Clinical trial NCT03816397: Adalimumab in JIA-associated Uveitis Stopping Trial
Official title: Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Uveitis
JIA
Keywords: chronic anterior uveitis
adalimumab
JIA-associated uveitis
stopping
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Philadelphia
name: Children's Hospital Medical Center, Cincinnati
name: Children's Mercy Hospital Kansas City
name: National Eye Institute (NEI)
name: Great Ormond Street Hospital for Children NHS Foundation Trust
name: University Hospitals Bristol and Weston NHS Foundation Trust
name: Alder Hey Children's NHS Foundation Trust
name: Newcastle-upon-Tyne Hospitals NHS Trust
name: Sheffield Children's NHS Foundation Trust
name: Cambridge University Hospitals NHS Foundation Trust
name: Royal Children's Hospital
name: Norfolk and Norwich University Hospitals NHS Foundation Trust
name: Vanderbilt University Medical Center
name: University of California, Davis
name: University of Texas at Austin
name: University of Miami
name: University Hospitals, Leicester
name: University of Utah
name: Colorado Retina Associates
name: Manchester University NHS Foundation Trust
First posted: 2019-01-25
Enrollment: 87
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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) 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.

Eligibility criteria: 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 (\<5 mmHg 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, Aspartate Aminotransferase (AST) or Alanine Transferase (ALT) ≥ 2 times the upper limit of normal range, creatinine ≥1.5

There are no sex, race, or ethnicity restrictions for this study.

Primary outcomes:
measure: Time to Treatment Failure
timeFrame: From baseline until 48 weeks post-randomization
Secondary outcomes:
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Lakewood
country: United States
facility: Colorado Retina Associates
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: University of Texas, Austin
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
city: Parkville
country: Australia
facility: Murdoch Children's Research Institute
state: Victoria
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol and Weston
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospital
city: Leicester
country: United Kingdom
facility: University Hospitals, Leicester
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: Great North Children's Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
Study officials:
affiliation: Principal Investigator
name: Nisha Acharya, MD MS
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Vazquez-Cobian LB, Flynn T, Lehman TJ. Adalimumab therapy for childhood uveitis. J Pediatr. 2006 Oct;149(4):572-5. doi: 10.1016/j.jpeds.2006.04.058.
citation: Chang CY, Meyer RM, Reiff AO. Impact of medication withdrawal method on flare-free survival in patients with juvenile idiopathic arthritis on combination therapy. Arthritis Care Res (Hoboken). 2015 May;67(5):658-66. doi: 10.1002/acr.22477.
citation: Baszis K, Garbutt J, Toib D, Mao J, King A, White A, French A. Clinical outcomes after withdrawal of anti-tumor necrosis factor alpha therapy in patients with juvenile idiopathic arthritis: a twelve-year experience. Arthritis Rheum. 2011 Oct;63(10):3163-8. doi: 10.1002/art.30502.
citation: Shakoor A, Esterberg E, Acharya NR. Recurrence of uveitis after discontinuation of infliximab. Ocul Immunol Inflamm. 2014 Apr;22(2):96-101. doi: 10.3109/09273948.2013.812222. Epub 2013 Jul 22.
citation: Acharya NR, Ebert CD, Kelly NK, Porco TC, Ramanan AV, Arnold BF; ADJUST Research Group. Discontinuing adalimumab in patients with controlled juvenile idiopathic arthritis-associated uveitis (ADJUST-Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial): study protocol for a randomised controlled trial. Trials. 2020 Oct 27;21(1):887. doi: 10.1186/s13063-020-04796-z.
citation: Acharya NR, Ramanan AV, Coyne AB, Dudum KL, Rubio EM, Woods SM, Guly CM, Moraitis E, Petrushkin HJD, Armon K, Puvanachandra N, Choi JT, Hawley DP, Arnold BF; ADJUST Study Group. Stopping of adalimumab in juvenile idiopathic arthritis-associated uveitis (ADJUST): a multicentre, double-masked, randomised controlled trial. Lancet. 2025 Jan 25;405(10475):303-313. doi: 10.1016/S0140-6736(24)02468-1.