Safety and Efficacy of an Injectable Fluocinolone Acetonide Intravitreal (FAI) Insert

This was a phase 3, multicenter, randomized, masked, controlled study to evaluate the safety and efficacy of an injectable FAI insert for the management of subjects with chronic non-infectious uveitis affecting the posterior segment of the eye. Subjects were randomized to receive either a sham injection or the FAI insert and were observed for 1 year following treatment.

• Sham Injector (Drug), also known as Sham Comparator: Intravitreal sham injection
• FAI Insert (Drug), also known as Active Drug: Yutiq 0.05 mg contains 0.05 mg FA and was designed to deliver FA into the vitreous humor for at least 24 weeks. Yutiq 0.05 mg was administered to the study eye by injection through the pars plana using a pre-loaded applicator with a 25-gauge needle.

Primary outcomes

• Percentage of Subjects With Recurrence of Uveitis in the Study Eye at Week 24 [Week 24]: Recurrence was defined as: * An increase in the vitreous haze of ≥2 steps compared to baseline or any visit time point prior to the Week 24 visit; or * A deterioration in visual acuity of at least 15 letters BCVA compared to baseline or any visit time point prior to the Week 24 visit.

Secondary outcomes

• Percentage of Subjects With Recurrence of Uveitis in the Study Eye at Week 52 [Week 52]: Recurrence was defined as: * An increase in the vitreous haze of ≥2 steps compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit); or * A deterioration in visual acuity of at least 15 letters BCVA compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit).
• Percentage of Subjects With Recurrence of Uveitis in the Fellow Eye at Weeks 24 and 52 [Weeks 24 and 52]: Recurrence was defined as: * An increase in the vitreous haze of ≥2 steps compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit); or * A deterioration in visual acuity of at least 15 letters BCVA compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit).
• Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Letter Score in the Study Eye at Weeks 24 and 52 [Weeks 24 and 52]: The BCVA was measured according to the standard procedure originally developed for Early Treatment Diabetic Retinopathy Study (ETDRS). The ETDRS letter score calculated when 20 or more letters were read correctly at 4.0 meters; the visual acuity letter score was equal to the total number of letters read correctly at 4.0 meters plus 30. The score ranges from 0 (worse) to 100 (best). Higher scores indicate positive outcome measure.
• Number of Recurrences of Uveitis Within 24 and 52 Weeks [Weeks 24 and 52]: Recurrence was defined as: An increase in the vitreous haze of ≥2 steps compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit); or A deterioration in visual acuity of at least 15 letters BCVA compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit).
• Time to Recurrence of Uveitis Through Weeks 24 and 52 [Weeks 24 and 52]: Recurrence was defined as: An increase in the vitreous haze of ≥2 steps compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit); or A deterioration in visual acuity of at least 15 letters BCVA compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit).
• Number of Adjunctive Treatments Required to Treat Recurrences of Uveitis at 24 and 52 Weeks [Weeks 24 and 52]: Recurrence was defined as: An increase in the vitreous haze of ≥2 steps compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit); or A deterioration in visual acuity of at least 15 letters BCVA compared to baseline or any visit time point prior to the Week 24 visit (or the Week 52 visit). In the event of a uveitis recurrence in either eye, peri-ocular or intraocular corticosteroid injections, or topical medications administered as first line local therapy.
• Percentage of Subjects With Recurrence of Iridocyclitis in the Study Eye Compared to Baseline at 24 and 52 Weeks [Weeks 24 and 52]: Iridocyclitis was defined as a >2-step increase in anterior chamber cells per high-power field (HPF) (1.6*using a 1-millimeter beam).
• Percentage of Subjects With Resolution of Macular Edema at Day 28 and Months 2, 3, 6 and 12 [At Day 28 and Months 2, 3, 6 and 12]: The macular edema was measured by spectral-domain - optical coherence tomography (SD-OCT) imaging.

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

1. Male or non-pregnant female at least 18 years of age at time of consent.
2. One or both eyes had a history of recurrent non-infectious uveitis affecting the posterior segment of the eye (intermediate, posterior, or panuveitis) with or without anterior uveitis >1 year duration.
3. During the 52 weeks prior to enrollment (Day 1), the subject must have received treatment for uveitis in the study eye with:

   1. Systemic corticosteroid or other systemic therapies for at least 12 consecutive or non-consecutive weeks, AND/OR
   2. at least 2 intra- or peri-ocular administrations of corticosteroid in the study eye, OR
   3. the study eye has experienced recurrence of uveitis at least 2 separate times requiring systemic, intra- or peri-ocular injection of corticosteroid.
4. At the time of enrollment (Day 1), the study eye has <10 anterior chamber cells/HPF (high power field) and a vitreous haze ≤ grade 2.
5. Visual acuity of study eye ≥15 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
6. Not planning to undergo elective ocular surgery during the study.
7. Able to understand and sign the Informed Consent Form (ICF).
8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Key Exclusion Criteria:

Ocular Exclusion Criteria (for the study eye, unless indicated otherwise):

