Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

JHSPH Center for Clinical Trials227 enrolled

Overview

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.

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

Sex: ALLMin age: 13 Years

Medical Language ↔ Plain English

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.

Locations (26)

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

...and 16 more locations

Outcomes

Primary Outcomes

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. Steroid dose and uveitis activity from visit months 6,8,10 and 12 were included in the analysis. Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid sparing between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix. Results were reported at 6 months (primary outcome) and 12 months (secondary outcome).

Time frame: 6 months

Secondary Outcomes

Corticosteroid-sparing Treatment Success Within the First 12 Months After Randomization

Time frame: 12 months

Corticosteroid Discontinuation Success by 6 Months

Corticosteroid 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. Steroid dose and uveitis activity from visit months 6,8,10 and 12 were included in the analysis. Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid discontinuation between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix. Results were reported at 6 months and 12 months.

Time frame: 6 months

Corticosteroid Discontinuation Success by 12 Months

Time frame: 12 months

Corticosteroid Exposure Over 12 Months

Corticosteroid dose was collected at baseline and months 1,2,3,4,5,6,8,10, and 12. Mean corticosteroid dose per day was estimated with a negative binomial model at 12 months.

Time frame: 12 months

Best Corrected Visual Acuity Change at 12 Months

Mean change in best-corrected visual acuity from baseline to 12 months. Participants' visual acuity was measured by certified examiners with best refractive correction in place. Participants were challenged with reading letters on lines of the standard ETDRS eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until no more meaningful readings could be made and were scored by how many letters could be correctly identified. More letters read is associated with higher visual acuity (85 letters is 20/20 vision). Visual acuity data was collected at baseline and months 1,2,3,4,5,6,8,10, and 12 and estimated at 12 months with a mixed model.

Time frame: 12 months

Macular Edema Over 12 Months of Follow up

Macular edema is defined as central retinal thickness greater than or equal to 300 micrometers as measured by a masked grader's review of OCT images. Greater retinal thickness is associated with poorer vision. Outcome measure is the odds ratio comparing macular edema at 12 months to baseline macular edema. Macular edema was measured at baseline and months 3, 6, and 12. The odds ratio at 12 months was estimated with a mixed model.

Time frame: 12 months

Incidence of Infections at 12 Months

Incidence of infections over 12 months of follow-up. Participants were asked about occurrences since the previous visit of infections requiring antibiotic or antiviral treatment. Data was collected at months 1,2,3,4,5,6,8,10, and 12. The rate of infections at 12 months was estimated with a negative binomial model.

Time frame: 12 months

Elevated Levels of AST or ALT (Hepatoxicity) by 12 Months.

Cumulative percent of participants having elevated levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than twice the upper level of normal by 12 months. Elevated levels of AST and ALT may indicate decline in liver function. Lab values of AST and ALT were measured at baseline and months 1,2,3,4,5,6,8,10, and 12 and the cumulative percent of participants with elevated lab values by 12 months was estimated by Kaplan Meier methods.

Time frame: 12 months

Elevated Creatine (Nephrotoxicity) by 12 Months

Cumulative percent of participants having elevated creatine values (creatine greater than 30% above baseline or creatine \> 1.5 mg/dL) by 12 months. Increases in creatine levels may indicate decreased kidney function. Lab values of creatine were measured at baseline and months 1,2,3,4,5,6,8,10, and 12 and the cumulative percent of participants with elevated creatine at 12 months was estimated by Kaplan Meier methods.

Time frame: 12 months

EQ-5D (Health Utility)

The EQ-5D (EuroQol Group - 5 Dimension questionnaire) is a participant reported validated questionnaire that measures the patient's health status in five dimensions of health: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. The range of questionnaire index scores is -0.59 to 1 where score of 1 indicates best possible health. The outcome measure is the odds of having EQ-5D score of 1 (perfect health) at 12 months compared to the odds of having EQ-5d score = 1 at the baseline visit. Participants completed the EQ-5D questionnaire at baseline and months 3, 6 and 12. General estimating equations with a log link were used to assess the odds ratio at 12 months.

Time frame: 12 months

General Health-related Quality of Life -Physical Component (SF-36)

Standard Form 36 item (SF-36) questionnaire is a validated participant reported measure of health related-quality of life. The physical component summary (PCS) is a score derived from the SF-36 that reflects a person's physical well-being. Range of scores is 0 to 100. Higher scores indicated better physical health. The minimally important clinical difference is 3-5 points. Outcome measure is the change in physical health score from baseline to 12 months. Participants completed the questionnaire at baseline and months 3, 6, and 12. The mean change from baseline at 12 months was estimated with a mixed model.

Time frame: 12 months

Quality of Life Mental Health Component Standard Form 36 Item (SF-36)

Standard Form 36 item (SF-36) questionnaire is a validated participant reported measure of health related-quality of life. The mental health component summary (MCS) is a score derived from the SF-36 that reflects a person's mental health and well-being. Range of scores is 0 to 100. Higher scores indicate better mental health. The minimally important clinical difference is 3-5 points. Outcome measure is the change in mental health score from baseline to 12 months. Participants completed the questionnaire at baseline and months 3, 6, and 12. The change from baseline at 12 months was estimated with a mixed model.

Time frame: 12 months

Vision-related Quality of Life

Vision-related quality of life was measured by the vision targeted subscale (excluding general health) from the National Eye Institute Visual Functioning Questionnaire 25 item (VFQ-25). The VFQ-25 is a validated, participant reported measure of the aspects of visual functioning that are most important for persons who have chronic eye diseases. Higher scores indicate better vision. Scores range from 0 to 100. Meaningful difference is 4-6 points. Participants completed the VFQ-25 at baseline and months 3, 6 and 12. The outcome is the change in VFQ-25 from baseline to 12 months estimated with a mixed model.

Time frame: 12 months

Cataract Surgery at 12 Months

Cumulative percent of uveitis eyes having cataract surgery by 12 months. Whether the patient had cataract surgery in the prior time period was determined at baseline and months 1,2,3,4,5,6,8,10,12 and the cumulative percent of eyes having cataract surgery by12 months was estimated by Kaplan-Meier methods.

Time frame: 12 months

Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

Overview

Conditions

Interventions

Eligibility

Locations (26)

Outcomes

Primary Outcomes

Secondary Outcomes