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

• ClinicalTrials.gov Identifier: NCT02092961
• Recruitment Status: Terminated
• First Posted: March 20, 2014
• Results First Posted: June 25, 2014
• Last Update Posted: June 25, 2014
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: Fostamatinib; Drug: Adalimumab; Drug: Placebo of Fostamatinib; Drug: Placebo of Adalimumab	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 198 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: February 2011
• Actual Primary Completion Date: July 2013
• Actual Study Completion Date: July 2013

Arms and Interventions

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 Fostamatinib; Placebo bid for 6 weeks.; Drug: Placebo of Adalimumab; Placebo injection once every two weeks.

Outcome Measures

Primary Outcome Measures :

1. OMERACT RAMRIS Synovitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [ Time Frame: Baseline, 6 and 24 weeks ]
   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.

Other Outcome Measures:

1. OMERACT RAMRIS Osteitis Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [ Time Frame: Baseline, 6 and 24 weeks ]
   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.
2. Joint Space Narrowing - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [ Time Frame: Baseline, 6 and 24 weeks ]
   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.
3. OMERACT RAMRIS Erosions Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab (Van Elteren) [ Time Frame: Baseline, 6 and 24 weeks ]
   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.
4. DAS-CRP Score - Comparison of Change From Baseline Between Fostamatinib and Placebo or Adalimumab [ Time Frame: Baseline, 6 and 24 weeks ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Research Site

Glendale, Arizona, United States

Research Site

Paradise Valley, Arizona, United States

Research Site

Phoenix, Arizona, United States

United States, New York

Research Site

Brooklyn, New York, United States

United States, Tennessee

Research Site

Jackson, Tennessee, United States

United States, Texas

Research Site

Austin, Texas, United States

Bulgaria

Research Site

Pleven, Bulgaria

Canada, Ontario

Research Site

Mississauga, Ontario, Canada

Czech Republic

Research Site

Prague, Czech Republic

Germany

Research Site

Hamburg, Germany

Research Site

Munich, Germany

Hungary

Research Site

Balatonfüred, Hungary

Research Site

Budapest, Hungary

Netherlands

Research Site

Amsterdam, Netherlands

Poland

Research Site

Warsaw, Poland

Russian Federation

Research Site

Yaroslavl, Russian Federation

South Africa

Research Site

Durban, South Africa

Research Site

Pretoria, South Africa

Research Site

Stellenbosch, South Africa

United Kingdom

Research Site

Manchester, United Kingdom

Research Site

Oxford, United Kingdom

Sponsors and Collaborators

AstraZeneca

Investigators

• Study Director: Neil MacKillop, MD PhD; AstraZeneca

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02092961
• Other Study ID Numbers: D4300C00004Sub
• First Posted: March 20, 2014
• Results First Posted: June 25, 2014
• Last Update Posted: June 25, 2014
• Last Verified: April 2014

Keywords provided by AstraZeneca:

Rheumatoid Arthritis; OSKIRA; fostamatinib; CE-MRI; DCE-MRI

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Adalimumab; Anti-Inflammatory Agents; Antirheumatic Agents