Adalimumab vs. Conventional Immunosuppression for Uveitis Trial (ADVISE)

Non-infectious intermediate, posterior, and panuveitides are chronic, potentially-blinding diseases. Vision-threatening cases require long-term therapy with oral corticosteroids and immunosuppression. Based upon preliminary data, adalimumab, a fully-human, anti-TNF-α monoclonal antibody, now US FDA-approved for uveitis treatment, may be a superior corticosteroid-sparing agent than conventional immunosuppressive drugs. The ADVISE Trial is multicenter randomized, parallel-treatment, comparative effectiveness trial comparing adalimumab to conventional (small molecule) immunosuppression for corticosteroid spring in the treatment of non-infectious, intermediate, posterior, and panuveitides.

Abstract from protocol: The uveitides are a collection of diseases characterized by intraocular inflammation. Collectively, they are the 5th leading cause of blindness in the US, and the estimated cost of treating them is similar to that of treating diabetic retinopathy. Non-infectious intermediate, posterior, and panuveitides have the highest rates of visual loss and typically are treated with oral corticosteroids and immunosuppression. The Multicenter Uveitis Steroid Treatment (MUST) Trial (a randomized, comparative effectiveness trial, which compared 2 treatment paradigms for these diseases, systemic therapy with corticosteroids and immunosuppression vs. regional therapy [the fluocinolone acetonide implant]), and Follow-up Study demonstrated the superiority of the systemic approach to the regional ocular approach in terms of long-term visual outcomes with essentially no increase in systemic side effects in the systemic group. One key to systemic therapy's success was the use of systemic immunosuppression in 88% of participants, coupled with tapering the prednisone to <7.5 mg/day, a relatively safe dose. Non-alklyating agents are typically the first choice and the most often used are azathioprine, methotrexate, mycophenolate, cyclosporine, and tacrolimus. The alkylating agents, cyclophosphamide and chlorambucil, are used less often because of concerns about potential increased malignancy risk. Data from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study suggest that each of the conventional, non-alkylating agent immunosuppressive drugs is effective in controlling the inflammation while permitting tapering prednisone in ~40-55% of patients; hence combination therapy often is needed. Furthermore, minimizing the daily dose of prednisone is important, as the risk of cardiovascular disease and mortality increase with the cumulative dose of oral corticosteroids. In June 2016, the fully-human, anti-TNF-α monoclonal antibody, adalimumab, was approved by the US Food and Drug Administration (FDA) for the treatment of uveitis. Anti-TNF-α monoclonal antibody therapy has revolutionized the management of the rheumatic diseases largely due to its superior efficacy compared to conventional Disease Modifying Anti-Rheumatic Drugs. Data from VISUAL III, the extension of the two phase 3 trials that led to the FDA approval of adalimumab for the treatment of uveitis, suggest that adalimumab may be superior to conventional immunosuppression, as ~75% of participants had controlled inflammation with prednisone doses <5 mg/day. The ADalimumab Vs. conventional ImmunoSupprEssion for uveitis (ADVISE) Trial is a randomized, comparative effectiveness trial comparing adalimumab to conventional agent immunosuppression for patients with non-infectious, intermediate, posterior, and panuveitides. The primary outcome is the ability to successfully taper prednisone to <7.5 mg/day by 6 months after randomization while maintaining control of the inflammation. Secondary outcomes include prednisone discontinuation by 1 year, visual acuity, and complications of uveitis and its treatment. ADVISE is being conducted under IND 132532. Adalimumab was FDA approved for the treatment of non-infectious intermediate, posterior, and panuveitides in adult patients in 2016 and in pediatric patients 2 years of age and older in 2018. In 2016, prior to the approval for pediatric patients, the FDA determined that use of adalimumab for the treatment of non-infectious intermediate, posterior, and panuveitides in adolescent patients in the ADVISE Trial does not increase risk for these patients as the drug is approved for treatment of pediatric patients for other indications. Although conventional immunosuppressive drugs are the standard approach and in widespread use, these drugs are not FDA approved for treatment of non-infectious intermediate, posterior, and panuveitides, and therefore an IND has been issued for this trial.

Randomized treatment assignment with allocation ratio: 1:1 and two stratification variables: (1) number of immunosuppressive drug patient is on at time of enrollment (zero vs. one); (2) Initial dose of prednisone patient will be on in trial (<30 mg/day vs. ≥30 mg/day). The unit of randomization is the patient,

Unmasked treatment administration and outcome assessments (participants, study ophthalmologists, visual function examiners, and study coordinators are all unmasked). Masked assessment of baseline, 1-month, 3-month, and 6-month photographic images and OCT by the Reading Center (graders masked).

Adalimumab administered by subcutaneous injection at dosage and frequency specified below; total duration of treatment is 12 months. Adults (≥ 18 years of age) and adolescents ≥30 kg: 80 mg as initial dose; one week later by 40 mg then 40 mg every two weeks. Adolescents <30 kg: 40 mg as initial dose; one week later 20 mg then 20 mg every 2 weeks.

Conventional immunosuppressive agent selected by study ophthalmologist at dose and frequency specified below;12 month treatment duration. Azathioprine: initially 2 mg/kg/day; max dose 200 mg/day. Methotrexate initially 15mg/wk; max dose 25 mg/wk. Mycophenolate initially 1 gm BID; max dose1.5 gm BID. Cyclosporine (Sandimmune - dose 2.5 mg/kg BID and Neoral dose 2 mg/kg BID. Tacrolimus initially 1 mg BID; max dose 3 mg BID.

