Effect of a Fluocinolone Acetonide Insert on

Recurrence Rates in Noninfectious

Intermediate, Posterior, or Panuveitis
Three-Year Results
Glenn J. Jaffe, MD,1 Carlos E. Pavesio, MD,2 on behalf of the Study Investigators

Purpose: To examine the 36-month efficacy and safety of a 0.2 mg/day fluocinolone acetonide insert (FAi) to
treat noninfectious uveitis of the posterior segment (NIU-PS).
Design: Phase 3, prospective, double-masked, multicenter study (clinicaltrials.gov, NCT01694186).
Participants: Adults (
18 years old) with a diagnosis of NIU-PS in
1 eye for
1 year and
2 recurrences of
uveitis requiring systemic corticosteroid, immunosuppressive treatment, or intraocular corticosteroids.
Methods: Participants were randomized 2:1 to FAi or sham (injection plus standard of care) treatment.
Main Outcome Measures: The primary outcome was the difference between the proportion of FAi-treated
and sham-treated patients who had a uveitis recurrence. Secondary outcomes included time to first recurrence,
number of recurrences, best-corrected visual acuity (BCVA) change from baseline, resolution of macular edema,
and number of adjunctive treatments.
Results: One hundred twenty-nine participants (n ¼ 87 FAi-treated; n ¼ 42 sham-treated) were enrolled. Over
36 months of treatment, cumulative uveitis recurrences were significantly reduced with FAi compared with sham
(65.5% vs. 97.6%, respectively; P < 0.001); time to first recurrence was commensurately longer (median 657.0
and 70.5 days, respectively; P < 0.001). The number of recurrences per eye was significantly lower in the FAi-
treated compared with the sham-treated group (mean 1.7 vs. 5.3, respectively, P < 0.001). At 36 months,
more FAi-treated eyes had a
15-letter increase in BCVA from baseline and fewer FAi-treated eyes had
investigator-determined macular edema at month 36 compared with sham-treated eyes (33.3% vs. 14.7% and
13.0% vs. 27.3% for BCVA and macular edema, respectively). Fewer FAi compared with sham-treated partici-
pants required adjunctive treatments (57.5% vs. 97.6%, respectively). Intraocular pressure (IOP) was similar for
both study groups at month 36 (mean  standard deviation 14.55.1 and 14.85.3, respectively), and
approximately half as many eyes in the FAi-treated group when compared with the sham-treated group under-
went IOP-lowering surgery (5.7% vs. 11.9%). Cataract surgery was required more frequently over 36 months in
the FAi-treated compared with the sham-treated group (73.8% vs. 23.8% of eyes, respectively).
Conclusions: Fluocinolone acetonide insertetreated eyes had significantly reduced uveitis recurrence rates
throughout the study duration, significantly increased recurrence-free durations, fewer recurrence episodes
among those with recurrences, less adjunctive therapy, and an acceptable side-effect profile compared with
sham-treated eyes. Ophthalmology 2020;127:1395-1404 ª 2020 by the American Academy of Ophthalmology. This
is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Supplemental material available at www.aaojournal.org.

Noninfectious uveitis of the posterior segment (NIU-PS),
which consists of intermediate, posterior, and panuveitis,
comprises a group of ocular inflammatory diseases that is
responsible for up to 20% of blindness in the developed
world.1 It frequently runs a chronic relapsing course over
years, resulting in ocular tissue damage and consequent
loss of visual function. Generally, NIU-PS is treated with
corticosteroids: In severe cases, repeated intravitreal or
systemic corticosteroid treatments may be necessary, which
may cause treatment-limiting adverse events.2,3 Topical
corticosteroid eye drops are not typically absorbed into the
vitreous at sufficiently high concentrations to provide
effective posterior segment treatment and therefore are not
an option for most patients.2 Although immunosuppressive
drugs may also be used to treat uveitis, these therapies
have their own potential treatment-limiting adverse events.
Given these clinical constraints, intravitreal corticosteroid
implants that can provide continuous release may offer a
treatment option for uveitis that is effective and reduces the
risk and impact of common adverse events;4,5 such

ª 2020 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ophtha.2020.04.001 1395

