ADVISE: Adalimumab vs. Conventional Immunosuppression for Uveitis Trial

• Sponsor: JHSPH Center for Clinical Trials (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03828019
• Collaborator: (none)
• Enrollment: 222
• Locations: 28
• Arms: 2
• Anticipated Duration (Months): 53.4
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Uveitis	Biological: Adalimumab (ADA); Drug: Conventional immunosuppression (CON)	Phase 3

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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,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,
• Masking: None (Open Label)
• Masking Description: Unmasked treatment administration and outcome assessments (participants, study ophthalmologists, visual function examiners, and study coordinators are all unmasked). Masked assessment of baseline, 1-month, 3-month, and 6-month photographic images and OCT by the Reading Center (graders masked).
• Primary Purpose: Treatment
• Official Title: Adalimumab vs. Conventional Immunosuppression for Uveitis Trial
• Actual Study Start Date: Sep 17, 2019
• Anticipated Primary Completion Date: Aug 31, 2023
• Anticipated Study Completion Date: Feb 29, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Corticosteroid-sparing treatment success within the first 6 months after randomization [6 months]

   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.

Secondary Outcome Measures

1. Corticosteroid-sparing treatment success within the first 12 months after randomization [12 months]

   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.

2. Prednisone discontinuation success [12 months]

   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.

3. Prednisone exposure [12 months]

   E.g., cumulative prednisone dose and/or mean prednisone dose

4. Best corrected visual acuity [12 months]

   Best corrected visual acuity measured after a standardized refraction using logarithmic visual acuity charts

5. Infections [12 months]

   Incidence of infections over 12 months of follow-up

6. Systemic adverse events [12 months]

   Systemic adverse events over 12 months of follow-up

7. Macular edema [12 months]

   Macular edema over 12 months of follow-up

8. Health utility [12 months]

   Health utility will be measured using the EQ-5D

9. Generic health-related quality of life [12 months]

   Generic health-related quality of life will be measured using the SF-36

10. Vision-related quality of life [12 months]

    Vision-related quality of life will be measured using the NEI-VFQ-25

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. 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

1. Currently receiving dose greater than 7.5 mg/day

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

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

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

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

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

6. 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

4. White blood count <3500 cells per microliter

5. Platelets <100,000 per microliter

6. Hematocrit <30%

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

8. Serum creatinine >1.1X upper limit normal value

9. Behçet disease

10. Multiple sclerosis or other demyelinating disease

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

12. Severe uncontrolled infection

13. Receipt of a live vaccine within past 30 days

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

15. Active malignancy

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

17. History of adalimumab intolerance or ineffectiveness

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

19. Current treatment with an alkylating agent

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

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

22. 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

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

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

25. Pregnancy or lactation

26. 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.

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• JHSPH Center for Clinical Trials

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: JHSPH Center for Clinical Trials
• ClinicalTrials.gov Identifier: NCT03828019
• Other Study ID Numbers: 9196
• First Posted: Feb 4, 2019
• Last Update Posted: Jun 21, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Uveitis; Cyclosporine; Adalimumab; Methotrexate; Azathioprine; Tacrolimus; Cyclosporins

Study Results

No Results Posted as of Jun 21, 2022