key: cord-0924400-jk8zm7ld
authors: Sangwan, Virender S.; Pearson, P. Andrew; Paul, Hemanth; Comstock, Timothy L.
title: Use of the Fluocinolone Acetonide Intravitreal Implant for the Treatment of Noninfectious Posterior Uveitis: 3-Year Results of a Randomized Clinical Trial in a Predominantly Asian Population
date: 2014-12-12
journal: Ophthalmol Ther
DOI: 10.1007/s40123-014-0027-6
sha: 82722b89a6c49087f09c56d5d6b58e2bfe33bc7e
doc_id: 924400
cord_uid: jk8zm7ld

INTRODUCTION: The fluocinolone acetonide (FA) intravitreal implant 0.59 mg (Retisert(®), Bausch + Lomb, Rochester, NY, USA) provides sustained release of FA directly to the vitreous cavity over a prolonged period of time. The purpose of this study was to evaluate the safety and efficacy of a 0.59- and 2.1-mg FA intravitreal implant in patients with noninfectious posterior uveitis. METHODS: A prospective, multicenter, randomized, double-masked, dose-controlled study was performed. Patients were randomized to the 0.59- or 2.1-mg FA implant surgically placed in the vitreous cavity through a pars plana incision and were evaluated at visits through 3 years. Patients with bilateral disease had the more severely affected eye implanted. Outcomes included uveitis recurrence rate, best-corrected visual acuity (BCVA), use of adjunctive therapy, and safety. RESULTS: A total of 239 patients, predominantly Asian, were implanted (n = 117, 0.59-mg implant; n = 122, 2.1-mg implant). Approximately 80% of patients had bilateral disease. Recurrence rates for implanted eyes decreased from 42.3% during the 1-year pre-implantation period to 25.9% during the 3-year post-implantation period (P = 0.0003) and increased for nonimplanted fellow eyes from 19.8 to 59.7% (P < 0.0001). More implanted eyes gained ≥3 lines of BCVA compared to nonimplanted fellow eyes (P ≤ 0.0046); and implanted eyes required less adjunctive systemic therapy and fewer periocular injections (P < 0.0001). Elevations of intraocular pressure (≥10 mm Hg) were frequent in implanted eyes (67.8%, 0.59-mg implant; 71.3%, 2.1-mg implant); nearly all (94.9%) phakic implanted eyes required cataract surgery. CONCLUSION: The FA intravitreal implant significantly reduced uveitis recurrence rates and led to improvements in visual acuity and reductions in adjunctive therapy. Lens clarity and intraocular pressure require monitoring. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40123-014-0027-6) contains supplementary material, which is available to authorized users.

The term 'uveitis' comprises a group of intraocular inflammatory conditions that directly or indirectly affects the iris, ciliary body, and choroid, collectively known as the uveal tract, as well as the retina, optic nerve, and vitreous [1] [2] [3] [4] . In most cases, the etiology of uveitis is unknown; however, it can be associated with autoimmune disease, infection (viral, fungal, or parasitic), or trauma [2] [3] [4] [5] [6] .

Uveitis results in significant visual impairment and is thought to account for 10-15% of all cases of total blindness in the United States (US) and developed world [1, 4, [6] [7] [8] . While posterior uveitis accounts for only 20% of the estimated 1 in 500 people in the US with uveitis [1] , it is the more severe form of the disease. The primary causes of vision loss in patients with uveitis are cystoid macular edema (CME) and/or cataract [1, 4, 7] , with CME being the leading cause of vision loss in posterior uveitis. Treatments aimed at reducing CME are therefore effective in the treatment of uveitis.

Corticosteroids are considered the mainstay of noninfectious uveitis treatment [4, 9] . However, since the disease is typically chronic in nature, patients often require long-term repeated treatment with either topical or systemic corticosteroids [10, 11] . In severe cases of uveitis, multiple rounds of sub-Tenon or intravitreal corticosteroid injections as well as systemic corticosteroids may be necessary. The potential for complications such as endophthalmitis, vitreous hemorrhage, and retinal detachment following use of repeated intravitreal injections is substantial [12, 13] . Systemic corticosteroids require high dosages to achieve therapeutic concentrations in the eye and are associated with systemic side effects including hypertension, hyperglycemia, and increased susceptibility to infection [14, 15] . Immunosuppressive agents can be an effective treatment option, but are associated with serious and potentially life-threatening systemic adverse events (AEs) such as renal and hepatic failure and bone marrow suppression [9, 16] . Thus, such therapy is usually reserved for patients with severe uveitis who are unresponsive to corticosteroid therapy or with corticosteroid-induced complications. 

This was a 3-year multicenter, randomized, double-masked, dose-controlled safety and efficacy study of two FA intravitreal implantsone containing 0.59 mg and the other 2.1 mgin patients with chronic, recurrent, unilateral or The FA implants and surgical implantation procedure have been described in detail elsewhere [11, 18, 19] . Briefly, the polymer- One week post-implantation, patients discontinued use of existing therapy for ocular inflammation as follows: (1) consequently, patients were evaluated with fluorescein angiography at screening, at week 8, week 34, and 1, 2, and 3 years using a standardized protocol with macular hyperfluorescence evaluated by masked readers as described previously [19] .