1. History of posterior uveitis only that is not accompanied by vitritis or macular edema.
2. History of iritis only associated with no vitreous cells, anterior chamber cells, or vitreous haze at Day 1.
3. Uveitis with infectious etiology.
4. Vitreous hemorrhage.
5. Intraocular inflammation associated with a condition other than noninfectious uveitis (eg, intraocular lymphoma).
6. Uveitis limited to the anterior segment, ie, anterior uveitis only.
7. Ocular malignancy in either eye, including choroidal melanoma.
8. Previous viral retinitis.
9. Toxoplasmosis scar or scar related to previous viral retinitis in the study eye.
10. Current viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, mycobacterial infections of the eye, or fungal diseases of ocular structures.
11. Media opacity precluding evaluation of retina and vitreous.
12. Peripheral retinal detachment in area of insertion.
13. Diagnosis of any form of glaucoma or ocular hypertension at Screening, unless previously treated with an incisional surgery procedure that has resulted in stable intraocular pressure (IOP) in the normal range \[10-21 millimeter of mercury (mmHg)\].
14. IOP >21 mmHg or concurrent therapy at Screening with any IOP lowering pharmacologic agent.
15. Chronic hypotony (<6 mmHg).
16. Ocular surgery within 12 weeks prior to Day 1.
17. Capsulotomy within 30 days prior to Day 1.
18. Prior intravitreal treatment with Retisert®, ILUVIEN®, or YUTIQ® (0.18 mg) within 156 weeks prior to Day 1.
19. Prior intravitreal treatment with OZURDEX® or sub-choroidal injection with XIPERE™ within 24 weeks prior to Day 1.
20. Prior intravitreal treatment with Triesence® or TRIVARIS™ within 12 weeks prior to Day 1.
21. Peri-ocular or subtenon steroid treatment within 12 weeks prior to Day 1.

    All other Exclusion Criteria:
22. Allergy to fluocinolone acetonide or any component of Yutiq 0.05 mg.
23. Requirement for chronic systemic or inhaled corticosteroid therapy (>15mg prednisone daily) or chronic systemic immunosuppressive therapy.
24. History of certain skin cancers (specifically, basal cell carcinoma and squamous cell carcinoma), any malignancy receiving treatment, or in remission less than 5 years prior to Day 1.
25. Positive test for human immunodeficiency virus (HIV) or syphilis during Screening.
26. Mycobacterial uveitis or chorioretinal changes of either eye which, in the opinion of the Investigator, result from infectious mycobacterial uveitis.
27. Systemic infection within 30 days prior to Day 1.
28. Any severe acute or chronic medical or psychiatric condition that could increase the risk associated with study participation or could interfere with the interpretation of study results and, in the judgment of the Investigator, could make the subject inappropriate for study enrollment.
29. Any other systemic or ocular condition which, in the judgment of the Investigator, could make the subject inappropriate for study enrollment.
30. Treatment with an investigational drug or device within 30 days prior to Day 1.
31. Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of contraception as outlined in the protocol from at least 14 days prior to Day 1 until the 52-week Visit.
32. Unlikely to comply with the study protocol or who are likely to be lost to follow-up within 52 weeks.

Participant flow

Outcome results

• Percentage of Subjects With Recurrence of Uveitis in the Study Eye at Week 24 (Primary), Number, percentage of subjects: Fluocinolone Acetonide 0.05 mg 0 (0 to 45.9); Sham Injection
• Percentage of Subjects With Recurrence of Uveitis in the Study Eye at Week 52 (Secondary), Number, percentage of subjects: Fluocinolone Acetonide 0.05 mg 0 (0 to 45.9); Sham Injection
• Percentage of Subjects With Recurrence of Uveitis in the Fellow Eye at Weeks 24 and 52 (Secondary)
• Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Letter Score in the Study Eye at Weeks 24 and 52 (Secondary), Mean, score on a scale: Fluocinolone Acetonide 0.05 mg 9.7 +/- 4.93; Sham Injection
• Number of Recurrences of Uveitis Within 24 and 52 Weeks (Secondary), Number, recurrences of uveitis: Fluocinolone Acetonide 0.05 mg 0; Sham Injection
• Time to Recurrence of Uveitis Through Weeks 24 and 52 (Secondary)
• Number of Adjunctive Treatments Required to Treat Recurrences of Uveitis at 24 and 52 Weeks (Secondary)
• Percentage of Subjects With Recurrence of Iridocyclitis in the Study Eye Compared to Baseline at 24 and 52 Weeks (Secondary)
• Percentage of Subjects With Resolution of Macular Edema at Day 28 and Months 2, 3, 6 and 12 (Secondary), Number, percentage of subjects: Fluocinolone Acetonide 0.05 mg 50.0; Sham Injection 60.0

Adverse events

Time frame: Treatment-emergent adverse events were collected from the study drug administration (Day 1) up to early termination of the study, approximately 52 weeks.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The Sponsor made the decision to stop study enrollment and terminate the study for reasons other than safety or efficacy in early May 2022 upon receipt of FDA comments on the clinical program in January 2022.

• Study Protocol (PDF, 2022-07-20)
• Statistical Analysis Plan (PDF, 2023-05-08)