As clinicians and scientists further the understanding of pathways and mechanisms involved in various disease processes, the clinical trial arena for uveitis is growing. This review will focus on the phase 1 through 4 uveitis trials listed as active on clinicaltrials.gov, with the majority focusing on noninfectious uveitis. Trials listed here have used systemic, topical, and intravitreal administrations of drugs to quell inflammation.

PHASE 1 UVEITIS TRIALS

The Minocycline for Chronic Autoimmune Uveitis trial is an interventional 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 field measured with 30-2 testing, and implicit time and amplitude of photopic and scotopic responses. These endpoints will be measured at 6 months and 12 months. Secondary outcome measures will include changes in macular vessels measured by optical coherence tomography angiography, contrast sensitivity, and a quality-of-life questionnaire; these also will be assessed at 6 months and 12 months.

PHASE 2 UVEITIS TRIALS

Intravitreal Sirolimus as Therapeutic Approach to Uveitis (SAVE-2), sponsored by Stanford University and Santen Inc, is a phase 2, randomized, nonmasked trial.² It will compare 2 dosages of sirolimus (440 μg once a month vs 880 μg every other month) with the primary outcome measurement being the number of uveitic attacks, while the secondary outcomes include adverse events, central retinal thickness, and steroid sparing effect.

Phase 2b 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 120 patients.³ Patients will be randomized to 4 arms: (1) placebo subcutaneous treatment administered weekly, (2) placebo subcutaneous treatment administered every 2 weeks, (3) izokibep administered subcutaneously weekly, or (4) izokibep administered subcutaneously every 2 weeks. Izokibep is 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 outcome measures 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.

The Effectivity of Antituberculosis Therapy in Idiopathic Uveitis With Positive Interferon Gamma Release Assay (IGRA): A Randomized Clinical Trial, 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.⁴ The primary outcome measurement will be percentage of treatment failure, defined as more than 0.5+ anterior chamber 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.

Reduction or Discontinuation of TNF-α Inhibitor in Non-infectious Uveitis Patients is a phase 2, nonmasked, interventional, single-group study 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.⁵ The study aims to enroll 28 patients, and will first administer the drug on a monthly basis (as it was initially administered every 2 weeks for disease control), and if the disease remains quiescent, the administration will stop at 6 months. The primary endpoint will be the relapse rate of inflammation, while secondary outcome measures will be BCVA and macular thickness assessments.

Abatacept in Patients With Birdshot HLA-A29 Uveitis (HLA-A29), sponsored by the Ziekehuizen Leuven University in Belgium, is a phase 2 prospective, open-label, interventional, proof-of-concept study assessing abatacept administered once weekly in patients with a known diagnosis of birdshot chorioretinopathy.⁶ 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, 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, central retinal thickness, choroidal thickness, visual functioning, and electroretinogram changes.

Golimumab for the Treatment of Refractory Behcet 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 Behcet disease.⁷ Primary outcome measures include the impact of the drug on the disease ocular attack score, BCVA, optical coherence tomography (OCT) findings, and recurrence rate of uveitis. Secondary outcomes include intraocular inflammation, corticosteroid tapering effects, and impact on quality of life.

Adalimumab Plus Methotrexate for the Treatment of Pediatric Uveitis, sponsored by the Sun Yat-Sen University, is a phase 2, single-group assignment study with a goal number of 30 participants to assess the effects of adalimumab and methotrexate in the treatment of noninfectious panuveitis in children.⁸ The primary outcome will be time to remission, while the secondary outcomes will include the first time of relapse once remission is reached, the total dosage of steroids used, and BCVA.

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 is organized by the University Hospitals of Dijon, France.⁹ It 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.

PHASE 3 UVEITIS TRIALS

Adalimumab vs Conventional Immunosuppression for Uveitis Trial (ADVISE), sponsored by JHSPH Center for Clinical Trials, 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).¹⁰ 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 outcome measurements include corticosteroid-sparing success within 12 months, the discontinuation of prednisone, BCVA, macular edema, and adverse events.

Efficacy, Safety, and Costs of Methotrexate, Adalimumab, or Their Combination in Noninfectious Nonanterior Uveitis (Co-THEIA), arranged by the San Carlos Hospital in Arizona, is a phase 3, randomized, single-blinded study assessing 3 arms: (1) adalimumab, (2) methotrexate, and (3) adalimumab and methotrexate for nonanterior, noninfectious uveitis.¹¹ The primary outcome will measure clinical response, while the secondary outcomes will include quality of life, visual functioning questionnaires, BCVA, cost efficacy, and adverse events.

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.¹² The primary outcome will measure the percentage of responders, while the secondary outcomes will assess the change in anterior chamber cell, BCVA, vitreous haze, and percentage of patients who were able to decrease their topical steroid use.

LUMINA Phase III Study Assessing the Efficacy and Safety of Intravitreal Injections of 440 μg DE-109 Sirolimus for the Treatment of Active, Noninfectious Uveitis of the Posterior Segment of the Eye, sponsored by Santen, is a phase 3, randomized, quadruple-masked trial assessing the efficacy and safety of intravitreal sirolimus (440 μg, administered every 2 months) in patients with noninfectious posterior uveitis compared to sham and compared to a dummy arm which will administer an undisclosed, fixed dose of sirolimus (between 44 μg and 880 μg, every 2 months).¹³ The primary outcome will be an assessment of vitreous haze at month 5.

