Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

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Brief Title

Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

Official Title

Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Corticosteroid-sparing treatment success within the first 6 months after randomization

Secondary Outcome

 Corticosteroid-sparing treatment success within the first 12 months after randomization

Condition

Uveitis

Intervention

Adalimumab (ADA)

Study Arms / Comparison Groups

 Adalimumab (ADA)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

222

Start Date

August 19, 2019

Completion Date

February 28, 2023

Primary Completion Date

August 30, 2022

Eligibility Criteria

        Inclusion criteria

          1. Age 13 years or older

          2. Weight 30 kg (66 lbs) or greater

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

          4. Prednisone indication meets one of the following:

               1. 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

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

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

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

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

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

          9. 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. Any of the following baseline lab values

               1. White blood count <3500 cells per microliter

               2. Platelets <100,000 per microliter

               3. Hematocrit <30%

               4. AST or ALT >1.5X upper limit normal value

               5. Serum creatinine >1.1X upper limit normal value

          4. Behçet disease

          5. Multiple sclerosis or other demyelinating disease

          6. For patients with anterior/intermediate or intermediate uveitis without systemic
             disease, abnormal magnetic resonance imaging (MRI) of the brain consistent with
             demyelinating disease

          7. Severe uncontrolled infection

          8. Receipt of a live vaccine within past 30 days

          9. Moderate to severe heart failure (NYHA class III/IV)

         10. Active malignancy

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

         12. History of adalimumab intolerance or ineffectiveness

         13. Hypersensitivity to any of the study treatments or their excipients

         14. Current treatment with an alkylating agent

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

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

         17. 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

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

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

         20. Pregnancy or lactation

         21. 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.

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

Gender

All

Ages

13 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Douglas A Jabs, MD MBA, 443-287-5791, [email protected]

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT03828019

Organization ID

9196


Responsible Party

Sponsor

Study Sponsor

JHSPH Center for Clinical Trials


Study Sponsor

Douglas A Jabs, MD MBA, Study Chair, CCTand Evidence Synthesis, JHU, Bloomberg School of Public Health


Verification Date

August 2020