This is an open access article under the CC BY-NC-ND license ISSN 0161-6420/20
(http://creativecommons.org/licenses/by-nc-nd/4.0/). Published by Elsevier Inc.
 Ophthalmology Volume 127, Number 10, October 2020
formulations can have a positive effect on patient adherence
by reducing the need for self-administered anti-inflamma-
tory drugs.
A 0.19 mg fluocinolone acetonide insert (FAi; Alimera
Sciences Ltd, Aldershot, Hampshire, UK; EyePoint Phar-
maceuticals Inc, Watertown, MA) continuously releases a
sub-microgram dose (0.2 mg/day) of the corticosteroid
fluocinolone acetonide to the posterior segment over a 36-
month period. A previous pilot study showed that an
injectable intraocular fluocinolone acetonide sustained drug-
delivery system can effectively treat uveitis over 2 years.6
The aims of the clinical study described were to examine
the long-term, 36-month efficacy, and safety of the 0.2
mg/day FAi to treat NIU-PS; the 12-month results of this
study have been reported.7
Methods
This phase 3, prospective, double-masked, multicenter study
(clinicaltrials.gov: NCT01694186) randomized subjects with NIU-
PS to treatment with 0.2 mg/day FAi or sham (sham injection plus
standard of care) treatment. The study was conducted at 33 sites in
the United States, United Kingdom, Germany, Hungary, Israel, and
India. The Institutional Review Board at each center approved the
study, which was performed in accordance with the tenets of the
Declaration of Helsinki.
Patients were eligible for study inclusion if they provided
written informed consent and were at least 18 years of age, had a
diagnosis of NIU-PS in at least 1 eye (with or without anterior
uveitis) for a minimum of 1 year, and had at least 2 separate re-
currences of uveitis requiring systemic corticosteroid or immuno-
suppressive treatment, or intraocular or periocular corticosteroids,
or had received in the 12 months preceding study entry (1) sys-
temic therapy (corticosteroid or other systemic treatment) for a
minimum of 3 months or (2) at least 2 intraocular or periocular
corticosteroid injections to manage uveitis.
Details of the study design have been described7 and are
summarized in Figure 1. Eyes were randomized 2:1 to FAi- and
sham-treated groups; the goal was to enroll 120 eyes. To mini-
mize bias, at all sites, one investigator administered study treat-
ments and performed study day 1 assessments, and a second
investigator, masked to the assigned treatment, performed all study
assessments after study day 1. Study personnel were also asked to
use every reasonable effort to maintain the study masking.
For subjects with unilateral uveitis, the study eye was the
affected eye. For subjects with bilateral uveitis, the study eye was
the more severely affected eye fitting the inclusion/exclusion
criteria (Jaffe et al 2019, Appendix 1 [available at
www.aaojournal.org] for further information on these criteria) or,
if the eyes are symmetrically affected, the study eye was the
right eye.
Primary analysis was planned at 6 months, and secondary an-
alyses were planned at 12 and 36 months. The primary outcome
was the difference in proportion of FAi- and sham-treated study
eyes that had a uveitis recurrence at 6 months. The study design
had an 89% power (2-sided type I error rate ¼ 0.05) to detect a
difference between a sham group recurrence-free rate of 0.600 and
a FAi-treated group recurrence-free rate of 0.880.
In the study, a protocol-defined recurrence was defined by 1 of
3 possible criteria: a
2-step increase in the number of anterior
chamber (AC) cells per high-powered field (1.6, using a 1-mm
beam), as assessed by slit-lamp examination, compared with any
visit before month 6; an increase in vitreous haze of
2 steps
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compared with any visit before month 6; or a deterioration in best-
corrected visual acuity (BCVA) of at least 15 letters compared with
any visit before month 6.
An analysis was performed to account for nonprotocol-defined
recurrences. For this analysis, recurrence was assumed if a previ-
ously nonrecurrent study eye was treated with a prohibited local or
systemic anti-inflammatory medication, defined as systemic,
injectable, or topical corticosteroids, or systemic immunosuppres-
sants, even when protocol-defined recurrence criteria defined were
not met. A recurrence was also assumed if the participant missed an
ophthalmic assessment at the 6-, 12-, or 36-month visit. The term
“imputed” was used to describe these assumed recurrences. To
prevent postprocedural inflammatory reactions from being reported
as uveitis recurrences, assessments for uveitis recurrence began
after the day 7 visit.
Secondary outcomes included the proportion of study eyes that
had a uveitis recurrence from baseline to 36 months, time to first
recurrence, number of recurrences, BCVA change from baseline,
resolution of macular edema (assessed using OCT imaging), and
number of adjunctive treatments received. The differences between
the FAi-treated and sham-treated groups were analyzed for statis-
tical significance, although the study was not powered to detect
differences in these secondary parameters.
Other outcomes that were also captured comprised changes in
BCVA, vitreous haze, AC cell count, intraocular pressure (IOP),
IOP-related events, and cataract development at 24 and 36 months.
Results
In total, 129 participants were enrolled in the study; 87 eyes of
these subjects were randomized to the FAi-treated group and 42 to
the sham-treated group. Baseline demographics and participant
characteristics are shown in Table 1. In the FAi-treated group there
was a longer uveitis duration, slightly lower percentage of female
patients, a greater percentage of eyes without cells in the AC, and
more eyes with central subfield thickness (CST) less than 300 mm
at baseline compared with the sham-treated group.
Uveitis Recurrence
Over 36 months of treatment, the FAi-treated group had a signif-
icantly reduced recurrence rate when compared with those in the
sham-treated group. The protocol-defined recurrence rate in the
FAi group compared with the sham-treated group was 5.7%
compared with 28.6% (a 5-fold difference; P < 0.001), and the
cumulative uveitis recurrence rate (that included imputed re-
currences) was 65.5% in the FAi-treated group compared with
97.6% in the sham-treated group (P < 0.001).
At month 36, the time to first recurrence in FAi-treated eyes
was significantly longer compared with sham-treated eyes (median
657.0; 95% confidence interval [CI], 395e1051] days and 70.5;
95% CI, 57e91 days, respectively; P < 0.001). Probability of
recurrence was greater in the sham group compared with the FAi
group throughout the study (Fig 2); the difference was significant at
the 6-, 12-, and 36-month time points (Table 2).
The number of recurrences per eye occurring over 36 months
was also significantly lower in the FAi-treated group compared
with the sham-treated group (mean  standard deviation [SD],
1.72.4 vs. 5.33.8, respectively, P < 0.001), and a higher pro-
portion of eyes in the FAi-treated group had no uveitis recurrence
compared with the sham-treated group (34.5% vs. 2.4%). In
addition, a greater proportion of eyes in the FAi-treated group
compared with the sham-treated group had uveitis recur only once
in 3 years (33.3% vs. 11.9%, respectively). Unsurprisingly,
frequent uveitis recurrence during the 3 years (defined as >5
 Jaffe and Pavesio 
FAi for NIU-PS

