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AZ decision to discontinue fostamatinib development in RA; rights to fostamatinib returned to Rigel Pharmaceuticals.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dosing Group A | Experimental | Oral treatment and subcutaneous injection. |
|
| Dosing Group D | Active Comparator | Oral treatment and subcutaneous injection. |
|
| Dosing Group E | Placebo Comparator | Placebo bid for 6 weeks followed by switch to 100 mg fostamatinib bid for 24 weeks, plus placebo subcutaneous injection every 2 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fostamatinib | Drug | Fostamatinib 100mg twice daily. |
| |
| 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 |
Not provided
| 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. |
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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Neil MacKillop, MD PhD | AstraZeneca | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Glendale | Arizona | United States | |||
| Research Site |
A total of 101 patients failed screening.
198 patients were enrolled: 34, 33 and 30 were randomised to Groups A, D and E (33, 28 and 29 received at least 1 dose of IP). Two of the randomised patients were in the main study (D4300C00004).
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| ID | Title | Description |
|---|---|---|
| FG000 | FOSTA 100 MG PO BID | Dosing Group A |
| FG001 | ADALIMUMAB 40 MG SC | Dosing Group D |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Adalimumab |
| Drug |
Adalimumab 40 mg by subcutaneous injection every 2 weeks for 24 weeks. |
|
| Placebo of Fostamatinib | Drug | Placebo bid for 6 weeks. |
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| Placebo of Adalimumab | Drug | Placebo injection once every two weeks. |
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| 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 |
| Paradise Valley |
| Arizona |
| United States |
| Research Site | Phoenix | Arizona | United States |
| Research Site | Brooklyn | New York | United States |
| Research Site | Jackson | Tennessee | United States |
| Research Site | Austin | Texas | United States |
| Research Site | Pleven | Bulgaria |
| Research Site | Mississauga | Ontario | Canada |
| Research Site | Prague | Czechia |
| Research Site | Hamburg | Germany |
| Research Site | Munich | Germany |
| Research Site | Balatonfüred | Hungary |
| Research Site | Budapest | Hungary |
| Research Site | Amsterdam | Netherlands |
| Research Site | Warsaw | Poland |
| Research Site | Yaroslavl | Russia |
| Research Site | Durban | South Africa |
| Research Site | Pretoria | South Africa |
| Research Site | Stellenbosch | South Africa |
| Research Site | Manchester | United Kingdom |
| Research Site | Oxford | United Kingdom |
| FG002 |
| PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID |
Dosing Group E |
| Randomised But Did Not Receive Treatment |
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| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | FOSTA 100 MG PO BID | Dosing Group A |
| BG001 | ADALIMUMAB 40 MG SC | Dosing Group D |
| BG002 | PLACEBO (6 WKS) THEN FOSTA 100 MG PO BID | Dosing Group E |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Number | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. | Posted | Median | Inter-Quartile Range | Units on a scale | Baseline, 6 and 24 weeks |
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| Other Pre-specified | 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. | The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. | Posted | Median | Inter-Quartile Range | Units on a scale | Baseline, 6 and 24 weeks |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | 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. | The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. | Posted | Median | Inter-Quartile Range | Units on a scale | Baseline, 6 and 24 weeks |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | 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. | The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment, but only those with available images were included in the analysis. | Posted | Median | Inter-Quartile Range | Units on a scale | Baseline, 6 and 24 weeks |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | 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. | The sub-study analysis set includes those patients who received at least 1 dose of investigational product in the MRI sub-study. Patients were analysed by randomised treatment in accordance with the intention to treat principle. | Posted | Mean | Standard Deviation | Units on a scale | Baseline, 6 and 24 weeks |
|
24 weeks
For placebo treated patients time frame includes both placebo(6 weeks) and fostamatinib(18 weeks) treatment. 1 SAE occurred in these treatment arms began during the 6 week placebo treated period
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ADALIMUMAB 40 MG | Dosing Group D | 3 | 28 | 7 | 28 | ||
| EG001 | FOSTA 100 MG BID | Dosing Group A | 3 | 33 | 17 | 33 | ||
| EG002 | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - FOSTA Period | 0 | 22 | 7 | 22 | |||
| EG003 | PLACEBO (6 WKS) THEN FOSTA 100 MG BID - Placebo Period | 1 | 29 | 4 | 29 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| GASTROENTERITIS | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
| |
| FEMORAL NECK FRACTURE | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
| |
| POST PROCEDURAL HAEMORRHAGE | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
| |
| EXOSTOSIS | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
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| INTERVERTEBRAL DISC PROTRUSION | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
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| MUSCULOSKELETAL CHEST PAIN | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
| |
| ASTHMA | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
| |
| ORTHOSTATIC HYPOTENSION | Vascular disorders | MedDRA 15.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| CONSTIPATION | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
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| DIARRHOEA | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
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| GASTROENTERITIS | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
| |
| NASOPHARYNGITIS | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
| |
| ALANINE AMINOTRANSFERASE INCREASED | Investigations | MedDRA 15.1 | Systematic Assessment |
| |
| RHEUMATOID ARTHRITIS | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
| |
| HEADACHE | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
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| HYPERTENSION | Vascular disorders | MedDRA 15.1 | Systematic Assessment |
| |
| NAUSEA | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
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| INFLUENZA LIKE ILLNESS | General disorders | MedDRA 15.1 | Systematic Assessment |
| |
| ASPARTATE AMINOTRANSFERASE INCREASED | Investigations | MedDRA 15.1 | Systematic Assessment |
| |
| GAMMA-GLUTAMYLTRANSFERASE INCREASED | Investigations | MedDRA 15.1 | Systematic Assessment |
| |
| DIZZINESS | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
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| DYSGEUSIA | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
| |
| RASH MACULAR | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
The disclosure restriction on the PI is that the sponsor can review and comment on results communications prior to publication. Sponsor will be allowed a review period of at least 60 days from submission but can request that publication be delayed for a period up to 6 months. Any reasonable comments made by the sponsor will be incorporated by the PI into the publication.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dave Goldstraw | AstraZeneca Pharmaceuticals | +44 (0)1625 512415 | dave.goldstraw@astrazeneca.com |
| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C523665 | fostamatinib |
| D000068879 | Adalimumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
Not provided
Not provided
| Male |
|
| Black or African American |
|
| Indian or Pakistani |
|
| Other |
|
|
| 24 weeks | Van Elteren | Estimated using the Van Elteren test stratified by DMARD naivety (DMARD naive vs DMARD-IR/intolerant). | 0.402 | A negative value for change from baseline in OMERACT RAMRIS synovitis score indicates a better clinical condition. | Treatment difference | 0.50 | 2-Sided | 90 | -1.00 | 2.00 | The point estimate for the median difference in change from baseline and associated 90% CI was calculated using the method of unstratified Hodges-Lehmann. A treatment difference <0 indicates a benefit towards fostamatinib. | No | Superiority or Other |
Dosing Group E |
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Dosing Group E
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Dosing Group E |
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