Adalimumab is a fully-human monoclonal antibody to TNF-α, which is approved by the U.S. FDA for the treatment of non-infectious intermediate, posterior, and panuveitides in adults and children 2 years of age and older.

Azathioprine, Imuran , Cyclosporine, Methotrexate, Rheumatrex, Mycophenolate, CellCept, Cyclosporine, Sandimmune, Neoral, Tacrolimus, Prograf

The study ophthalmologist will select amongst the permissible drugs (methotrexate, mycophenolate mofetil or azathioprine for antimetabolites; cyclosporine or tacrolimus for calcineurin inhibitors) taking into account the side effect profile of each drug with respect to subject's clinical situation.

Corticosteroid-sparing success is defined as achieving inactive uveitis for two consecutive visits >= 28 days apart while on <= 7.5 mg/day of corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging.

Corticosteroid-sparing success is defined as achieving inactive uveitis for two consecutive visits >= 28 days apart while on <= 7.5 mg/day of corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging.

Prednisone discontinuation success is defined as achieving inactive uveitis for two consecutive visits >= 28 days apart after discontinuing corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging.

Best corrected visual acuity measured after a standardized refraction using logarithmic visual acuity charts

Inclusion criteria Age 13 years or older Weight 30 kg (66 lbs) or greater Active or recently active (≤ 60 days) non-infectious intermediate, posterior, or panuveitis Prednisone indication meets one of the following: Active uveitis requiring one of the following i. Initiation of prednisone at dose greater than 7.5 mg/day ii. Increasing prednisone dose to greater than 7.5 mg/day iii. Currently receiving dose greater than 7.5 mg/day Inactive uveitis on current dose greater 7.5 mg/day Initiation or addition of an immunosuppressive drug (i.e., a conventional immunosuppressive drug or adalimumab) is indicated If currently receiving a conventional immunosuppressive drug, the drug and dose have been stable for at least 30 days Patient able and willing to self-administer subcutaneous injections or have a qualified person available to administer subcutaneous injections If posterior segment disease is present, ability to assess activity in at least one eye with uveitis Visual acuity of light perception or better in at least one eye with uveitis Exclusion criteria Active tuberculosis or untreated latent tuberculosis (e.g., positive interferon-γ release assay [IGRA] test, such as Quantiferon-gold) Untreated active hepatitis B or C infection Any of the following baseline lab values White blood count <3500 cells per microliter Platelets <100,000 per microliter Hematocrit <30% AST or ALT >1.5X upper limit normal value Serum creatinine >1.1X upper limit normal value Behçet disease Multiple sclerosis or other demyelinating disease For patients with anterior/intermediate or intermediate uveitis without systemic disease, abnormal magnetic resonance imaging (MRI) of the brain consistent with demyelinating disease Severe uncontrolled infection Receipt of a live vaccine within past 30 days Moderate to severe heart failure (NYHA class III/IV) Active malignancy Use of anti-TNF monoclonal antibody therapy within past 60 days History of adalimumab intolerance or ineffectiveness Hypersensitivity to any of the study treatments or their excipients Current treatment with an alkylating agent Current treatment with more than one immunosuppressive drug, not including oral corticosteroids Shorter-acting regional corticosteroids administered within the past 30 days in any eye(s) with uveitis Long-acting ocular corticosteroid implants, i.e., fluocinolone acetonide implant (e.g., Retisert®, YutiqTM, Iluvien®) placed within past 3 years unless uveitis is active in all eye(s) with an implant Systemic disease that is sufficiently active such that it dictates therapy with systemic corticosteroids or immunosuppressive agents at the time of enrollment Immunodeficiency disease for which immunosuppressive therapy would be contraindicated according to best medical judgment Pregnancy or lactation For persons of child-bearing potential or impregnating potential, unwillingness to use appropriate birth control (abstinence, combination barrier and spermicide, hormonal, or intrauterine device) for the next 18 months or plans to become a biological parent within the next 18 months. * In the UK, use of combination barrier and spermicide alone does not meet birth control requirements. † UK female study participants must use highly effective methods of contraception. UK male study participants must use condoms for at least 6 months after the end of study treatment and their female partners of child-bearing potential are recommended to use highly effective contraception for the same duration. In addition, male participants should not donate semen during therapy or for 6 months following discontinuation of study treatment. Medical problems or drug or alcohol dependence problems sufficient to prevent adherence to treatment and study procedures.

A public use dataset corresponding to the primary manuscript and compliant with HIPAA regulations will be prepared within 1 year of completion of data collection. An encrypted data set containing de-identified data, a data dictionary and other study documentation (e.g. protocol and study manuals) will be provide after the data use agreement has been executed (see access criteria below).

Requests for access to data will be reviewed by the Executive Committee to confirm oversight authority approval (e.g. IRB approval) and a minimum standard of scientific merit. Once a request is approved, the investigator will be required to sign a data use agreement approved by the Johns Hopkins Bloomberg School of Public Health Office of Research Administration. An encrypted data set containing de-identified data, a data dictionary and other study documentation (e.g. protocol and study manuals) will be provide after the data use agreement has been executed.