Protocol Title : A Randomised, open labelled study in anti ... - EME
Protocol Title : A Randomised, open labelled study in anti ... - EME
Protocol Title : A Randomised, open labelled study in anti ... - EME
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
1 INTRODUCTION<br />
!<br />
1.1 Background<br />
Rheumatoid arthritis (RA) is one of the most important chronic <strong>in</strong>flammatory disorders <strong>in</strong> the UK.<br />
The diagnosis of RA leads to considerable morbidity and an <strong>in</strong>creased mortality 1, 2 . Accord<strong>in</strong>g to<br />
the National Audit Office (2009 - http://www.nao.org.uk/) there are 26,000 new cases of RA each<br />
year with 582,000 prevalent cases <strong>in</strong> England. 45% of these people are of work<strong>in</strong>g age and with<strong>in</strong><br />
1 year of diagnosis 30% are unemployed. RA is characterized by a symmetrical, erosive<br />
polyarthritis, result<strong>in</strong>g from chronic synovitis, and the presence of circulat<strong>in</strong>g auto<strong>anti</strong>bodies such<br />
as rheumatoid factor (RF) and <strong>anti</strong>-cyclic citrull<strong>in</strong>ated peptide (ACPA), strongly suggest<strong>in</strong>g an<br />
autoimmune pathogenesis. Although biological therapies have revolutionized the treatment of RA,<br />
a sizable group of patients (30-40%) are “resistant” 3, 4 .<br />
Recently there has been a greater understand<strong>in</strong>g of the importance of B cells <strong>in</strong> driv<strong>in</strong>g the<br />
<strong>in</strong>flammatory processes <strong>in</strong>volved <strong>in</strong> RA. B cells may drive synovial <strong>in</strong>flammation by production of<br />
auto<strong>anti</strong>bodies, act<strong>in</strong>g as effective <strong>anti</strong>gen-present<strong>in</strong>g cells and may promote synovial<br />
<strong>in</strong>flammation by produc<strong>in</strong>g pro-<strong>in</strong>flammatory cytok<strong>in</strong>es 5 . Thus, depletion of B cells could <strong>in</strong>terfere<br />
with important mechanisms <strong>in</strong>volved <strong>in</strong> the perpetuation of the <strong>in</strong>flammatory response <strong>in</strong> RA.<br />
Rituximab is a chimeric monoclonal <strong>anti</strong>body directed aga<strong>in</strong>st the CD20 <strong>anti</strong>gen expressed by B<br />
cells, has been approved by the US Food and Drug Adm<strong>in</strong>istration and by the European Medic<strong>in</strong>es<br />
Agency <strong>in</strong> Europe for the treatment of patients with RA who have had an <strong>in</strong>adequate response (ir)<br />
or were <strong>in</strong>tolerant to tumour necrosis factor alpha (TNF) <strong>in</strong>hibitors. Current evidence on the efficacy<br />
of rituximab relates primarily to rheumatoid factor positive patients, although even with<strong>in</strong> this<br />
population cl<strong>in</strong>ical responses are heterogeneous with only 60% achiev<strong>in</strong>g an ACR20 response at 6<br />
months 6, 7 . Recent synovial-based studies suggest that the heterogeneous cl<strong>in</strong>ical response may <strong>in</strong><br />
part be expla<strong>in</strong>ed by variable B cell depletion with<strong>in</strong> the synovial tissue rather than simply <strong>in</strong> the<br />
peripheral blood 8-10 . A grow<strong>in</strong>g body of evidence would suggest that a more rational approach to<br />
Rituximab therapy and a stratified approach to patients may be required 11-13 . Despite this, NICE<br />
guidel<strong>in</strong>es have recommended that all patients with <strong>in</strong>adequate response to <strong>anti</strong>-TNF therapy<br />
should receive Rituximab (NICE, http://www.nice.org.uk/CG79). A “bl<strong>in</strong>d” implementation of these<br />
guidel<strong>in</strong>es will result <strong>in</strong> many patients, unlikely to respond, receiv<strong>in</strong>g a B Cell deplet<strong>in</strong>g agent with<br />
the associated risks with none of the potential benefits. A tailored approach to this <strong>in</strong>tervention with<br />
patient stratification is required to better identify both responders and non-responders. In this<br />
proposed <strong>study</strong> we will test the hypothesis that the presence or absence of B cells and B cellassociated<br />
signatures with<strong>in</strong> the jo<strong>in</strong>t will enrich for response/non-response to the B cell deplet<strong>in</strong>g<br />
agent Rituximab. We also hypothesize that <strong>in</strong> patients with a B-cell poor synovial biopsy,<br />
alternative biologics such as the IL-6 receptor blocker Tocilizumab will be more effective. This<br />
<strong>study</strong> is considered a type A cl<strong>in</strong>ical <strong>study</strong> accord<strong>in</strong>g to MHRA risk.<br />
1.2 Investigational Medic<strong>in</strong>al Products<br />
1.2.1 Rituximab<br />
With<strong>in</strong> the remit of this <strong>study</strong> Rituximab is be<strong>in</strong>g used <strong>in</strong> accordance with its UK licence. Rituximab<br />
is a chimeric <strong>anti</strong>body consist<strong>in</strong>g of a human immunoglobul<strong>in</strong> G1 (IgG1) kappa constant region<br />
with a variable region derived from a mur<strong>in</strong>e <strong>anti</strong>-CD20 <strong>anti</strong>body. Rituximab selectively targets<br />
CD20, a cell surface <strong>anti</strong>gen that is uniquely expressed on a subset of B cells dur<strong>in</strong>g the<br />
maturation process. Rituximab has a high b<strong>in</strong>d<strong>in</strong>g aff<strong>in</strong>ity for the CD20 <strong>anti</strong>gen, with specificity for<br />
the CD20 <strong>anti</strong>gen resid<strong>in</strong>g <strong>in</strong> the variable mur<strong>in</strong>e regions. This represents a novel biological<br />
strategy for the treatment of rheumatoid arthritis (RA) compared with traditional disease-modify<strong>in</strong>g<br />
<strong>anti</strong>-rheumatic drugs or tumour necrosis factor (TNF) <strong>in</strong>hibitors. Rituximab can disrupt a number of<br />
different events <strong>in</strong> the <strong>in</strong>flammatory process ow<strong>in</strong>g to the central role and multiple actions of B cells<br />
<strong>in</strong> the pathogenesis of RA. The synovial fluid of a jo<strong>in</strong>t affected by RA conta<strong>in</strong>s an abundance of B<br />
cells, and it is now recognised that the B lymphocyte plays three key roles <strong>in</strong> the pathogenesis of<br />
RA: <strong>anti</strong>gen presentation lead<strong>in</strong>g to T cell activation, auto<strong>anti</strong>body production and cytok<strong>in</strong>e<br />
production<br />
Rituximab <strong>in</strong> comb<strong>in</strong>ation with methotrexate is licensed for the treatment of adults with severe<br />
active rheumatoid arthritis who have had an <strong>in</strong>adequate response to or <strong>in</strong>tolerance of other<br />
DMARDs, <strong>in</strong>clud<strong>in</strong>g one or more tumour necrosis factor α (TNF-α) <strong>in</strong>hibitor therapies.<br />
Study: R4RA EudraCT: 2012-002535-28 11 / 34