Rheumatoid Arthritis Clinical Trial
Official title:
Optimal Management of Rheumatoid Arthritis Patients Requiring Biologic Therapy
That anti-TNF therapy and rituximab therapy are equally effective in treating patients with rheumatoid arthritis who meet the eligibility criteria for biologic therapy in the British Society for Rheumatology guidelines, and have not previously been exposed to biologic therapy.
Anti-TNF therapy has become an established part of the treatment of patients with rheumatoid
arthritis (RA) who fail to have (or maintain) an adequate response to conventional disease
modifying anti-rheumatic drugs (DMARDs) according to the BSR Biologics guidelines which have
been approved by NICE 1,2 Other biologic drugs, such as rituximab, have been approved for
use in the NHS in patients who have failed anti-TNF therapy.3 Rituximab is also effective in
patients who have failed conventional DMARDs but have not yet been exposed to anti-TNF
therapy.4 It is possible that rituximab is more or less effective than anti-TNF therapy in
biologic naïve patients but head to head trials have not been carried out. Rheumatologists
are faced with the question - which biologic should be used first?
All biologics are expensive, and the relative cost effectiveness of available therapies
needs to be considered. NICE and the Scottish Medicines Consortium (SMC) are charged with
providing guidance to the NHS about the use of biologic drugs, but it is recognised that
there is a great deal of uncertainty associated with the health economic modelling that is
the basis of NICE/SMC decisions. Currently, randomised controlled trials have shown that
anti-TNF and rituximab therapy are both effective. Whilst the overall response rates appear
similar, there were important differences between the trial populations which make
comparisons between trials of limited usefulness, and the data are compatible with important
clinical differences in efficacy. The financial risk that the NHS is exposed to is
considerable: the cost of anti-TNF therapy is approximately £9-10,000 per annum; rituximab
costs ~£3,500 per treatment course, which need to be repeated (on average) every 6-9 months
giving an annual cost of £4700 - 7000. In Scotland, there were ~450 biologic-naive RA
patients started on an anti-TNF drug in 2007 (personal communication) which translates to
~4-5000 patients starting anti-TNF therapy each year in the UK, at an annual cost of
~£40million. Were rituximab to prove be as effective in biologic-naive patients as anti-TNF
therapy this could result in savings to the NHS of £9 - 20 million per annum, depending on
the frequency of re-treatment with rituximab that was required. On the other hand, if
anti-TNF therapy is more effective than rituximab therapy, it would be very important to
have good evidence to inform NICE/SMC appraisals which might otherwise conclude from the
current literature that rituximab affords a more cost-effective approach.
The proposed trial is a randomised controlled trial that will compare the efficacy and
cost-effectiveness of two treatment strategies in patients who require biologic treatment
according to the BSR guidelines: starting with anti-TNF therapy first, compared to the use
of rituximab first. Treatment will be switched to the alternative technology in the event of
toxicity, lack or loss of response. Treatment doses and schedules will be according to the
current licensed doses of all medications; rituximab will be used in accordance with recent
trials in biologic-naïve patients which is expected to form the basis of Roche's application
for a license extension (personal communication).5,6 A pragmatic approach to anti-TNF
therapy will be taken: there are variations in the choice of anti-TNF drug (etanercept,
infliximab or adalimumab) and there is no consensus (or evidence) that one is superior to
another. This fact is recognised by NICE who recommends the use of anti-TNF therapy but has
not identified an anti-TNF drug of choice. In the UK, the vast majority of patients are
treated with one of the two sub-cutaneous preparations (etanercept or adalimumab) rather
than infliximab for logistical reasons. Hence, patients enrolling in the trial and who are
randomised to anti-TNF therapy will be treated with either adalimumab or etanercept,
following discussion and advice from their rheumatologist. There is evidence that patients
who are sero-negative for rheumatoid factor and anti-CCP antibodies are less likely to
respond to rituximab therapy,7 and the consensus is that such patients should be treated
with anti-TNF therapy and will be not be eligible for the trial. Safety remains an important
concern for patients and clinicians and all adverse events will be carefully recorded,
although a trial of this size will not have the power to exclude clinically relevant
differences between treatments in the rate of serious adverse events. The side effect
profiles for anti-TNF and rituximab therapy differ, but both treatment modalities are
associated with an increased risk of infection. In contrast some adverse effects are
associated specifically with anti-TNF (e.g. demyelination) or rituximab (e.g. Progressive
Multifocal Leucoencephalopathy) therapy. The safety of adding anti-TNF therapy to patients
who remain B-cell depleted is important. The evidence to date suggests that there is no
significant increase in the risk of serious infective complications in these patients,8 but
a comparison of the rate of adverse events in patients switching from rituximab to anti-TNF
therapy will be compared to the rate seen in those switching form anti-TNF to rituximab.
In addition, co-existing depression is common in patients with severe RA and has been shown
to significantly reduce patients' response to, and increase side effects from, anti-TNF
therapy. It is not known whether a similar effect occurs with Rituximab. If the effect of
pre-existing depression on response differs between anti-TNF and rituximab therapy, this
could have a major impact on biologic choice for depressed patients in routine clinical
care.
It is known that only a proportion of patients achieve remission or a low disease activity
state (LDAS) with biologic therapy. Partial or non-response entails significant cost,
encompassing an economic burden on the NHS and exposure to potential adverse events for the
patient. Predicting those patients in whom clinical responses are most likely to occur would
aid decision making for clinicians, reduce unnecessary adverse effects for patients and
confer considerable health utility benefits. Patients who agree to participate in ORBIT will
be asked to consider whether, in addition, they would consent to undergo synovial biopsy as
part of a pilot study that will test the hypothesis that synovial tissue in RA patients
carries a molecular and/or cellular signature ('pathotype') that can be captured to optimise
the rational choice of biologic agents to thereby enhance the proportion of patients
achieving high-hurdle endpoints.
Ultrasound-guided biopsy is a safe, well-tolerated technique that renders synovium
accessible in a high proportion of patients. Following treatment with a variety of
immune-modulatory agents, certain molecular and cellular features within synovial biopsies
(e.g. SL-CD68 expression) predict subsequent clinical improvement. However, clinical trials
and experience indicate heterogeneity of responses to targeting discrete cellular or
molecular components of inflammation with biologic therapies such that at present,
determining the optimum biologic therapy for a given individual is largely a matter of trial
and error. Therefore we aim to investigate whether pathologic features within the synovial
membrane (which we propose to call a 'synovial pathotype') could be used to direct the
choice of biologic agent a priori and a sub-group of patients enrolling in the trial will be
asked to undergo synovial biopsy. Specifically, we will address the question: does the use
of rituximab in patients with synovial biopsies containing features commensurate with
ectopic germinal formation, or of TNF blocker to patients with diffuse inflammation, improve
the response rates? If successful, this study will provide a novel biopsy-led rationale for
the choice of biologic agent. In addition, samples of serum, RNA and genomic DNA from all
patients enrolled in ORBIT will contribute to the MRC-funded PEAC (Pathobiology of Early
Arthritis Cohort) biobank. They will provide a resource for future analysis and separate
relevant applications.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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