Figure 1. Study design.

recurrences) occurred in a lower proportion of eyes in the FAi-
treated group compared with the sham-treated group (8.0% vs.
40.5%, respectively).
Observed protocol-defined uveitis recurrences occurred in a
greater percentage of the sham-treated eyes, whereas the
percentage of eyes with an imputed recurrence was more similar in
the 2 groups (59.8% and 69.0%, respectively) (Table 3). A greater
proportion of imputed recurrences were treated with systemic
medications in the FAi-treated group compared with the sham-
treated group (28.7% vs. 11.9%); however, a lesser proportion of
local injections were administered (8.0% vs. 38.1%).

Table 1. Baseline Demographics and Patient Characteristics

Adjunctive Treatments
FAi Sham Control
(n [ 87) (n [ 42) Fewer participants in the FAi-treated group compared with the
sham-treated group required adjunctive treatments over 36 months
Age, mean  SD (yrs) 48.313.9 48.313.7 of follow-up (Fig 3); the percentage of eyes receiving any
Sex (%) adjunctive medication in the FAi-treated group was 57.5%
Female 57.5 69.0 compared with 97.6% in the sham-treated group. The mean num-
Male 42.5 31.0 ber of adjunctive treatments per eye in the FAi-treated group was
Systemic uveitis treatment (% eyes) 50.6 50.0 0.48 compared with 1.52 in the sham-treated group.
Duration of uveitis, mean  SD (yrs) 7.86.7 5.66.8
Vitreous haze absent (% eyes) 25.3 19.0
Vitreous haze grade (% eyes)
0/0.5þ 55.2 50.0
Visual Acuity Outcomes
1/2þ 44.8 50.0 At 36 months, 33.3% of eyes in the FAi-treated group had a
15-
3/4þ 0.0 0.0 letter increase in BCVA from baseline compared with 14.7% of
AC cells absent (% eyes) 62.1 47.6 eyes in the sham-treated group. Furthermore, there was a signifi-
AC cells grade (% eyes) cantly greater mean change in BCVA over 36 months: þ9.1 Early
0/0.5þ 88.5 78.6
Treatment Diabetic Retinopathy Study letters (SD ¼ 13.0) for the
1/2þ 11.5 21.4
FAi-treated group compared with þ2.5 letters (SD ¼ 14.2) for the
3/4þ 0.0 0.0
BCVA, mean  SD (ETDRS letters) 66.915.5 64.915.5
sham-treated group (P ¼ 0.020; Fig 4). Conversely, fewer patients
CST (% eyes) in the FAi-treated group had a
15 letter decrease in BCVA
<300 mm 42.5 33.3 compared with the sham group (1.4% vs. 8.8%, respectively).

