • Research Site
• United States
  • Arizona
    • Glendale, Arizona, United States
      • Research Site
    • Paradise Valley, Arizona, United States
      • Research Site
    • Phoenix, Arizona, United States
      • Research Site
  • New York
    • Brooklyn, New York, United States
      • Research Site
  • Tennessee
    • Jackson, Tennessee, United States
      • Research Site
  • Texas
    • Austin, 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
• 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)
• 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)
  • Presence of at least one swollen hand or wrist joint.
  • Presence of synovitis on baseline MRI scan, defined as at least 1 joint with RAMRIS synovitis score of +1 or greater.

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
• Unable to undergo an MRI examination (e.g. presence of a pacemaker, defibrillator, or other implanted metallic device such as anterior interbody cages, aneurysm clip or pedicle screws)
• Known allergy to Gadolinium-based contrast agent,
• Tattoos [in area of examination if contains metallic pigment]
• Likely to require sedation for the procedure
• eGFR less than 55 mL/min

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 Group A; Oral treatment and subcutaneous injection.	Drug: Fostamatinib; Fostamatinib 100mg twice daily.; Drug: Placebo of Adalimumab; Placebo injection once every two weeks.
Active Comparator: Dosing Group D; Oral treatment and subcutaneous injection.	Drug: Adalimumab; Adalimumab 40 mg by subcutaneous injection every 2 weeks for 24 weeks.; Drug: Placebo of Fostamatinib; Placebo bid for 6 weeks.
Placebo Comparator: Dosing Group E; Placebo bid for 6 weeks followed by switch to 100 mg fostamatinib bid for 24 weeks, plus placebo subcutaneous injection every 2 weeks.	Drug: Fostamatinib; Fostamatinib 100mg twice daily.; Drug: Placebo of Adalimumab; Placebo injection once every two weeks.; Drug: Placebo of Fostamatinib; Placebo bid for 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OMERACT RAMRIS Synovitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren)	OMERACT RAMRIS synovitis score was based on 8 joints, scored from MRI images, and ranged from 0 to 24 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous.	Baseline, 6 and 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
OMERACT RAMRIS Osteitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren)	OMERACT RAMRIS osteitis score was based on 25 joints, scored from MRI images, and ranged from 0 to 75 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous.	Baseline, 6 and 24 weeks
Joint Space Narrowing - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren)	Joint space narrowing score was based on 20 joints, scored from MRI images and ranged from 0 to 80 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, JSN = joint space narrowing, MRI = magnetic resonance imaging, PO = orally, SC = subcutaneous.	Baseline, 6 and 24 weeks
OMERACT RAMRIS Erosions Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren)	OMERACT RAMRIS erosions score was based on 25 joints and ranged from 0 to 250 with a smaller value indicating a better clinical condition. Median changes from baseline are shown at each visit (defined as post-baseline minus baseline) with negative values indicative of a better clinical condition. BID = twice daily, CI = confidence interval, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, OMERACT = Outcome Measures in Rheumatoid Arthritis Clinical Trials, PO = orally, RAMRIS = Rheumatoid Arthritis Magnetic Resonance Image Scoring system, SC = subcutaneous.	Baseline, 6 and 24 weeks
DAS-CRP Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or 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. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, MRI = magnetic resonance imaging, PO = orally, SC = subcutaneous.	Baseline, 6 and 24 weeks

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: March 19, 2014
• First Submitted That Met QC Criteria: March 19, 2014
• First Posted (Estimate): March 20, 2014

Study Record Updates

• Last Update Posted (Estimate): June 25, 2014
• Last Update Submitted That Met QC Criteria: May 28, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis; fostamatinib; DCE-MRI; OSKIRA; CE-MRI
• 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: D4300C00004Sub