Uveitis Clinical Trial
Official title:
Evaluation of the Efficacy of Adalimumab for the Treatment of Uveitis in Juvenile Idiopathic Arthritis: Randomized Double-blind Placebo-controlled Trial
The investigators propose to study the efficacy of adalimumab versus placebo (double-blind randomization on inclusion into 2 equal groups) on reduction of ocular inflammation quantified by laser flare photometry after two months of treatment in patients with active uveitis despite well conducted treatment with steroid eye drops and MTX. The primary objective is to demonstrate a higher response rate at 2 months in the adalimumab arm versus the placebo arm. Will be considered as responding patients those in whom the evaluated eye, 2 months after inclusion, presents at least 30% reduction of inflammation on laser flare photometry and improvement or a stable appearance on slit lamp examination. After the second month, all patients wishing to continue the trial and presenting a satisfactory clinical state will be treated with adalimumab for a total of one year after inclusion to descriptively evaluate the efficacy and safety of treatment over 10 to 12 months.
20% of patients with juvenile idiopathic arthritis (JIA) develop usually bilateral, chronic
anterior uveitis, dependent on steroid eye drops and sometimes systemic steroid therapy, with
a risk of complications such as cataract, band keratopathy and glaucoma, usually responsible
for loss of vision. No maintenance treatment has been demonstrated to be effective.
Methotrexate (MTX), the maintenance treatment most commonly used in JIA, could have a
beneficial effect, but this effect is not sufficient to stop progression of uveitis in most
patients. Our preliminary experience and that of other teams based on small series of
patients is in favour of the efficacy of anti-Tumour Necrosis Factor alpha (TNFalpha)
monoclonal antibodies (Ab) in JIA-associated uveitis. An international multicentre randomized
trial of a humanized monoclonal antibody, adalimumab, in JIA has demonstrated its efficacy on
joint lesions and its good safety as monotherapy or in combination with methotrexate.
However, children with active uveitis were excluded from this trial.
The investigators propose a French multicentre, randomized, double-blind, placebo-controlled
trial to evaluate the efficacy of adalimumab in JIA-associated uveitis in patients over the
age of 4 years. These patients must have active uveitis (Laser flare-cell meter score of at
least 30 photons/ms) despite topical steroid therapy, with intolerance or failure to at least
3 months of MTX therapy. The dose of adalimumab will be 40 mg eow for children age 13 and
over and for children younger than 13 adalimumab 24 mg per m2 BSA (up to a maximum total body
dose of 40 mg). The activity of uveitis will be evaluated by laser flare photometry, a
recently validated technique for follow-up of the efficacy of treatments of anterior uveitis.
Seven hospital ophthalmology departments in France are equipped with laser flare photometry
and have a sufficient experience to participate in this trial (Paris-Pitie-Salpetriere,
Paris-Cochin, Nantes, Lille, Grenoble, Bordeaux and Lyon). Several teams of paediatric
rheumatologists and hospital rheumatologists working with these ophthalmology departments
will also be able to include patients. The primary endpoint is an at least 30% reduction of
ocular inflammation after 2 months of treatment, quantified by laser flare photometry,
considering the more severely affected eye in the case of bilateral uveitis. Based on the
hypothesis of a response rate of at least 50% with adalimumab versus a maximum of 10% with
placebo, comparison of two groups of 19 patients would be sufficient to conclude on a
significant difference for a two-sided alpha risk of p=0.05 and a power of 80%. The
investigators therefore plan to include 40 patients with randomization to two equal groups,
one receiving 4 subcutaneous injections of adalimumab and the other receiving 4 injections of
placebo on D0, D14, D28, and D42 with assessment of the primary endpoint at M2. The planned
duration of inclusion is 2 years with a total duration of the trial of 3 years. From visit M2
onwards, all patients will be treated by adalimumab injections every 2 weeks and will be
followed for 1 year of treatment. Clinical, laboratory and ophthalmological evaluation
including laser flare photometry and conventional slit lamp examination will be performed at
each visit (pre-inclusion, D0, D14, M1, M2, M3, M4, M5, M6, M9 and M12). Deterioration of
ocular inflammation during the first 2 months will justify decoding for the patient concerned
who will be considered to be a treatment failure.
A study will be conducted in parallel: gene expression profile studies on whole blood by a
team experienced in the study of JIA and other inflammatory diseases (Dr Pascual, Dallas,
USA).
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