Adalimumab in JIA-associated Uveitis Stopping Trial

Uveitis Clinical Trial

— ADJUST  

Official title:

Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03816397
• Other study ID #: 17-23987
• Secondary ID: UG1EY029658
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: March 15, 2020
• Est. completion date: July 30, 2025

Study information

• Verified date: March 2024
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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)-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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 118
• Est. completion date: July 30, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• JIA
• Uveitis

Intervention

Biological:
• Adalimumab
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.

Other:
• Placebo
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.

Locations

Country	Name	City	State
Australia	Murdoch Children's Research Institute	Parkville	Victoria
United Kingdom	University Hospitals Bristol and Weston	Bristol
United Kingdom	Cambridge University Hospital	Cambridge
United Kingdom	University Hospitals, Leicester	Leicester
United Kingdom	Alder Hey Children's Hospital	Liverpool
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	Manchester University NHS Foundation Trust	Manchester
United Kingdom	Great North Children's Hospital	Newcastle Upon Tyne
United Kingdom	Norfolk and Norwich University Hospital	Norwich
United Kingdom	Sheffield Children's Hospital	Sheffield
United States	University of Colorado Denver	Aurora	Colorado
United States	University of Texas, Austin	Austin	Texas
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Colorado Retina Associates	Lakewood	Colorado
United States	University of Miami	Miami	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of California, Davis	Sacramento	California
United States	University of Utah Health	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California

Sponsors (21)

Lead Sponsor

Collaborator

Nisha Acharya

Alder Hey Children's NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, Children's Hospital Medical Center, Cincinnati, Children's Hospital of Philadelphia, Children's Mercy Hospital Kansas City, Colorado Retina Associates, Great Ormond Street Hospital for Children NHS Foundation Trust, Manchester University NHS Foundation Trust, National Eye Institute (NEI), Newcastle-upon-Tyne Hospitals NHS Trust, Norfolk and Norwich University Hospitals NHS Foundation Trust, Royal Children's Hospital, Sheffield Children's NHS Foundation Trust, University Hospitals Bristol and Weston NHS Foundation Trust, University Hospitals, Leicester, University of California, Davis, University of Miami, University of Texas at Austin, University of Utah, Vanderbilt University Medical Center

Countries where clinical trial is conducted

United States,  Australia,  United Kingdom, 

References & Publications (8)

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. — View 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. — View 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. — View Citation

Jaffe GJ, Dick AD, Brezin AP, Nguyen QD, Thorne JE, Kestelyn P, Barisani-Asenbauer T, Franco P, Heiligenhaus A, Scales D, Chu DS, Camez A, Kwatra NV, Song AP, Kron M, Tari S, Suhler EB. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med. 2016 Sep 8;375(10):932-43. doi: 10.1056/NEJMoa1509852. — View Citation

Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, Schlaen A, Pavesio C, Cimino L, Van Calster J, Camez AA, Kwatra NV, Song AP, Kron M, Tari S, Brezin AP. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016 Sep 17;388(10050):1183-92. doi: 10.1016/S0140-6736(16)31339-3. Epub 2016 Aug 16. Erratum In: Lancet. 2016 Sep 17;388(10050):1160. — View Citation

Ramanan AV, Dick AD, Benton D, Compeyrot-Lacassagne S, Dawoud D, Hardwick B, Hickey H, Hughes D, Jones A, Woo P, Edelsten C, Beresford MW; SYCAMORE Trial Management Group. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). Trials. 2014 Jan 9;15:14. doi: 10.1186/1745-6215-15-14. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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