300 mm 55.2 64.3
Macular edema present (% eyes) 56.5 65.9
Lens status (% eyes) Control of Edema
Pseudophakic 51.7 50.0
Phakic 48.3 50.0
There was a tendency for fewer eyes in the FAi-treated group to
IOP, mean  SD (mmHg) 13.93.1 13.63.2 have investigator-determined macular edema at month 36
compared with sham-treated eyes (13.0% vs. 27.3%, respectively);
however, this difference did not reach statistical significance (P ¼
AC ¼ anterior chamber; BCVA ¼ best-corrected visual acuity; CST ¼ 0.079). The reduction in CST and its subsequent maintenance
central subfield thickness; ETDRS ¼ Early Treatment Diabetic Retinop- occurred more quickly in the FAi group than in the sham group;
athy Study; FAi ¼ fluocinolone acetonide insert; IOP ¼ intraocular pres- this difference in CST in favor of the FAi-treated group was
sure; SD ¼ standard deviation.
observed from day 28 onward (Fig 5).

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Figure 2. Probability of recurrence by days from treatment (intention-to-treat population).

Vitreous Haze and Anterior Chamber Cells Discussion

A similar percentage of eyes in the FAi- and sham-treated groups
had no vitreous haze or AC cells at month 36 (vitreous haze
absence: 88.9% vs. 91.2%, respectively; AC cell absence: 84.7%
vs. 85.3%, respectively); however, FAi-treated eyes achieved an
absence of vitreous haze and AC cells sooner than sham-treated
ones (vitreous haze absent at 6 months: 80.5% vs. 59.5%; AC
cells absent at 6 months: 89.7% vs. 64.3%, respectively; Fig 6).
Safety: Intraocular Pressure and Cataract
Intraocular pressure was well controlled in both study groups (Fig
7); IOP was similar for both study groups at month 36, and
comparable proportions of eyes in the 2 groups had IOP-related
events over 36 months (Table 4). Most IOP elevations were
treated with IOP-lowering medication; 42.5% of eyes in the FAi-
treated group received IOP-lowering medication compared with
33.3% of eyes in the sham-treated group. The proportion of eyes in
the FAi-treated group that underwent IOP-lowering surgery was
approximately half that in the sham-treated group (5.7% vs.
11.9%). As expected, cataract surgery was required more
frequently over 36 months in the FAi-treated group compared with
the sham-treated group (73.8% of eyes vs. 23.8% of eyes,
respectively). Cataract removal had a similar effect on visual acuity
outcomes for both treatment groups when measured at the first
assessment after removal (þ20.3 letters for the FAi-treated group
vs. þ23.4 letters for the sham-treated group).
In this study, the FAi-treated group had significantly fewer
uveitis recurrences over 36 months and fewer recurrences
per study eye compared with the sham-treated group; the
FAi group required fewer adjunctive treatments and had a
longer median time to onset of recurrence. More than one-
third (34.5%) of FAi-treated eyes remained free of recur-
rence or did not need any adjunctive medication for 36
months compared with 2.4% of eyes in the sham group. In
addition, more FAi- than sham-treated eyes had uveitis recur
only once in 3 years. Over this period, the FAi-treated group
had a significantly greater improvement in BCVA, less vi-
sual acuity loss, and a reduction in CST that was maintained
from day 28.
These long-term results confirm and extend the month 6,
12, and 24 results that were reported previously6-8 and
demonstrate that uveitis recurrence rates were significantly
reduced compared with sham-treated eyes over the entire 36
months of this study (P < 0.001 at 6, 12, and 36 months).
Most notably, there were far fewer observed recurrences in
the FAi-treated group, supporting the beneficial effect of
treatment on the observable clinical end points of cellular
infiltrate in the AC, vitreous haze, and BCVA. Indeed,
where reanalyses using alternative definitions of recurrence

Table 2. Proportion of Subjects with Uveitis Recurrence in the Study Eye over 36 Months

Time Since Treatment FAi (n [ 87) n (%) Sham Control (n [ 42) n (%) Odds Ratio (95% CI) P Value
6 mos 24 (27.6) 38 (90.5) 24.94 (8.04e77.39) <0.001
12 mos 33 (37.9) 41 (97.6) 67.09 (8.81e511.06) <0.001
36 mos 57 (65.5) 41 (97.6) 21.58 (2.83e164.70) <0.001

CI ¼ confidence interval; FAi ¼ fluocinolone acetonide insert.

