Introduction
Methods (see Supplementary Material for detail)
Patients and treatment
DCE-MRI biomarkers
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K trans /min-1: volume transfer constant for Gd-CA between blood plasma and extravascular extracellular space from extended Tofts [5] compartmental model.
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IRE/ mM.s-1: initial rate (gradient) of enhancement following Gd-CA over 60 s post-arrival in tissue.
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IAUC 60 , IAUC 120 /mM.s: initial area under Gd-CA concentration curve over 60 s or 120 s post-arrival in tissue.
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VEP/mL: volume of enhancing pannus [12].
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ME/mM: maximum enhancement of Gd-CA concentration curve during DCE-MRI series.
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v e , v p : volumes respectively of extravascular extracellular space, and blood plasma volume, per unit volume tissue (dimensionless).
Statistical analysis
Results
MR biomarker | Patients with two baseline scans | Treated patients at baseline | ||||
---|---|---|---|---|---|---|
N for repeatability | Repeatability (intra-subject CoV %) | Variability (inter-subject CoV %) | N for range | Geometric mean | Range | |
K
trans
(min-1) | 14 | 30.0% | 59.3% | 45 | 0.069 | 0.025–0.273 |
IRE (mM.s-1) | 14 | 29.5% | 51.3% | 45 | 0.003 | 0.001–0.013 |
IAUC
60
(mM.s) | 14 | 31.4% | 58.3% | 45 | 7.69 | 1.92–28.17 |
IAUC
120
(mM.s) | 14 | 29.3% | 55.7% | 45 | 18.23 | 5.58–70.27 |
VEP (mL) | 15 | 22.0% | 41.3% | 45 | 1.06 | 0.20–2.48* |
ME (mM) | 14 | 27.5% | 52.4% | 45 | 0.32 | 0.11–1.31 |
v
e
(%) | 0 | n/a | n/a | 0 | n/a | n/a |
v
p
(%) | 14 | 53.4% | 60.1% | 45 | 1.2 | 0.3–4.5 |
RAMRIS synovitis score** | 13 | 1.30 (SD) | 6.20 (SD) | 31 | 6.95 (arithmetic mean) | 0.0–21.8 |
Biomarker | Fostamatinib (N = 11) vs. placebo (N = 10) at 6 weeks | Fostamatinib (N = 11) vs. adalimumab (N = 10) at 6 weeks | Fostamatinib (N = 6) vs. adalimumab (N = 5) at 24 weeks | |||
---|---|---|---|---|---|---|
Treatment ratio* (tr) or difference (td) (90% CI) | Two-sided p-value | Treatment ratio* (tr) or difference (td) (90% CI) | Two-sided p-value | Treatment ratio* (tr) or difference (td) (90% CI) | Two-sided p-value | |
K
trans
| tr = 0.95 (0.68–1.33) | 0.794 | tr = 1.92 (1.36–2.72) | 0.003 | tr = 1.59 (0.95–2.68) | 0.137 |
IRE
| tr = 0.86 (0.62–1.18) | 0.417 | tr = 1.55 (1.12–2.15) | 0.031 | tr = 1.60 (1.06–2.42) | 0.064 |
IAUC
60
| tr = 0.91 (0.66–1.24) | 0.603 | tr = 1.67 (1.21–2.30) | 0.012 | tr = 1.57 (0.97–2.54) | 0.120 |
IAUC
120
| tr = 0.88 (0.65–1.19) | 0.478 | tr = 1.67 (1.22–2.28) | 0.010 | tr = 1.60 (0.98–2.61) | 0.116 |
VEP
| tr = 0.85 (0.66–1.08) | 0.130 | tr = 0.77 (0.60–1.00) | 0.053 | tr = 1.23 (0.62–2.11) | 0.508 |
ME
| tr = 0.95 (0.70–1.28) | 0.756 | tr = 1.64 (1.20–2.25) | 0.012 | tr = 1.57 (1.05–2.36) | 0.070 |
v
e
| n/a | n/a | n/a | n/a | n/a | n/a |
v
p
| tr = 0.90 (0.60–1.29) | 0.610 | tr = 1.75 (1.21–2.54) | 0.016 | tr = 1.75 (1.21–2.54) | 0.065 |
RAMRIS synovitis score | td = -2.00 (-3.25–-0.75) | 0.023 | td = -1.50 (-2.50–0.00) | 0.175 | td = 2.00 (-0.50–5.00) | 0.230 |
DAS-28 CRP | td = 0.65 (-0.11–1.41) | 0.155 | td = -0.13 (-0.89–0.64) | 0.780 | td = -1.48 (-3.43–0.47) | 0.200 |
Discussion
Acknowledgments
Compliance with ethical standards
Guarantor
Conflict of interest
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John Waterton is a former employee of, and has stock in, AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics. He does not consider that this creates any conflict of interest with the subject-matter of the present manuscript, as fostamatinib is no longer a development product of AstraZeneca.
