JIA, Uveitis
Conditions
Keywords
chronic anterior uveitis, adalimumab, JIA-associated uveitis, stopping
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.
Interventions
BIOLOGICALAdalimumab
Adalimumab is a fully human monoclonal anti-tumor necrosis factor alpha antibody, a biologic, immunomodulatory drug. Adalimumab 20mg/0.8 mL and 40mg/0.8 mL 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.
OTHERPlacebo
The placebo solution is a clear, colorless solution provided in a single-use, pre-filled syringe for subcutaneous injection. The volume-matched (0.8mL) placebo is designed to match the characteristics of the citrate-free adalimumab during injection.
Sponsors
Children's Hospital of Philadelphia
Children's Hospital Medical Center, Cincinnati
Children's Mercy Hospital Kansas City
National Eye Institute (NEI)
Great Ormond Street Hospital for Children NHS Foundation Trust
University Hospitals Bristol and Weston NHS Foundation Trust
Alder Hey Children's NHS Foundation Trust
Newcastle-upon-Tyne Hospitals NHS Trust
Sheffield Children's NHS Foundation Trust
Cambridge University Hospitals NHS Foundation Trust
Royal Children's Hospital
Norfolk and Norwich University Hospitals NHS Foundation Trust
Vanderbilt University Medical Center
University of California, Davis
University of Texas at Austin
University of Miami
University Hospitals, Leicester
University of Utah
Colorado Retina Associates
Manchester University NHS Foundation Trust
Nisha Acharya
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure | From baseline until 48 weeks 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. Time (days) from all participants is included in the analysis. |
Countries
Australia, United Kingdom, United States
Participant flow
Recruitment details
Patients were enrolled from March 3, 2020, to Feb 14, 2024, at 20 ophthalmology and rheumatology clinical sites across the United States, the United Kingdom, and Australia.
Participants by arm
| Arm | Count |
|---|---|
| Continue Adalimumab Patients randomized to this arm will continue adalimumab at their current dose administered subcutaneously every other week. | 43 |
| Stop Adalimumab Patients randomized to this arm will receive a volume-matched placebo (0.8 mL) administered subcutaneously every other week. | 44 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Censored at interim analysis date. | 13 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Stop Adalimumab | Continue Adalimumab |
|---|---|---|---|
| Age at diagnosis of juvenile idiopathic arthritis, years | 3.30 years | 3.71 years | 2.77 years |
| Age, Continuous | 12.31 years | 12.26 years | 12.56 years |
| Arthritis category None; chronic anterior uveitis | 14 Participants | 7 Participants | 7 Participants |
| Arthritis category Oligoarthritis | 58 Participants | 29 Participants | 29 Participants |
| Arthritis category Polyarthritis | 13 Participants | 6 Participants | 7 Participants |
| Arthritis category Psoriatic arthritis | 1 Participants | 1 Participants | 0 Participants |
| Arthritis category Undifferentiated arthritis | 1 Participants | 1 Participants | 0 Participants |
| Conventional DMARD Use Azathioprine | 4 Participants | 3 Participants | 1 Participants |
| Conventional DMARD Use Leflunomide | 3 Participants | 1 Participants | 2 Participants |
| Conventional DMARD Use Methotrexate (oral) | 22 Participants | 9 Participants | 13 Participants |
| Conventional DMARD Use Methotrexate (subcutaneous) | 29 Participants | 15 Participants | 14 Participants |
| Conventional DMARD Use Mycophenolate mofetil | 4 Participants | 3 Participants | 1 Participants |
| Conventional DMARD Use None | 25 Participants | 13 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 8 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 28 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 67 Participants | 33 Participants | 34 Participants |
| Region of Enrollment Australia | 5 participants | 3 participants | 2 participants |
| Region of Enrollment United Kingdom | 54 participants | 27 participants | 27 participants |
| Region of Enrollment United States | 28 participants | 14 participants | 14 participants |
| Sex: Female, Male Female | 64 Participants | 32 Participants | 32 Participants |
| Sex: Female, Male Male | 23 Participants | 12 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 44 |
| other Total, other adverse events | 34 / 43 | 29 / 44 |
| serious Total, serious adverse events | 4 / 43 | 0 / 44 |
Outcome results
Primary
Time to Treatment Failure
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. Time (days) from all participants is included in the analysis.
Time frame: From baseline until 48 weeks post-randomization
Population: Two patients dropped out of the trial before reaching the primary endpoint (one in each group). The length of time that these patients participated in the trial before dropout is included in the primary outcome analysis given the nature of survival analyses. Patients still in active follow-up who had not yet reached the primary endpoint (13 in the adalimumab group and six in the placebo group) were censored at the interim analysis date, Feb 14, 2024. No patients were lost to follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continue Adalimumab | Time to Treatment Failure | NA Time to treatment failure (days) |
| Stop Adalimumab | Time to Treatment Failure | 119 Time to treatment failure (days) |
Comparison: A Cox proportional hazards regression was used to compare time to treatment failure between the adalimumab and placebo groups up to the primary endpoint of 48 weeks, with country and conventional DMARD use included as fixed effects in the model. The null hypothesis was an hazard ratio (HR) of 1. Hypothesis testing was based on a permutation test of the log hazard ratio (100,000 replicates). The model was checked for the assumption of proportional hazards by assessing Schoenfeld residuals.p-value: <0.000195% CI: [3.6, 21.2]Log Rank