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 Jaffe and Pavesio 
Table 3. Recurrences and Reasons for Imputing an Event
Recurrence rate within 36 mos (%)
Observed
Imputed
Reason for imputed event (%)
Missing data
Systemic corticosteroid or immunosuppressant
Intraocular/periocular corticosteroid
Topical corticosteroid
FAi ¼ fluocinolone acetonide insert.
have been conducted that exclude topical corticosteroid use
as a proxy for recurrence (per US Food and Drug Admin-
istration guidance), the difference in recurrences between
the FAi- and sham-treated groups was even greater (56.3%
vs. 92.9%, respectively). On the basis of these favorable
study results, the Food and Drug Administration approved
FAi for the treatment of NIU-PS.9
A significantly lower recurrence rate was observed in
FAi-treated eyes compared with sham-treated eyes, whether
recurrence rate was calculated strictly according to the
protocol definition or whether imputed recurrences
(as defined previously) were included. The approximately
1.5-fold magnitude of the recurrence rate difference between
FAi-treated and sham-treated eyes was less than the 5-fold
magnitude of the recurrence rate difference, when
protocol-defined recurrence rates were determined. In
addition, missed visits, which occurred in 4 instances in the
FAi-treated group, but in none of the sham-treated group,
were imputed as recurrences. Because it is unknown
whether these subjects truly had a uveitic recurrence, it is
possible that the imputed recurrences based on missed visits
Figure 3. Study participants receiving at least 1 adjunctive treatment (systemic treatment, local injections, or topical ophthalmic treatment) over a 36-
month period. FAi ¼ fluocinolone acetonide insert.
FAi for NIU-PS
FAi (n [ 87) Sham control (n [ 42)
65.5 97.6
5.7 28.6
59.8 69.0
4.6 0.0
28.7 11.9
8.0 38.1
18.4 19.0
could have overestimated the cumulative recurrence rate in
FAi-treated eyes. Likewise, treatment of the fellow eye was
considered an imputed recurrence, as was systemic anti-
inflammatory agents for systemic anti-inflammatory dis-
ease. Inclusion of these events as a study eye recurrence
could have overestimated the recurrence rate in the
FAi-treated eyes. Accordingly, for these reasons, which
resulted in a smaller magnitude of the cumulative recurrence
rate difference between FAi- and sham-treated eyes,
when compared with protocol-defined recurrence rates,
respectively, we would consider the inclusion of imputed
recurrences to be a more conservative estimate of uveitis
recurrence rate.
Treatment with local or systemic anti-inflammatory
agents was one of the reasons for an imputed uveitis
recurrence. There are several possible reasons why the
subject might have been treated with one of these agents:
inflammation that did not meet the minimum threshold for a
recurrence (e.g., a 1-step increase in AC cells or vitreous
haze, or <15-letter decrease in Early Treatment Diabetic
Retinopathy Study visual acuity letters compared with any
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Figure 4. Mean best-corrected visual acuity (BCVA) change in treated eyes over a 36-month period. ETDRS ¼ Early Treatment Diabetic Retinopathy
Study; FAi ¼ fluocinolone acetonide insert.

month before month 6). Presumably, the investigator
considered this mild inflammation to be a recurrence, even
though it did not meet the strict recurrence threshold. It is
also likely that the investigator treated eyes with anti-
inflammatory therapy for macular edema attributed to
inflammation for which he believed that treatment was
necessary, even though recurrent macular edema was not a
protocol-defined recurrence criterion.
Although the proportion of imputed (nonprotocol-
defined) recurrences was similar in the FAi- and sham-
treated groups, the treatment reasons for these imputed re-
currences were different. A higher proportion of FAi-treated
eyes had recurrence imputed due to treatment with systemic
therapy, whereas many more eyes in the sham-treated group
had recurrence imputed due to treatment with local corti-
costeroid injections. The reasons for these differences are
not entirely clear, and further investigations are warranted to
understand these differences.
The decreased number of uveitis recurrences and the
delayed median time to first recurrence in the FAi-treated
group compared with the sham-treated group are evidence
that inflammation was better controlled in the FAi- than the
sham-treated group. There are no direct comparative data for
other injectable delivery systems. The dexamethasone

Figure 5. Mean central subfield thickness (CST) in treated eyes over a 36-month period. FAi ¼ fluocinolone acetonide insert.