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Meilien Ho (deceased) is a former employee of AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics.
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Lars Nordenmark has employment and stock in AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics. He does not consider that this creates any conflict of interest with the subject-matter of the present manuscript, as fostamatinib is no longer a development product of AstraZeneca.
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Martin Jenkins has employment and stock in AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics. He does not consider that this creates any conflict of interest with the subject-matter of the present manuscript, as fostamatinib is no longer a development product of AstraZeneca.
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Julie DiCarlo has employment in Spire Sciences, Inc., a for-profit company providing centralized image analysis services to multiple pharmaceutical, biotechnology and medical device companies. She also has received consulting fees from Abbvie, Amgen, AstraZeneca, BMS, Five Prime Therapeutics, Genentech, Roche, Janssen, Lilly, Merck, Novartis, Samsung, Salix-Santarus and UCB.
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Gwenael Guillard has employment and stock options in Imorphics, a for-profit company engaged in the discovery, development, and marketing of imaging biomarkers.
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Caleb Roberts has employment and stock options in Bioxydyn, a for-profit company engaged in the discovery, development, and marketing of imaging biomarkers.
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Giovanni Buonaccorsi has employment in Bioxydyn, a for-profit company engaged in the discovery, development, and marketing of imaging biomarkers.
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Geoffrey Parker has employment and stock in, and is a director of, Bioxydyn, a for-profit company engaged in the discovery, development, and marketing of imaging biomarkers.
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Michael Bowes has employment and stock in, and is a director of, Imorphics, a for-profit company engaged in the discovery, development, and marketing of imaging biomarkers.
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Charles Peterfy has employment, and is owner and chief executive officer of, Spire Sciences, Inc., a for-profit company providing centralized image analysis services to multiple pharmaceutical, biotechnology and medical device companies. He is also on the speakers bureau for Amgen, and has received consulting fees from Abbvie, Amgen, AstraZeneca, BMS, Five Prime Therapeutics, Genentech, Roche, Janssen, Lilly, Merck, Novartis, Samsung, Salix-Santarus and UCB.
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Peter Taylor has received grant/research support from UCB and is a consultant for AstraZeneca, Pfizer, Lilly and Celgene. He would like to acknowledge NIHR for funding of the Oxford Biomedical Research Unit.
Funding
Statistics and biometry
Ethical approval
Informed consent
Study subjects or cohorts overlap
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The data presented here arise from the magnetic resonance imaging (MRI) substudy in OSKIRA-4 (Oral SYK Inhibition in Rheumatoid Arthritis), a Phase IIb monotherapy study of fostamatinib in RA.
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OSKIRA-4 was a 6-month Phase IIb study evaluating improvements in signs and symptoms of RA in 280 patients who had never previously used a disease-modifying anti-rheumatic drug (DMARD), were DMARD-intolerant or had an inadequate response to DMARDs and were randomised to receive fostamatinib as a monotherapy, adalimumab as a monotherapy, or placebo. The findings of this study have recently been reported in Annals of the Rheumatic Diseases (/link?doi=10.1136/annrheumdis-2014-205361).
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AstraZeneca terminated the development of fostamatinib in 2013 before the OSKIRA-4 MRI substudy was complete.
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There was almost no overlap between the patients (only two patients overlap) between the patients in the MRI substudy and those patients in the main OSKIRA-4 study who were not examined by MRI. No data from the MRI substudy have previously been disclosed or submitted for publication.
Methodology
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prospective
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randomised controlled trial
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multicentre study