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.

Study Overview

• Status: Active, not recruiting
• Conditions: Uveitis
• Intervention / Treatment: Biological: Adalimumab (ADA); Drug: Conventional immunosuppression (CON)

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 Type: Interventional
• Enrollment (Estimated): 222
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Janet T Holbrook, PhD MPH; Phone Number: 443-287-5791; Email: jholbro1@jhu.edu
• Study Contact Backup: Name: Elizabeth A Sugar, PhD; Email: esugar2@jhu.edu

Study Locations

• Australia
  • Sydney, Australia
    • University of Sydney
  • Victoria
    • East Melbourne, Victoria, Australia
      • Centre for Eye Research Australia
• Canada
  • Quebec
    • Montréal, Quebec, Canada, H4A 3S5
      • McGill University
• United Kingdom
  • Bradford, United Kingdom
    • Bradford Teaching Hospital NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University NHS Trust
  • Leicester, United Kingdom, LE1 5WW
    • University Hospitals of Leicester
  • London, United Kingdom, EC1V 9EL
    • Moorfields Eye Hospital NHS Foundation Trust
  • Birmingham
    • Edgbaston, Birmingham, United Kingdom, B15 2TH
      • University Hospital Birmingham
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Jules Stein Eye Institute, UCLA
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Florida
    • Miami, Florida, United States, 33136
      • Anne Bates Leach Eye Hospital, University of Miami Miller School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Bethesda, Maryland, United States, 20892
      • National Eye Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Ophthalmic Consultants of Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan Health System, Kellogg Eye Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • MidAtlantic Retina, Wills Eye Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Retina
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Eye Institute
  • Texas
    • Bellaire, Texas, United States, 77401
      • Retinal Consultants of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah, Moran Eye Center
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington, Medicine Eye Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Biological: 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.; Other Names: Adalimumab, Humira
Active Comparator: 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 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.	Drug: 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.; Other Names: Azathioprine, Imuran , Cyclosporine; Methotrexate, Rheumatrex; Mycophenolate, CellCept; Cyclosporine, Sandimmune, Neoral; Tacrolimus, Prograf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corticosteroid-sparing treatment success within the first 6 months after randomization	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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corticosteroid-sparing treatment success within the first 12 months after randomization	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.	12 months
Prednisone discontinuation success	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.	12 months
Prednisone exposure	E.g., cumulative prednisone dose and/or mean prednisone dose	12 months
Best corrected visual acuity	Best corrected visual acuity measured after a standardized refraction using logarithmic visual acuity charts	12 months
Infections	Incidence of infections over 12 months of follow-up	12 months
Systemic adverse events	Systemic adverse events over 12 months of follow-up	12 months
Macular edema	Macular edema over 12 months of follow-up	12 months
Health utility	Health utility will be measured using the EQ-5D	12 months
Generic health-related quality of life	Generic health-related quality of life will be measured using the SF-36	12 months
Vision-related quality of life	Vision-related quality of life will be measured using the NEI-VFQ-25	12 months

Collaborators and Investigators

• Sponsor: JHSPH Center for Clinical Trials
• Investigators: Study Chair: Douglas A Jabs, MD MBA, CCTand Evidence Synthesis, JHU, Bloomberg School of Public Health

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2019
• Primary Completion (Estimated): April 12, 2024
• Study Completion (Estimated): September 17, 2024

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: January 31, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Uveal Diseases; Uveitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Tumor Necrosis Factor Inhibitors; Calcineurin Inhibitors; Adalimumab; Methotrexate; Azathioprine; Tacrolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 9196 (CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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).
• IPD Sharing Time Frame: One year after completion of data collection, the data set will be available upon request .
• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No