Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

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.

Inclusion Criteria:

1. Age 13 years or older

2. Active or recently active (≤ 60 days) non-infectious, intermediate, posterior, or
panuveitis

3. Prednisone indication meets one of the following:

a. 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

b. Inactive uveitis on current dose greater 7.5 mg/day

4. Initiation or addition of an immunosuppressive drug (i.e., a conventional
immunosuppressive drug or adalimumab) is indicated

5. If currently receiving a conventional immunosuppressive drug, the drug and dose have
been stable for at least 30 days

6. Patient able and willing to self-administer subcutaneous injections or have a
qualified person available to administer subcutaneous injections

7. If posterior segment disease is present, ability to assess activity in at least one
eye with uveitis

8. Visual acuity of light perception or better in at least one eye with uveitis

Exclusion Criteria:

1. Active tuberculosis or untreated latent tuberculosis (e.g., positive interferon-γ
release assay [IGRA] test, such as Quantiferon-gold)

2. Untreated active hepatitis B or C infection

3. Behçet disease

4. Multiple sclerosis

5. For patients with intermediate uveitis, abnormal magnetic resonance imaging (MRI) of
the brain consistent with demyelinating disease

6. Use of anti-TNF monoclonal antibody therapy within past 60 days

7. History of adalimumab intolerance or ineffectiveness

8. Current treatment with an alkylating agent

9. Current treatment with more than one immunosuppressive drug, not including oral
corticosteroids

10. Shorter-acting regional corticosteroids administered within the past 30 days in any
eye(s) with uveitis

11. 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

12. Systemic disease that is sufficiently active such that it dictates therapy with
systemic corticosteroids or immunosuppressive agents at the time of enrollment

13. Immunodeficiency disease for which immunosuppressive therapy would be contraindicated
according to best medical judgment

14. Pregnancy, lactation, or for women of child-bearing potential unwillingness to use
appropriate birth control for the duration of the trial

15. Medical problems or drug or alcohol dependence problems sufficient to prevent
adherence to treatment and study procedures.