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Evaluation of the Efficacy of Adalimumab for the Treatment of Uveitis in Juvenile Idiopathic Arthritis: Randomized Double-blind Placebo-controlled Trial

Phase 2/Phase 3
4 Years
Open (Enrolling)
Uveitis, Juvenile Arthritis

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Trial Information

Evaluation of the Efficacy of Adalimumab for the Treatment of Uveitis in Juvenile Idiopathic Arthritis: Randomized Double-blind Placebo-controlled Trial

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,

Inclusion Criteria:

1. Active uveitis associated with juvenile idiopathic arthritis, with the exclusion of
systemic JIA, juvenile-onset rheumatoid arthritis, and enthesitis-related JIA

2. Uveitis resistant to well conducted topical steroid therapy comprising either
dexamethasone or rimexolone at a dose adapted to the patient's situation as validated
by one of the investigating ophthalmologists.

3. Failure of systemic treatment with methotrexate at a dose of 0.3 to 0.6
(without exceeding 25 mg) once a week for at least 3 months (except in the case of
methotrexate intolerance).

4. Patient who can be evaluated by laser flare photometry.

5. Patient at least 4 years old on initiation of trial medication and weighing a minimum
of 15 kg

6. Signed informed consent both parents and/or patient's agreement

7. Patient has a social security or similar

Exclusion Criteria:

1. Systemic JIA, juvenile-onset rheumatoid arthritis, enthesitis-related JIA (with a
risk of red eye uveitis).

2. History of treatment with anti-TNF alpha monoclonal antibody (either adalimumab or

3. Any contraindication to administration of immunosuppressive therapy (immune deficit,
opportunistic infection, other severe chronic disease)

- History of cancer or lymphoproliferative disease other than successfully and
completely resected squamous cell or basal cell skin cancer,

- Any uncontrolled disease: unstable diabetes with documented history of recurrent
infections, unstable ischaemic heart disease, moderate to severe heart failure
(NYHA stage III/IV), recent stroke and any other disease or condition inducing,
in the investigator's opinion, a risk for the patient related to his/her
participation in the trial,

- Positive hepatitis B or C serology indicating active infection,

- History of positive HIV serology,

- Persistent infection or severe infections requiring hospitalisation or IV
antibiotic therapy during the 30 days prior to inclusion in the trial or oral
antibiotic therapy during the 14 days prior to inclusion in the trial,

- History of clinically significant alcohol or other substance abuse during the
previous year,

- Previous diagnosis or signs of demyelinating disease of the central nervous

- History of active tuberculosis, histoplasmosis or listeriosis,

- Signs of latent tuberculosis (based on a history of nontreated contamination, or
an opacity greater than 1 cm on chest x-ray, or a positive intradermal reaction
to 5 IU of tuberculin ≥ 5 mm).

- Negative urine pregnancy test in girls with childbearing potential

4. Chronic rupture of the blood-aqueous barrier with marked flare on the initial
examination but not modified by one month of anti-inflammatory therapy.

5. Impossibility to monitor flare:

- Children < 4 years

- False flare due to the presence of giant cells on the surface of an artificial
lens or in an aphakic child.

6. Children presenting complications such as refractory glaucoma or cataract rapidly
requiring surgery.

7. Phthisis bulbi with hypotonia and atrophy of the ciliary body.

8. Any other situation raising problems for maintenance of stable doses of steroids and
immunosuppressive drugs during the period between 4 weeks before D0 and the M2
evaluation. Authorized immunosuppressive therapies that must be maintained at stable
dose are steroid eye drops, systemic steroid therapy and once weekly oral or
subcutaneous MTX at a dose of 0.3 to 0.6 mg (without exceeding 25 mg).

9. Any ophthalmologic contraindication

10. If female and childbearing potential should have an appropriate contraceptive method
during all study period and 5 months after last adalimumab dose. Abstinence with no
oral contraception can be considered.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

To demonstrate that a higher proportion of subjects will have an improvement of uveitis on adalimumab versus placebo after 2 months relative to baseline

Outcome Description:

The primary objective is to demonstrate the efficacy of 2 months of treatment with adalimumab versus placebo on reduction of ocular inflammation in JIA-associated uveitis. By defining response to treatment as a reduction of at least 30% of ocular inflammation quantified by laser flare photometry in the initially more severely inflamed eye without deterioration of cell count or flare protein on slit lamp examination, we formulate the hypothesis that at least 50% of patients treated with adalimumab for 2 months will respond to treatment versus a maximum 10% of patients on placebo.

Outcome Time Frame:

Final visit could occur at any point up to 78 weeks

Safety Issue:


Principal Investigator

Pierre Quartier dit Maire, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

hospital Necker Enfants Malades


France: Ministry of Health

Study ID:




Start Date:

June 2011

Completion Date:

December 2014

Related Keywords:

  • Uveitis
  • Juvenile Arthritis
  • Uveitis
  • Juvenile arthritis
  • Anti-tumor necrosis factor alpha monoclonal antibody
  • treatment
  • Arthritis
  • Uveitis
  • Chorioretinitis
  • Arthritis, Juvenile Rheumatoid