SYCAMORE
A Randomised Controlled Trial of the Clinical Effectiveness,
SafetY and Cost Effectiveness of Adalimumab in Combination with
MethOtRExate for the Treatment of Juvenile Idiopathic Arthritis
Associated Uveitis
Chief Investigator
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Institution
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Dates
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Funding Stream
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Grant Ref
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Amount
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Professor Athimalaipet Ramanan
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University Hospitals Bristol NHS Foundation Trust
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01/04/2011 - 30/09/2017
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NIHR Health Technology Assessment (HTA)
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09/51/01
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£1,472,523
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Summary
Juvenile idiopathic arthritis (JIA) is the name for a type of
arthritis that primarily affects young people and whose cause is
unknown. 'Arthritis' means inflammation of the joints, but in JIA
the inflammation could also affect the eyes and internal organs.
Approximately 1 in 1000 children in the UK develop JIA. Both boys
and girls are affected and of those children with JIA around 30-40
% are at risk of inflammation of the uvea in the eye, known as
uveitis.
In one third of the children who develop uveitis, the disease is
of significant severity to cause visual loss, cataracts, increased
pressure in the eye and blindness. The severity of the disease is
partly due to the level of damage in the eye already present when
the diagnosis is made. As the disease is silent there is an
extensive screening programme to try to minimise the delay in
diagnosis. Much of the damage also occurs in the years following
diagnosis; firstly because the disease persists for decades in a
minority of patients, and secondly because present treatments are
unable to completely control the inflammation in significant
numbers of patients. The current treatments include steroid eye
drops and those with moderate or more severe disease will be
treated with methotrexate. This is either as a medicine or tablets,
or injected into the fatty layer just under the skin (called a
subcutaneous injection). These treatments do not cure the uveitis
or JIA but reduce inflammation, so relieving symptoms and reducing
the level of permanent damage.
Even when treated with methotrexate, the majority of children
with moderate to severe disease continue to have active
inflammation in the eye and lose significant vision in one eye and
end up certified blind as a result of uncontrolled inflammation.
TNF is a protein in the body which is involved in inflammation
processes. TNF has been shown to be important in the inflammation
seen in both the arthritis and uveitis caused by JIA. Some research
has shown that treatment with drugs that block the action of the
TNF protein (called anti-TNF drugs) may help reduce symptoms of
swollen joints in children with JIA. Adalimumab is an example of an
anti-TNF drug which has been shown to be helpful in these
circumstances. It is given as a subcutaneous injection every
fortnight. There are indications that adalimumab may also be
effective in treating uveitis symptoms, but the only way to test
this properly is to carry out a research project called a clinical
trial, which has not yet been done. Having started treatment with
adalimumab, patients will generally continue on this treatment for
at least a year once the inflammation in the eye has settled. It
can take a quite while for the inflammation to settle initially,
even up to a year.
We wish to conduct a clinical trial to test whether adding
adalimumab to the methotrexate treatment for children with severe
uveitis will enable us to prevent the serious complications that
can occur from uncontrolled uveitis in children with JIA. In this
clinical trial we will recruit 154 children with severe uveitis.
All children will receive subcutaneous methotrexate. The purpose of
this clinical trial is to examine how effective the addition of
adalimumab is for treating their uveitis symptoms. The only way of
testing this accurately is to compare children who are treated with
methotrexate plus adalimumab against children who are treated with
methotrexate plus a treatment that looks exactly the same as the
adalimumab but contains no medicine (called a 'placebo'). We would
allocate the different treatments at random, which is a bit like
throwing a dice to decide. No one would know in advance which
treatment a child will get. This sort of study is called a
randomised controlled trial or RCT. We use a placebo and carry out
RCTs so we can be sure the information provided about the treatment
is fair and has not been swayed by knowledge of whether it is the
test medicine or the placebo that is being given.
Children will be treated initially for 18 months and will be
monitored very closely throughout to look for improvement or
worsening of the inflammation. Those children whose eyes do not
improve, or worsen, whilst receiving their randomised treatment
will be classed as treatment failures. Treatment failures will stop
trial treatment and be treated with alternative therapy as
determined by their ophthalmologist and rheumatologist. After the
18 months trial period, all children will continue to be followed
up for a further 18 months as part of the study for a total 3 years
follow up.
This trial will be carried out in hospital out patient
departments by a network of doctors experienced in the treatment of
JIA and uveitis. If this trial shows that adalimumab is effective
in treating children with severe uveitis, this would result in
better control of inflammation in children with this severe eye
complication of JIA and would hopefully decrease the proportion of
children who develop serious visual complications and blindness
from uncontrolled uveitis.
Consumer representatives have been involved in all stages of
developing this proposal, from prioritisation to protocol
development. Investigators will secure full approval from all
relevant ethical and regulatory authorities prior to commencing to
ensure it is conducted safely and according to Good Clinical
Practice. It will be reviewed regularly and carefully by a Trial
Steering Committee including lay-representatives, and an
Independent Data and Safety Monitoring Committee. All
parents/patients will be required to give fully informed
consent/assent before starting the trial. All data will be
processed in accordance with the principles and conditions set out
in the Data Protection Act 1998 and with proper safeguards to
ensure confidentiality.
Links to further information
https://research-information.bristol.ac.uk/en/publications/a-randomised-controlled-trial-of-the-clinical-effectiveness-safety-and-costeffectiveness-of-adalimumab-in-combination-with-methotrexate-for-the-treatment-of-juvenile-idiopathic-arthritis-associated-uveitis-sycamore-trial(cc15ca4a-03c0-4ef5-bff8-d49987d3a6ff).html
https://www.ncbi.nlm.nih.gov/pubmed/24405833