Three types of comparisons were utilized in the study: ( (2) a maximum vitreous haze score\2; and (3) a maximum reduction in visual acuity of.30 logarithm of the minimum angle resolution (logMAR) or Snellen equivalent was not considered sufficiently severe to be counted in this analysis. If the medical chart lacked sufficient detail to determine whether the preimplantation recurrence met the protocol definition, no pre-implantation recurrence was recorded for this analysis. Recurrence within the 3-year post-implantation period was defined as follows: (1) a C2-step increase compared to baseline in the number of AC cells not attributable to any condition other than NIPU, (2) a C2-step increase compared to baseline in vitreous haze not attributable to any condition other than NIPU, or (3) a deterioration in BCVA from baseline of at least 0.30 logMAR not attributable to any condition other than NIPU. Recurrences were considered 'observed' when they were seen and recorded by study investigators, whereas they were considered 'imputed' when a subject was not seen within 10 weeks of the final scheduled visit.

Secondary efficacy outcomes were evaluated using the fellow nonimplanted eye as a control for the study eye and included: rate of and time to post-implantation recurrence of uveitis; change in BCVA; and area of CME using a 300-s fluorescein angiogram, and the proportion of eyes requiring systemic therapy or periocular injections to control inflammation using the pre-implantation comparison group data. Secondary efficacy outcomes included observed and imputed recurrence data where applicable.

Safety outcomes included intraocular pressure (IOP), lens opacity estimated using the lens opacity classification system (LOCS) II, visual field, ocular and nonocular AEs, visual acuity, and ophthalmoscopic examination findings.

Ophthalmol Ther (2015) 4: [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Ocular AEs were defined as any unexpected ocular condition that was considered by the investigator to be clinically significant including but not limited to: (1) any IOP increase requiring medication or increased dosage/frequency, (2) any IOP[30 mm Hg 3 months post-surgery, (3) any IOP\6 mm Hg, (4) any loss of C3 lines visual acuity from baseline or last scheduled visit, and (5) retinal tear.

Statistical analyses were performed using SAS, Table 3 Uveitis recurrence rates in implanted eyes pre-and post-implantation 

Uveitis recurrence rates for implanted eyes are shown in Table 3 

Kaplan-Meier analysis was used to evaluate time to recurrence of uveitis for implanted and nonimplanted eyes (Fig. 1) Kaplan-Meier analysis of implanted study eyes versus nonimplanted fellow eyes performed only for patients with bilateral disease yielded similar results: the time to recurrence of uveitis was significantly longer in implanted eyes than in fellow nonimplated eyes (P.0001, data not shown).

The FA intravitreal implant reduced the need for adjunctive uveitis treatment. The proportion of patients requiring adjunctive treatment to control inflammation before and after FA implantation is shown in Table 4 3-year visit (LOCF mean CME was 12.8 mm 2 ). In nonimplanted fellow eyes for both dose groups combined, the mean area of CME fluctuated Comparisons were made during the entire 1-year pre-implantation period and the 1-and 3-year post-implantation periods. One fellow eye (2.1-mg FA implant group) was prosthetic, and thus the sample size for fellow eyes was 238) c P value for 1 year pre-implantation data compared with 3 year postimplantation data within a narrow range over the 3-year postimplantation follow-up period and the area of CME at screening was very similar to that at the 3-year visit (approximately 15-20 mm 2 ). The number of patients experiencing any reduction in the area of CME between baseline and 3-year post-implantation is presented in Table 5 .

Mean (±SD) exposure to FA was 1,038.9 (188.0) days in the 0.59-mg implant group and 1,016.1 (225.1) days in the 2.1-mg implant group.

Treatment-emergent ocular AEs (including perioperative events) were reported in 99.6%

(238/239) of implanted study eyes and in 81.6%

(195/239) of fellow nonimplanted eyes. Table 6 presents the most frequently occurring AEs in implanted study eyes and in nonimplanted fellow eyes in each of the implant dose groups and combined. Among the most frequently observed ocular AEs reported for implanted study eyes, elevated IOP and cataract are commonly associated with ocular steroid use. Other frequently reported AEs in implanted eyes (e.g., eye pain, hypotony, conjunctival hemorrhage, and hyperemia) appear to be primarily associated with surgery. In fellow eyes, the most frequently observed ocular AEs (decreased visual acuity, cataract formation, and eye pain) were in part due to uveitic inflammation experienced when the effects of Table 7 

The rate of C2-grade changes in lens opacities from baseline for subcapsular, nuclear, and 

Visual field sensitivity was quantified as the mean deficit (MD), measured in decibels (dB). 

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Retisert Ò (fluocinolone acetonide intravitreal implant) 0.59 mg prescribing information