Adalimumab in JIA-associated Uveitis Stopping Trial

Study Overview
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Brief Summary
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The proposed study is a stratified, block-randomized, double-masked, controlled trial to determine the feasibility of discontinuing adalimumab treatment in patients with quiescent uveitis associated with juvenile idiopathic arthritis (JIA) or chronic anterior uveitis (CAU).

Detailed Description
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Background: Juvenile idiopathic arthritis (JIA)-associated uveitis is a chronic pediatric ocular inflammatory condition that can result in visual impairment. Chronic anterior uveitis (CAU) does not have systemic manifestations of disease but presents similarly in the eye and can result in identical visual complications as JIA-associated uveitis. Adalimumab, a tumor necrosis factor (TNF)-alpha inhibitor, effectively controls joint and eye inflammation; however, its long-term use may increase the risk of adverse health outcomes and place an undue financial burden on the patient and healthcare system given its high cost. There is great interest for patients to stop adalimumab following remission due to these reasons but there is a lack of information on the ability to maintain control after discontinuing adalimumab. Methods: The Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Trial (ADJUST) is a multi-center international trial that will randomize 118 participants aged 2 years and older with controlled JIA-associated uveitis or chronic anterior uveitis to either continue adalimumab or discontinue adalimumab and receive a placebo. The trial will compare the time to uveitis recurrence between the two groups over 12 months. All participants will receive the standard weight-based dose of adalimumab or placebo: 20 mg biweekly (if < 30 kg) or 40 mg biweekly (if ≥ 30 kg). Impact: This is the first randomized controlled trial to assess the efficacy of discontinuing adalimumab after demonstrating control of JIA-associated uveitis for at least 12 months. The results of ADJUST will provide information on clinical outcomes to guide clinicians in their decision-making regarding discontinuation of adalimumab.

Official Title
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Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial

Conditions
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Uveitis, JIA

Intervention / Treatment
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* Biological: Adalimumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (must meet all of the following to qualify): Stated willingness to comply with all study procedures and availability for the duration of the study period ≥ 2 years of age History of JIA or CAU diagnosed prior to 16 years of age (patient may be older than 16 at time of enrollment) Formal diagnosis of JIA-associated uveitis or CAU with no other suspected etiology ≥12 consecutive months of controlled ocular inflammation (≤0.5+ anterior chamber cell, ≤0.5+ vitreous haze, no active retinal/choroidal lesions in either eye) ≥ 12 consecutive months of controlled arthritis verified by a pediatric rheumatologist, if defined as JIA-associated uveitis ≥12 consecutive months of treatment with adalimumab or a biosimilar of adalimumab ≥180 days on a stable dose of adalimumab or a biosimilar; must be biweekly dose of either 20mg (if<30kg) or 40mg (if ≥30kg) If on a biosimilar of adalimumab, ≥90 days on the biosimilar If on concomitant antimetabolite (injectable or oral methotrexate, mycophenolate mofetil, azathioprine, or leflunomide), dose must be ≤25 mg weekly for methotrexate, ≤3 g daily for mycophenolate mofetil, ≤250 mg daily for azathioprine, or ≤20 mg daily for leflunomide; dose and route of administration must be stable for ≥90 days If on topical corticosteroids, dose must be ≤2 drops prednisolone acetate 1% or equivalent per day and stable for ≥90 days Willingness to limit consumption of alcohol during the study period Agreement to avoid live attenuated vaccinations Agreement to use highly effective contraception for ≥28 days prior to screening and throughout study period (for males and females of reproductive age) Suitable, in the opinion of the Investigator, to continue treatment with adalimumab or placebo per regional labeling No contraindications to receive adalimumab as per the local Summary of Product Characteristics (SmPC) Exclusion Criteria (any one of these excludes the patient): Intraocular surgery in the past 90 days or planned surgery in the next 12 months Severe cataract or opacity preventing view to the posterior pole in both eyes Chronic hypotony (<5mmHg for ≥90 days) in either eye Treatment with oral corticosteroids or intraocular corticosteroid injection within the last 12 months Use of NSAID eye drops within the last 90 days Acute anterior uveitis characterized by redness and symptoms, including but not limited to floaters, pain, and light sensitivity Pregnancy or lactation (a pregnancy test will be conducted at baseline and all follow-up visits for females of reproductive age) Presence of intraretinal or subretinal fluid in either eye Prior safety or tolerability issues with adalimumab History of cancer, active tuberculosis, or hepatitis B Other medical condition expected to dictate treatment course during the study Any of the following laboratory test results on their most recent tests within the past 90 days prior to screening/enrollment: leukocyte count <2500, platelet count ≤75000, hemoglobin<9.0, AST or ALT ≥ 2 times the upper limit of normal range, creatinine ≥1.5 There are no sex, race, or ethnicity restrictions for this study.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Continue adalimumab<br>Patients randomized to this arm will continue adalimumab at their current dose (either 20mg/0.2mL or 40mg/0.4mL) administered subcutaneously every other week. | Biological: Adalimumab<br>* Adalimumab is a fully human monoclonal anti-tumor necrosis factor alpha antibody, a biologic, immunomodulatory drug. Adalimumab 20mg/0.8mL and 40mg/0.8mL is a clear, colorless solution provided in a pre-filled syringe for subcutaneous injection. The formulation is adalimumab, mannitol, polysorbate 80, and water for injection Each pre-filled syringe has a fixed 29-gauge thin wall and ½ inch needle with black protective cover and is intended for a single dose to a single patient.<br>* Other names: HUMIRA;|
| Placebo Comparator: Stop adalimumab<br>Patients randomized to this arm will receive a volume-matched placebo (0.8mL) administered subcutaneously every other week. | Other: Placebo<br>* The placebo solution is a clear, colorless solution provided in a single-use, pre-filled syringe for subcutaneous injection. The placebo is designed to match the characteristics of the citrate-free adalimumab during injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure | Time to treatment failure until 12 months post-randomization. Treatment failure is defined by recurrence of ocular inflammation in at least one eye as follows: 3+ anterior chamber (AC) for a single visit •>0.5+ anterior chamber (AC) cell for ≥28 days 2-step increase in AC cell observed at two separate visits ≥7 days apart 0.5+ vitreous haze, active retinal or choroidal inflammation, or macular edema observed at a single visit. Treatment failure can also be declared by recurrence of joint inflammation that is persistent and severe enough to necessitate unmasking to manage the arthritis recurrence. | From baseline until 12 months post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic anterior uveitis, adalimumab, JIA-associated uveitis, stopping