Clinical trial NCT03828019: Adalimumab vs. Conventional Immunosuppression for Uveitis Trial
Official title: Adalimumab vs. Conventional Immunosuppression for Uveitis Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Uveitis
Keywords: Immunosuppression
Adalimumab
Antimetabolites
Calcineurin inhibitors
Corticosteroid sparing
Lead sponsor: JHSPH Center for Clinical Trials
Sponsor class: OTHER
First posted: 2019-02-04
Enrollment: 227
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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,
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Corticosteroid-sparing Treatment Success Within the First 6 Months After Randomization
timeFrame: 6 months
Secondary outcomes:
measure: Corticosteroid-sparing Treatment Success Within the First 12 Months After Randomization
timeFrame: 12 months
measure: Corticosteroid Discontinuation Success by 6 Months
timeFrame: 6 months
measure: Corticosteroid Discontinuation Success by 12 Months
timeFrame: 12 months
measure: Corticosteroid Exposure Over 12 Months
timeFrame: 12 months
measure: Best Corrected Visual Acuity Change at 12 Months
timeFrame: 12 months
measure: Macular Edema Over 12 Months of Follow up
timeFrame: 12 months
measure: Incidence of Infections at 12 Months
timeFrame: 12 months
measure: Elevated Levels of AST or ALT (Hepatoxicity) by 12 Months.
timeFrame: 12 months
measure: Elevated Creatine (Nephrotoxicity) by 12 Months
timeFrame: 12 months
measure: EQ-5D (Health Utility)
timeFrame: 12 months
measure: General Health-related Quality of Life -Physical Component (SF-36)
timeFrame: 12 months
measure: Quality of Life Mental Health Component Standard Form 36 Item (SF-36)
timeFrame: 12 months
measure: Vision-related Quality of Life
timeFrame: 12 months
measure: Cataract Surgery at 12 Months
timeFrame: 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Jules Stein Eye Institute, UCLA
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Miami
country: United States
facility: Anne Bates Leach Eye Hospital, University of Miami Miller School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Bethesda
country: United States
facility: National Eye Institute
state: Maryland
city: Boston
country: United States
facility: Ophthalmic Consultants of Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System, Kellogg Eye Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Philadelphia
country: United States
facility: MidAtlantic Retina, Wills Eye Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Retina
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Eye Institute
state: Tennessee
city: Bellaire
country: United States
facility: Retinal Consultants of Texas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Moran Eye Center
state: Utah
city: Seattle
country: United States
facility: University of Washington, Medicine Eye Institute
state: Washington
city: East Melbourne
country: Australia
facility: Centre for Eye Research Australia
state: Victoria
city: Sydney
country: Australia
facility: University of Sydney
city: Edgbaston
country: United Kingdom
facility: University Hospital Birmingham
state: Birmingham
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospital NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester
city: London
country: United Kingdom
facility: Moorfields Eye Hospital NHS Foundation Trust
Study officials:
affiliation: CCTand Evidence Synthesis, JHU, Bloomberg School of Public Health
name: Douglas A Jabs, MD MBA
role: STUDY_CHAIR
References: