The clinical trial options continue to increase for treatments to address uveitic disease. This review, which updates a previous article on clinical trials in uveitis that appeared in the October 2022 issue of Retinal Physician, will focus on phase 1 through 4 uveitis trials listed as active on clinicaltrials.gov , most of which are assessing noninfectious uveitis. Trials listed here use systemic, topical, and intravitreal administrations of drugs to quell inflammation.

PHASE 1 UVEITIS TRIALS

The Minocycline for Chronic Autoimmune Uveitis trial is an interventional, phase 1 study with an estimated enrollment of 10 participants at Sun Yat-Sen University in China.¹ Patients will take oral minocycline 100 mg daily to assess its impact on various endpoints, including changes in macular sensitivity, best-corrected visual acuity (BCVA), visual fields, and electroretinogram (ERG) fluctuations at 6 and 12 months.

PHASE 2 TRIALS

Pivotal Study of Izokibep in Noninfectious, Intermediate-, Posterior-, or Panuveitis, sponsored by Acelyrin Inc, is a phase 2b trial constructed as an interventional study of an estimated 100 patients.² Patients will be randomized to 2 arms: (1) placebo subcutaneous treatment administered weekly or (2) izokibep administered subcutaneously weekly. The study will assess izokibep, a blocker of interleukin-17A, an integral player in the inflammatory cascade. The primary outcome will measure the time to treatment failure, which is defined in the study protocol. Secondary outcomes include, but are not limited to, the proportion of subjects who achieved quiescence, change in BCVA, change in central retinal thickness, and incidence of treatment-emergent adverse events (TEAE).

The Effectivity of Antituberculosis Therapy in Idiopathic Uveitis With Positive Interferon Gamma Release Assay (IGRA), sponsored by Fakultas Kedokteran University in Indonesia, is a triple-masked phase 2 study assessing 80 participants randomized to either antituberculosis therapy or oral steroid for patients with uveitis with a positive IGRA test.³ The primary outcome measurement will be percentage of treatment failure, defined as more than 0.5+ anterior chamber (AC) cell or vitreous haze, active retinal or choroidal lesions, or the inability to taper down to less than 7.5 mg of oral prednisone or 2 drops of prednisolone acetate 1% daily.

Abatacept in Patients With Birdshot HLA A29 Uveitis, sponsored by the Ziekehuizen Leuven University in Belgium, is a phase 2 prospective, open-label, interventional, proof-of-concept study assessing abatacept administered once a week to patients diagnosed with birdshot chorioretinopathy.⁴ The goal number of participants will be 15. The primary outcome will be time to recurrence in at least 1 eye, established by a worsening of BCVA by at least 15 letters, a 30% increase in central retinal thickness (CRT), a 2-step increase in vitreous haze, or new inflammatory lesions in the choroid or retinal vascular changes. Secondary outcome measures include a change in vitreous haze, BCVA, CRT, choroidal thickness, visual functioning, and ERG changes.

Adalimumab Plus Methotrexate for the Treatment of Pediatric Uveitis, sponsored by Sun Yat-Sen University, is a phase 2, single-group assignment study with a goal number of 30 participants.⁵ The purpose is to assess the effects of adalimumab and methotrexate in the treatment of noninfectious panuveitis in children. The primary outcome will be time to reach remission, and the secondary outcomes will include the first time of relapse once remission is reached, the total dosage of steroids used, and BCVA.

Intravitreal Sirolimus as Therapeutic Approach to Uveitis (SAVE-2), sponsored by Stanford University and Santen Inc, is a phase 2, randomized, nonmasked trial comparing 2 dosages of sirolimus (440 µg once a month vs 880 µg every other month) in 30 participants.⁶ The primary outcome measurement is the number of uveitic attacks, and the secondary outcomes include adverse events, CRT, and steroid-sparing effect.

A Study of Brepocitinib in Adults With Active Noninfectious Nonanterior Uveitis (NEPTUNE), sponsored by Priovant Therapeutics, is a phase 2, randomized, triple-masked study assessing the effect of oral brepocitinib in active intermediate uveitis, posterior uveitis, and panuveitis.⁷ The estimated number of participants is 24. The primary outcome measurement will be the incidence of TEAE and serious adverse events.

A Multicenter Phase 2 Single-arm Proof-of-concept Trial to Assess the Efficacy and Safety of Ustekinumab in Association With Prednisone for the Treatment of Noninfectious Severe Uveitis (NISU) is organized by the University Hospitals of Dijon in France.⁸ This is a phase 2, single-group assignment study of an estimated 29 participants to assess the effects of prednisone and ustekinumab (90 mg, administered subcutaneously), with the primary outcomes being percentage of remission and percentage of patients free from disease relapse.

Reduction or Discontinuation of TNF-α Inhibitor in Noninfectious Uveitis Patients is a phase 2, nonmasked, interventional, single-group study of 28 patients at the Sun Yat-Sen University, which will assess the outcomes of tapering off adalimumab in patients with uveitis that was previously controlled with the drug.⁹ The drug will be administered monthly (as it was initially administered every 2 weeks for disease control). If the disease remains quiescent, the administration will stop at 6 months. The primary endpoint will be the relapse rate of inflammation, and secondary outcome measures will include BCVA and macular thickness assessments.

Golimumab for the Treatment of Refractory Behcet’s Uveitis, organized by the Peking Union Medical College Hospital in China, is a phase 2, interventional, single-group assignment study assessing the role of golimumab, an anti-TNF-α monoclonal antibody in refractory Behçet disease.¹⁰ Primary outcome measures include the impact of the drug on the disease ocular attack score, BCVA, optical coherence tomography findings, and recurrence rate of uveitis. Secondary outcomes include intraocular inflammation, corticosteroid tapering effects, and impact on quality of life.

PHASE 3 UVEITIS TRIALS

Adalimumab vs Conventional Immunosuppression for Uveitis Trial (ADVISE), sponsored by the Johns Hopkins Center for Clinical Trials and Evidence Synthesis in Baltimore, Maryland, is a phase 3, randomized, open-label trial of an estimated 222 participants, comparing adalimumab to conventional immunosuppression (including azathioprine, methotrexate, mycophenolate, cyclosporine, and tacrolimus).¹¹ The primary outcome will be obtaining corticosteroid-sparing success (7.5 mg of daily corticosteroid or below) for 2 consecutive visits within the first 6 months. Secondary outcomes include prednisone discontinuation by 1 year, visual acuity, and complications of uveitis and its treatment.

Efficacy, Safety, and Costs of Methotrexate, Adalimumab, or Their Combination in Noninfectious Nonanterior Uveitis (Co-THEIA), arranged by the Hospital San Carlos in Spain, is a phase 3, randomized, single-blinded study assessing 3 arms: (1) adalimumab, (2) methotrexate, and (3) adalimumab and methotrexate for nonanterior, noninfectious uveitis.¹² The study aims to include 192 participants. The primary outcome will measure clinical response, defined as complete resolution of inflammation by week 16 and maintained until week 52.

A Study of Baricitinib (LY3009104) in Participants From 2 Years to Less Than 18 Years Old With Active JIA-associated Uveitis or Chronic Anterior Antinuclear Antibody-Positive Uveitis, sponsored by Eli Lilly and Company, is a phase 3, randomized, nonmasked trial assessing baricitinib vs adalimumab in children with active juvenile idiopathic arthritis (JIA)–associated uveitis or chronic anterior antinuclear antibody positive–associated uveitis.¹³ The primary outcome will measure the percentage of responders, which is defined as a 2-step decrease in inflammation.

A Study of TRS01 in Subjects With Active Noninfectious Anterior Uveitis Including Subjects With Uveitic Glaucoma, organized by Tarsier, is a phase 3, randomized, quadruple-masked assessment of a drop, TRS01, compared to FDA-approved steroid drops in the treatment of active, noninfectious, anterior uveitis.¹⁴ The study has 162 participants. The primary outcome measured will be the amount of AC cell, and the secondary outcome will be changes in AC cell from baseline, among others.

Safety and Efficacy of an Injectable Fluocinolone Acetonide Intravitreal Insert (FAI), sponsored by EyePoint Pharmaceuticals, is a phase 3, randomized, parallel assignment of 12 participants assessing the FAI insert (Yutiq; now commercially marketed by Alimera Sciences) against a sham injection in posterior uveitis patients.¹⁵ The primary endpoints will analyze the proportion of subjects with recurrence within 6 months of treatment.

The Use of 2 Yutiq vs Sham for Treatment of Chronic Noninfectious Intraocular Inflammation Affecting the Posterior Segment (TYNI), sponsored by Texas Retina Associates and Eye Point Pharmaceuticals, is a phase 3, prospective, randomized, double-masked collaborative study of 30 participants assessing patients who undergo 2 FAI implants on day 1 vs those who receive 2 sham injections on day 1.¹⁶ The primary outcome measurement will be the recurrence of uveitis at month 6.

Systemic and Topical Antivirals for Control of Cytomegalovirus Anterior Uveitis: Treatment Outcomes (STACCATO), sponsored by the University of California, San Francisco, is a double-masked, randomized trial comparing oral valgancyclovir, topical gancyclovir (2%), and placebo for cytomegalovirus (CMV) anterior uveitis.¹⁷ The primary outcome measured is change in viral load from day 0 to day 28, and secondary outcomes include disease quiescence as well as effect of topical steroid on eyes prior to enrollment.

Preventing Extension of Oligoarticular Juvenile Idiopathic Arthritis (Limit-JIA), sponsored by Duke University, is an open-label, phase 3, parallel assignment, nonmasked study assessing the efficacy of subcutaneous abatacept (Orencia; Bristol Myers-Squibb) in preventing the extension of juvenile idiopathic arthritis.¹⁸ The study has 2 parts, with part 1 discontinued in February 2022. Part 2 is a nonrandomized continuation assessing the administration of abatacept vs the usual care of JIA, in patients with limited JIA to see if the medication can prevent extension of the disease or uveitis.

Since publication of the previous overview of clinical trials in uveitis in the October 2022 issue of Retinal Physician, Santen has terminated its LUMINA phase 3 study assessing the efficacy and safety of intravitreal sirolimus in patients with noninfectious posterior uveitis.¹⁹

PHASE 4 UVEITIS TRIALS

Fluocinolone Acetonide Intravitreal Implant 0.18 mg in the Treatment of Chronic Noninfectious Posterior Segment Uveitis, sponsored by EyePoint Pharmaceuticals, is a phase 4, prospective, open-label study assessing the 2-year outcomes of the FAI implant.²⁰ The primary outcomes will include BCVA change as well as central subfield thickness change, and the secondary outcomes will include recurrence of inflammation, vascular leakage, and macular edema.

Adalimumab in JIA-associated Uveitis Stopping Trial (ADJUST), sponsored by the University of California, San Francisco, is a phase 3, randomized, quadruple-masked trial of an estimated 118 participants with either JIA-associated uveitis or chronic ANA-positive anterior uveitis, comparing the continuation of adalimumab vs the discontinuation of the drug (with placebo administered).²¹ The primary outcome will be time to treatment failure.

Biologic Therapy in Pediatric JIA Uveitis, sponsored by Kasr El Aini Hospital in Egypt, aims to assess through an open-label study the efficacy of TNF-α inhibitors in 250 Egyptian pediatric patients with JIA.²² The primary outcome will focus on the steroid-sparing effects of the medication by 24 months.

A Clinical Trial of Infliximab for Childhood Uveitis, sponsored by Tianjin Medical University in China, is an open-label study of 10 participants receiving intravenous infliximab.²³ The primary outcome will measure the change in BCVA from baseline to each visit over 24 weeks, and secondary outcomes will include the change in AC cell grade and vitreous haze from baseline to each visit.

A Study to Assess Change in Disease Activity and Adverse Events of Adalimumab in Chinese Participants Requiring High Dose Corticosteroids for Active Noninfectious Intermediate, Posterior, or Panuveitis is an AbbVie-sponsored, phase 4, nonmasked, single-group assignment study being conducted in China.²⁴ Participants will receive adalimumab for either intermediate, posterior, or panuveitis, with the primary outcome measuring the percentage of patients who obtain disease quiescence in both eyes. Secondary outcome measurements will track active lesions, AC cell grade and vitreous haze grade, BCVA, and requiring less than 7.5 mg of systemic corticosteroids.

The Efficacy and Safety of Adalimumab in Noninfectious Anterior Pediatric Uveitis With Peripheral Vascular Leakage is sponsored by the Peking Union Medical College Hospital in China.²⁵ It is a phase 4, randomized, open-label trial assessing adalimumab (40 mg, administered subcutaneously every 2 weeks) compared to methotrexate (oral administration of 10 mg every week) in 50 children with anterior uveitis and peripheral vascular leakage on fluorescein angiogram. The primary endpoint will be the development of a uveitis flare. Secondary endpoints will measure vascular leakage, keratic precipitates, vitreous haze, BCVA, and adverse events.

Topical 2% Ganciclovir Eye Drop for CMV Anterior Uveitis/Endotheliitis is sponsored by Singapore National Eye Centre.²⁶ This open-label phase 4 study will assess the treatment response of 2% guttae ganciclovir in 25 patients diagnosed with cytomegalovirus anterior-segment infection. After 6 weeks, an aqueous chamber paracentesis will be done to test for viral load as well as ganciclovir drug levels. The primary outcome will be the median concentration of ganciclovir in aqueous. Secondary outcome will be clinical efficacy in clearing CMV viral load, measured by resolution of anterior uveitis/endotheliitis and an aqueous tap negative for CMV.

The Ozurdex Monotherapy Trial (OM), sponsored by the Ottawa Hospital Research Institute in Canada, is a randomized, parallel assignment, triple-masked study to assess the efficacy and safety of the dexamethasone 0.7 mg intravitreal implant (Ozurdex; Allergan/AbbVie) for the treatment of noninfectious intermediate, posterior, or panuveitis.²⁷ Patients will be treated with Ozdurex or an oral prednisone taper. The primary endpoint will measure the percentage of patients with a vitreous haze score of 0 at the 6-month mark. Secondary measures will include BCVA, CRT, time to vitreous haze resolution, and time to failure defined as the number of months with the Ozurdex implant until an adjunct therapy is indicated.

CONCLUSION

With so many therapeutic options under investigation, the future of uveitis management is bright. The results of these ongoing studies, and the integration of new treatments into patient care, will improve outcomes for patients with complex uveitis. RP

