Effect of Adalimumab for the Treatment of Uveitis in Juvenile Idiopathic Arthritis (ADJUVITE)
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.
Drug: Anti-tumor necrosis factor alpha monoclonal antibody
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Evaluation of the Efficacy of Adalimumab for the Treatment of Uveitis in Juvenile Idiopathic Arthritis: Randomized Double-blind Placebo-controlled Trial|
- To demonstrate that a higher proportion of subjects will have an improvement of uveitis on adalimumab versus placebo after 2 months relative to baseline [ Time Frame: Final visit could occur at any point up to 78 weeks ] [ Designated as safety issue: Yes ]
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.
- Evaluation of adverse events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]To evaluate the safety of treatment at 2 months then at 12 months
- Proportion of subjects at each study time point with an improvement of uveitis [ Time Frame: 2 months ] [ Designated as safety issue: No ]To evaluate the response of the treatment on ocular inflammation quantified by slit lamp examination and laser flare photometry at each visit comparatively between the adalimumab arm and the placebo arm during the double-blind period (until M2, as a complement to the laser flare photometry evaluation performed for the primary objective) and then descriptively on adalimumab. Analyses will be performed on the eye evaluated for the primary objective and for the fellow eye in patients with bilateral uveitis.
- Eyes with active uveitis [ Time Frame: 2 months ] [ Designated as safety issue: No ]To compare the proportion of eyes with active uveitis on inclusion improved after 2 months between the adalimumab arm and the placebo arm
- The efficacy of treatment on juvenile idiopathic arthritis [ Time Frame: 2 months ] [ Designated as safety issue: No ]To evaluate the efficacy of treatment on JIA, particularly the joint lesions at each visit, comparatively between the adalimumab arm and the placebo arm until M2 then descriptively on adalimumab
- Decrease topical or systemic steroid therapy [ Time Frame: 12 months ] [ Designated as safety issue: No ]To evaluate the possibility to decrease topical steroid therapy and when applicable systemic steroid therapy between M2 and M12
- Transcriptome modifications on whole blood [ Time Frame: 12 months ] [ Designated as safety issue: No ]To evaluate possible transcriptome modifications on whole blood in the context of a collaboration with a team experienced in analysis of cytokine signatures associated with JIA and other inflammatory diseases in children (team directed by V. Pascual in Dallas).
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||June 2016|
|Estimated Primary Completion Date:||November 2015 (Final data collection date for primary outcome measure)|
Anti-tumor necrosis factor alpha monoclonal antibody
Drug: Anti-tumor necrosis factor alpha monoclonal antibody
The dose of adalimumab will be 40 mg 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).
Other Name: Anti-tumor necrosis factor alpha monoclonal antibody
Placebo Comparator: placebo
Patients will receive 4 injections of placebo on D0, D14, D28, and D42 with assessment of the primary endpoint at M2
Other Name: placebo
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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01385826
|Contact: Pierre Quartier dit Maire, MD, PhD||+33 (0)1 44 49 48 firstname.lastname@example.org|
|Contact: Raphael SERREAU, MD, PhD||+33 (0)1 58 41 11 email@example.com|
|Hospital of necker Enfants malades||Recruiting|
|Paris, France, 75015|
|Contact: Pierre Quartier dit Maire, MD, PhD ++33144494828 firstname.lastname@example.org|
|Principal Investigator:||Pierre Quartier dit Maire, MD, PhD||hospital Necker Enfants Malades|