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 primary outcome measured will be the amount of anterior chamber cell, while the secondary outcome will be changes in anterior chamber cell from baseline, among others.

Beta-1,3/1,6-D-Glucan Ganoderma Lucidum on Noninfectious and Idiopathic Uveitis, sponsored by Fakultas Kedokteran University, is a phase 3, triple-masked, randomized trial that will compare the administration of beta-1,3/1,6-D-Glucan Ganoderma lucidum capsules vs placebo in noninfectious uveitis.¹⁵ Primary outcomes include the change in anterior chamber cells and serum TNF-α levels.

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 anterior uveitis.¹⁶ The primary outcome measured is change in viral load, while secondary outcomes include disease quiescence and well as effect of topical steroid on eyes prior to enrollment.

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 flucinolone acetonide intravitreal implant (Yutiq).¹⁷ The primary outcomes will include BCVA change as well as central subfield thickness change, while 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).¹⁸ The primary outcome will be time to treatment failure.

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 trial based in China, with a target group of 87 participants, who will receive adalimumab for intermediate, posterior, or panuveitis, with the primary outcome measuring the percentage of patients who obtain disease quiescence in both eyes.¹⁹ Secondary outcomes will include 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 trial is sponsored by the Peking Union Medical College Hospital. It is a phase 4, randomized, open-label trial assessing adalimumab compared to methotrexate in children with anterior uveitis and peripheral vascular leakage on fluorescein angiogram.²⁰ The primary endpoint will be the development of a uveitis flare, while secondary outcomes will measure peripheral vascular leakage, keratic precipitates, vitreous haze, and BCVA.

CONCLUSION

There are a great number of clinical trials under way to help elucidate which treatment algorithms may be best for this difficult to manage group of diseases. The results of these ongoing studies will help to answer clinical queries and shape the management of complex uveitis patients. RP

REFERENCES

1. Minocycline for chronic autoimmune uveitis. Clinicaltrials.gov identifier: NCT05474729. Updated July 26, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05474729
2. Intravitreal sirolimus as therapeutic approach to uveitis (SAVE-2). Clinicaltrials.gov identifier: NCT01280669. Updated May 7, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT01280669
3. Phase 2b pivotal study of izokibep in non-infectious, intermediate-, posterior- or pan-uveitis. Clinicaltrials.gov identifier: NCT05384249. Updated September 2, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05384249
4. The effectivity of antituberculosis therapy in idiopathic uveitis with positive IGRA. Clinicaltrials.gov identifier: NCT05005637. Updated September 14, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05005637
5. Reduction or discontinuation of TNF-α inhibitor in non-infectious uveitis patients. Clinicaltrials.gov identifier: NCT05155592. Updated December 13, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05155592
6. Abatacept in patients with birdshot HLA A29 uveitis (HLA-A29). Clinicaltrials.gov identifier: NCT03871361. Updated January 5, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03871361
7. Golimumab for the treatment of refractory Behcet’s uveitis. Clinicaltrials.gov identifier: NCT04218565. Updated Accessed April 26, 2022. September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04218565
8. Adalimumab plus methotrexate for the treatment of pediatric uveitis. Clinicaltrials.gov identifier: NCT04588818. Updated December 28, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04588818
9. 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 September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03847272
10. Adalimumab vs. conventional immunosuppression for uveitis trial (ADVISE). Clinicaltrials.gov identifier: NCT03828019. Updated June 21, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03828019
11. Efficacy, safety and costs of methotrexate, adalimumab, or their combination in non-infectious non-anterior uveitis (Co-THEIA). Clinicaltrials.gov identifier: NCT04798755. Updated March 16, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04798755
12. 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 June 23, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04088409
13. LUMINA phase iii study assessing the efficacy and safety of intravitreal injections of 440 ug DE-109 sirolimus for the treatment of active, non-infectious uveitis of the posterior segment of the eye. Clinicaltrials.gov identifier: NCT03711929. Updated November 5, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03711929
14. A study of TRS01 in subjects with active non-infectious anterior uveitis including subjects with uveitic glaucoma. Clinicaltrials.gov identifier: NCT05042609. Updated July 14, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05042609
15. Beta-1,3/1,6-D-Glucan Ganoderma lucidum on non-infectious and idiopathic uveitis. Clinicaltrials.gov identifier: NCT04162314. Updated February 3, 2021. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04162314
16. Systemic and topical antivirals for control of cytomegalovirus anterior uveitis: treatment outcomes (STACCATO). Clinicaltrials.gov identifier: NCT03586284. Updated July 6, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03586284
17. 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 September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05322070
18. Adalimumab in JIA-associated uveitis stopping trial (ADJUST). Clinicaltrials.gov identifier: NCT03816397. Updated March 25, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03816397
19. 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 September 2, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05414201
20. 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 September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05015335