REFERENCES

1. Minocycline for Chronic Autoimmune Uveitis. Clinicaltrials.gov identifier: NCT05474729. Updated April 18, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05474729
2. Phase 2b Pivotal Study of Izokibep in Non-infectious, Intermediate-, Posterior- or Pan-uveitis. Clinicaltrials.gov identifier: NCT05384249. Updated May 11, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05384249
3. The Effectivity of Antituberculosis Therapy in Idiopathic Uveitis With Positive IGRA. Clinicaltrials.gov identifier: NCT05005637. Updated September 14, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05005637
4. Abatacept in Patients With Birdshot HLA A29 Uveitis (HLA-A29). Clinicaltrials.gov identifier: NCT03871361. Updated January 27, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03871361
5. Adalimumab Plus Methotrexate for the Treatment of Pediatric Uveitis. Clinicaltrials.gov identifier: NCT04588818. Updated December 18, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04588818
6. Intravitreal Sirolimus as Therapeutic Approach to Uveitis (SAVE-2). Clinicaltrials.gov identifier: NCT01280669. Updated May 7, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT01280669
7. A Study of Brepocitinib in Adults With Active Non-Infectious Non-Anterior Uveitis (NEPTUNE). Clinicaltrials.gov identifier: NCT05523765. Updated May 3, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05523765
8. A Multicenter Phase 2 Single-arm Proof-of-concept Trial to Assess the Efficacy and Safety of Ustekinumab in Association With Prednisone for the Treatment of Non-infectious Severe Uveitis (NISU) (USTEKINISU). Clinicaltrials.gov identifier: NCT03847272. Updated April 13, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03847272
9. Reduction or Discontinuation of TNF-α Inhibitor in Non-infectious Uveitis Patients. Clinicaltrials.gov identifier: NCT05155592. Updated December 13, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05155592
10. Golimumab for the Treatment of Refractory Behcet’s Uveitis. Clinicaltrials.gov identifier: NCT04218565. Updated April 7, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04218565
11. Adalimumab vs Conventional Immunosuppression for Uveitis Trial (ADVISE). Clinicaltrials.gov identifier: NCT03828019. Updated June 21, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03828019
12. Efficacy, Safety and Costs of Methotrexate, Adalimumab, or Their Combination in Non-infectious Non-anterior Uveitis (Co-THEIA). Clinicaltrials.gov identifier: NCT04798755. Updated March 6, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04798755
13. A Study of Baricitinib (LY3009104) in Participants From 2 Years to Less Than 18 Years Old With Active JIA-Associated Uveitis or Chronic Anterior Antinuclear Antibody-Positive Uveitis. Clinicaltrials.gov identifier: NCT04088409. Updated April 18, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04088409
14. A Study of TRS01 in Subjects With Active Noninfectious Anterior Uveitis Including Subjects With Uveitic Glaucoma. Clinicaltrials.gov identifier: NCT05042609. Updated April 18, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05042609
15. Safety and Efficacy of an Injectable Fluocinolone Acetonide Intravitreal Insert (FAI). Clinicaltrials.gov identifier: NCT05070728. Updated December 21, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05070728
16. The Use of Two YUTIQ Versus Sham for Treatment of Chronic Noninfectious Intraocular Inflammation Affecting the Posterior Segment (TYNI). Clinicaltrials.gov identifier: NCT05486468. Updated October 31, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05486468
17. Systemic and Topical Antivirals for Control of Cytomegalovirus Anterior Uveitis: Treatment Outcomes (STACCATO). Clinicaltrials.gov identifier: NCT03586284. Updated July 6, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03586284
18. Preventing Extension of Oligoarticular Juvenile Idiopathic Arthritis (Limit-JIA). Clinicaltrials.gov identifier: NCT03841357. Updated August 18, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03841357
19. A Phase 3 Study Assessing the Efficacy and Safety of Intravitreal Injections of 440 µg DE-109 for the Treatment of Active, Noninfectious Uveitis of the Posterior Segment of the Eye (LUMINA). Clinicaltrials.gov identifier: NCT03711929. Updated November 10, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT03711929
20. Fluocinolone Acetonide Intravitreal Implant 0.18 mg in the Treatment of Chronic Non-Infectious Posterior Segment Uveitis. Clinicaltrials.gov identifier: NCT05322070. Updated August 22, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05322070
21. Adalimumab in JIA-associated Uveitis Stopping Trial (ADJUST). Clinicaltrials.gov identifier: NCT03816397. Updated March 30, 2023. Accessed May 15, 2023. https://www.clinicaltrials.gov/ct2/show/NCT03816397
22. Biologic Therapy in Pediatric JIA Uveitis. Clinicaltrials.gov identifier: NCT05540743. Updated October 4, 2022. Accessed May 15, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05540743
23. A Clinical Trial of Infliximab for Childhood Uveitis. Clinicaltrials.gov identifier: NCT04150770. Updated November 2, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04150770
24. A Study to Assess Change in Disease Activity and Adverse Events of Adalimumab in Chinese Participants Requiring High Dose Corticosteroids for Active Non-Infectious Intermediate, Posterior, or Pan-Uveitis. Clinicaltrials.gov identifier: NCT05414201. Updated February 10, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05414201
25. The Efficacy and Safety of Adalimumab in Non-infectious Anterior Pediatric Uveitis With Peripheral Vascular Leakage. Clinicaltrials.gov identifier: NCT05015335. Updated November 10, 2021. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05015335
26. Topical 2% Ganciclovir Eye Drop for CMV Anterior Uveitis / Endotheliitis. Clinicaltrials.gov identifier: NCT02943057. Updated November 17, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT02943057
27. Ozurdex Monotherapy Trial (OM). Clinicaltrials.gov identifier: NCT05101928. Updated December 16, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05101928