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 Jaffe and Pavesio
Figure 6. Percentage of eyes without (A) vitreous haze or (B) anterior chamber (AC) cells over 36 months. FAi ¼ fluocinolone acetonide insert.
(DEX) insert is another example of an injectable intravitreal
corticosteroid implant to treat NIU-PS, but differences in
study designs (duration and end points) and enrolled patient
populations preclude quantitative comparisons between the
DEX insert and the FAi, for example, uveitis recurrence was
not recorded in a previous study of a DEX insert,10 nor were
between recurrence rates in implant-treated eyes relative to
controls.
The FAi differs from the DEX insert in its long-term (36
months vs. 3e6 months, respectively), microdose, sustained
release, from which patients with recurrent uveitis may

FAi for NIU-PS
achieve additional benefit from a sustained-release single
injection technology.6 In clinical practice, the features of
these corticosteroid inserts are likely to substantially affect
treatment decisions and long-term outcomes. In a study of
uveitis treatment with the DEX insert,10 there was a
reduction in BCVA after week 8, which may indicate a
waning effect of DEX on BCVA at this time point. The
difference in duration of action between the DEX insert
and FAi may be reasonably expected to result in similar
temporal treatment effects in uveitis, and the shorter
duration of drug release afforded by the DEX insert would
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Figure 7. Intraocular pressure (IOP) over 36 months’ follow-up in the fluocinolone acetonide insert (FAi)- and sham-treated groups.

imply a greater recurrence rate over an extended follow-up needed in the sham-treated group might suggest that these
time with this treatment method. patients would need to return more frequently for clinic
Fewer participants in the FAi-treated group compared visits, which would increase the burden on both patient and
with the sham-treated group required adjunctive systemic provider. Finally, by decreasing or eliminating adjunctive
corticosteroid or immunosuppressive therapy, intraocular therapy, side effects associated with these treatments can be
corticosteroids, or topical corticosteroids. These clinically minimized or eliminated. For example, by decreasing sys-
important data are further evidence that inflammation was temic therapy, potentially toxic systemic side effects could
better controlled in the FAi-treated group when compared be minimized or eliminated, and by reducing the frequency
with the sham-treated group. Uveitis often runs a chronic of periocular or intraocular injections, complications asso-
course that requires excellent patient compliance to self- ciated with these procedures could be minimized.
administer systemic or topical medications, often over Retinal structural and functional benefits were observed
many years, which many patients find difficult. Suboptimal for patients with the FAi. The FAi-treated group experi-
compliance could lead to suboptimal uveitis control. enced a rapid and sustained reduction of macular edema
Furthermore, the increased number of local injections (CST) over the 36 months of the study, compared with the
sham-treated group, and a smaller proportion of FAi-treated
eyes had edema at 36 months compared with sham-treated
Table 4. Intraocular PressureeRelated Events over 36-Month eyes. Likewise, patients who received the FAi had a rapid
Follow-up and sustained BCVA improvement over the 36 months of
study and substantially more FAi-treated eyes had a
15-
FAi Sham control letter BCVA gain compared with the sham group.
(n [ 87) (n [ 42) Conversely, fewer eyes had a
15-letter BCVA loss.
IOP at month 36 (mmHg) Collectively, these efficacy outcomes suggest that it is more
Mean  SD 14.55.1 14.85.3 beneficial to maintain steady, long-term uveitis control, as
Change from baseline  SD 0.85.0 1.45.7 produced by the FA, than can be achieved by providing
IOP events up to month 36 (% of eyes) more frequent, episodic treatment for each recurrence, as
>25 mmHg 24.1 23.8
was needed in the sham group.
>30 mmHg 16.1 11.9
Change from baseline
12 mmHg 23.0 26.2 The adverse event (AE) rates were higher with the FAi
IOP-lowering medication 42.5 33.3 than in the treated-sham group; however, the AE rates with
IOP-lowering surgery 5.7 11.9 the FAi, with the exception of cataract, did not appear to be
Hypotony 10.3 11.9 substantially higher than in the sham-treated group
Cataract (Appendix 1 and Table S1, available at
Phakic at baseline (n) 42 21 www.aaojournal.org). Hypotony was a transient
Cataract surgeries (n, %) 31 (73.8) 5 (23.8)
phenomenon associated with the injection procedure in
eyes receiving the FAi implant, and there was no
FAi ¼ fluocinolone acetonide insert; IOP ¼ intraocular pressure; SD ¼ meaningful difference in the incidence of hypotony
standard deviation.
between FAi- and sham-treated eyes. On the basis of these

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 Jaffe and Pavesio
data, the risk of hypotony is not considered significant
enough to override the benefit of the FAi to treat NIU-PS.
Intraocular pressure was generally well controlled in both
study groups; most frequently, IOP-lowering medications
were used to control IOP elevations. The lower rate of IOP-
lowering surgery in the FAi-treated group compared with
the sham-treated group is notable and contrasts with previ-
ous studies of the surgically implanted Retisert (Bausch þ
Lomb, Bridgewater, NJ) implant, which resulted in a higher
rate of IOP surgery compared with the DEX implant.11,12
Results of 3 phase 2b/3 trials evaluating the safety and
efficacy of the Retisert implant (0.59 mg fluocinolone
acetonide) to treat NIU-PS revealed that 10.9% of
Retisert-treated eyes required IOP-lowering surgery within 1
year of treatment and 32.0% of eyes within 3 years of
treatment.13 This reduction in IOP-lowering surgery
required with the injectable FAi compared with the surgi-
cally implanted Retisert implant is likely related to the lower
daily corticosteroid dose.
There is some controversy as to the interpretation of the
long-term outcome data of Retisert in comparison with the
systemic approach for the management of NIU-PS.14 The
MUST Trial 7-year follow-up data suggested that sus-
tained control of inflammation results in better long-term
visual outcomes than does a relapsing and retreating
course, with the implication that scheduled replacement of
regional therapies might be considered as a strategy.15 With
respect to regional fluocinolone acetonide therapies, the
design of the FAi intravitreal insert (injectable) facilitates
easier re-treatment than does the surgically implanted
Retisert. However, the lower dose and release rate of the
0.19-mg insert seem to result in a higher relapse rate than
the 0.59-mg surgically placed implant. Comparative studies
of these 2 regional modalities might provide data on their
relative effectiveness.
An FAi similar to the one used in the current study has
been studied and approved to treat diabetic macular edema
(DME).16 The incidence of IOP-lowering surgery was 4.8%
in patients receiving the FAi to treat DME, compared with
5.7% of patients receiving the FAi to treat NIU-PS; a
smaller proportion of sham-treated eyes in the DME study
received IOP-lowering surgery compared with sham-treated
eyes in the present NIU-PS study (0.5% vs. 11.9%). This
difference may be due to the higher proportion of eyes
treated with corticosteroid adjunctive treatment in the sham-
treated group of the NIU-PS study; alternative treatments to
corticosteroids were more readily available to treat DME in
that sham-treated group.
In the current study, the cataract surgery rate was higher
in the FAi-treated group compared with the sham-treated
group (73.8% and 23.8%, respectively); these rates are
comparable to those in a previous study of FAi for the
treatment of DME (80.0% and 27.3%, respectively). Studies
of Retisert to treat NIU-PS have described similarly high
proportions of phakic eyes that require cataract extraction.17
During the 6-month HURON trial, cataracts were reported
in 15% of phakic eyes treated with DEX compared with 7%
of control-treated eyes,10 whereas in the current study,
14.9% of FAi-treated eyes and 4.8% of sham-treated eyes
had cataract at 6 months. Collectively, these data indicate

