Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

NCT ID: NCT03828019

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 227 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-16
• Study Completion Date: 2024-09-09

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-tumor necrosis(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-alkylating 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 investigational new drug (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.

Conditions

Uveitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Adalimumab (ADA)

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.

Group Type: ACTIVE_COMPARATOR

Adalimumab (ADA)

Intervention Type: BIOLOGICAL

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.

Conventional immunosuppression (CON)

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 twice daily (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.

Group Type: ACTIVE_COMPARATOR

Conventional immunosuppression (CON)

Intervention Type: DRUG

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.

Interventions

Adalimumab (ADA)

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.

Intervention Type: BIOLOGICAL

Conventional immunosuppression (CON)

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.

Intervention Type: DRUG

Other Intervention Names

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

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 [Interferon-gamma 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. aspartate aminotransferase (AST) or alanine transaminase (ALT) >1.5 times (X) upper limit normal value

5. Serum creatinine >1.1 times (X) 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®, Yutiq™, 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 United Kingdom (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.

• Minimum Eligible Age: 13 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

JHSPH Center for Clinical Trials

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Douglas A Jabs, MD MBA

Role: STUDY_CHAIR

CCTand Evidence Synthesis, JHU, Bloomberg School of Public Health

Locations

Jules Stein Eye Institute, UCLA

Los Angeles, California, United States

University of California, San Francisco

San Francisco, California, United States

Anne Bates Leach Eye Hospital, University of Miami Miller School of Medicine

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

Johns Hopkins University

Baltimore, Maryland, United States

National Eye Institute

Bethesda, Maryland, United States

Ophthalmic Consultants of Boston

Boston, Massachusetts, United States

University of Michigan Health System, Kellogg Eye Center

Ann Arbor, Michigan, United States

Washington University

St Louis, Missouri, United States

MidAtlantic Retina, Wills Eye Hospital

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Tennessee Retina

Nashville, Tennessee, United States

Vanderbilt University Eye Institute

Nashville, Tennessee, United States

Retinal Consultants of Texas

Bellaire, Texas, United States

University of Utah, Moran Eye Center

Salt Lake City, Utah, United States

University of Washington, Medicine Eye Institute

Seattle, Washington, United States

Centre for Eye Research Australia

East Melbourne, Victoria, Australia

University of Sydney

Sydney, , Australia

University Hospital Birmingham

Edgbaston, Birmingham, United Kingdom

Bradford Teaching Hospital NHS Foundation Trust

Bradford, , United Kingdom

Cambridge University NHS Trust

Cambridge, , United Kingdom

University Hospitals of Leicester

Leicester, , United Kingdom

Moorfields Eye Hospital NHS Foundation Trust

London, , United Kingdom

Countries

United States; Australia; United Kingdom

References

Teabagy S, Wood E, Bilsbury E, Doherty S, Janardhana P, Lee DJ. Ocular immunosuppressive microenvironment and novel drug delivery for control of uveitis. Adv Drug Deliv Rev. 2023 Jul;198:114869. doi: 10.1016/j.addr.2023.114869. Epub 2023 May 10.

Reference Type: DERIVED

PMID: 37172782 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

9196

Identifier Type: -

Identifier Source: org_study_id