FAi for NIU-PS
that the risk of cataract surgery and cataract formation
resulting from the FAi’s continuous, long-term, daily sub-
microgram corticosteroid exposure is similar to the risk
from other corticosteroids.
This study has limitations. First and foremost, data on
specific types of intermediate, posterior, and panuveitis were
not collected, and so the relative efficacy for specific uveitis
diagnoses is unclear. Furthermore, the study was likely
underpowered to detect significant efficacy differences
based on underlying uveitis etiology, even had those data
been available. It is reassuring that the overall study popu-
lation appeared to respond well to the FAi. An important
limitation of the long-term results reported is that the study
was originally designed and powered to investigate differ-
ences in uveitis recurrence at 6 months; consequently, the
current statistical comparisons are all powered from sec-
ondary objectives. It is also important to recognize the high
number of imputed recurrences, which could confound the
results reported here; however, the clear separation in
observed recurrences supports a benefit for FAi treatment.
The treatment effect on BCVA may have been under-
estimated because proportionally more study eyes had a
baseline visual acuity of more than 70 letters, which would
have limited mean BCVA gains and the proportion of
subjects whose visual acuity could have improved by 15
letters from baseline. A further limitation was that resolution
of macular edema was not defined quantitatively in the
protocol. Also, the use of nonstandardized measurements of
macula edema was allowed according to the study protocol
so that macular edema resolution could be accurately
assessed for a given subject but not between subjects.
In conclusion, notwithstanding these limitations, the col-
lective data show that FAi-treated eyes had significantly
reduced rates of uveitis recurrence over the entire study dura-
tion, significantly increased duration of recurrence-free time,
fewer recurrence episodes among those with recurrences, less
adjunctive therapy, and an acceptable side-effect profile when
compared with sham-treated eyes. These data support the FAi
as an office-based rather than a surgical procedure that provides
a useful long-term treatment option for NIU-PS.
Acknowledgments
The authors acknowledge the vital contribution of the study
investigators and sites (Appendix 2, available at
www.aaojournal.org).
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Footnotes and Financial Disclosures
Originally received: October 1, 2019.
Final revision: March 30, 2020.
Accepted: April 2, 2020.
Available online: April 16, 2020. Manuscript no. D-19-00457
1
Department of Ophthalmology, Duke University Eye Center, Duke Uni-
versity, Durham, North Carolina.
2
Moorfields Eye Hospital, London, United Kingdom.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): G.J.J.: Consultant e
AbbVie, Inc (North Chicago, IL), Novartis Pharma AG (Basel,
Switzerland), Neurotech USA, Inc (Lincoln, RI), EyePoint Pharmaceuticals
(Watertown, MA), EYEVENSYS (Paris, France).
C.P.: Consultant e Allergan (Dublin, Ireland), Alimera Sciences (Alder-
shot, Hampshire, UK), EYEVENSYS (Paris, France), Servier Laboratories
(Suresnes, France), Santen Pharmaceutical Co, Ltd (Japan), AbbVie, Inc
(North Chicago, IL). EyePoint Pharmaceuticals participated in the design
and conduct of the study; collection, management, analysis, and interpre-
tation of the data. Medical writing assistance was provided by Helios
Medical Communications, Alderley Edge (Cheshire, UK). Alimera Sci-
ences supported the preparation and final review of the manuscript. The
authors had access to all study data, participated in the data analysis, made
critical revisions to the manuscript, and received no payments for the
preparation of the manuscript.
1404
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implant (Retisert) for noninfectious posterior uveitis: thirty-
four-week results of a multicenter randomized clinical study.
Ophthalmology. 2006;113:1020e1027.
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(Ozurdex) intravitreal implants in uveitis. J Ocul Pharmacol
Ther. 2013;29:501e507.
13. Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure
in patients with uveitis treated with fluocinolone acetonide
implants. Arch Ophthalmol. 2007;125:1478e1485.
14. Albini TA, Callaway NF, Jaffe GJ, et al. Beg to differ.
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or panuveitis. JAMA. 2017;317:1993e2005.
16. Campochiaro PA, Brown DM, Pearson A, et al. Sustained
delivery fluocinolone acetonide vitreous inserts provide benefit
for at least 3 years in patients with diabetic macular edema.
Ophthalmology. 2012;119:2125e2132.
17. Callanan DG, Jaffe GJ, Martin DF, et al. Treatment of
posterior uveitis with a fluocinolone acetonide implant:
three-year clinical trial results. Arch Ophthalmol. 2008;126:
1191e1201.
HUMAN SUBJECTS: Human subjects were included in this study. The
human ethics committees at each institution approved the study. All
research adhered to the tenets of the Declaration of Helsinki. All partici-
pants provided informed consent.
No animal subjects were used in this study.
Author Contributions:
Conception and design: Jaffe, Pavesio
Data collection: Jaffe, Pavesio
Analysis and interpretation: Jaffe, Pavesio
Obtained funding: N/A
Overall responsibility: Jaffe, Pavesio
Abbreviations and Acronyms:
AC ¼ anterior chamber; BCVA ¼ best-corrected visual acuity;
CI ¼ confidence interval; CST ¼ central subfield thickness;
DEX ¼ dexamethasone; DME ¼ diabetic macular edema;
FAi ¼ fluocinolone acetonide insert; IOP ¼ intraocular pressure; NIU-
PS ¼ noninfectious uveitis of the posterior segment; SD ¼ standard
deviation.
Correspondence:
Glenn J. Jaffe, MD, Department of Ophthalmology, Duke Eye Center, 2351
Erwin Road, Durham, NC 27705. E-mail: jaffe001@mc.duke.edu.