Study reference

Study characteristics

Patient characteristics

Intervention (I)

Control (C)

Follow-up

Outcome measures and effect size

Comments

0.7 mg dexamethasone implant vs 0.35 dexamethasone implant vs sham procedure

Lowder, 2011

Type of study: multicentre RCT

Country: 18 countries

Competing interests: This study was sponsored by Allergan,Inc, which participated in the design of the study,

data analysis, and interpretation and supervised the prepa-

ration of the manuscript and approved the final version.

Drs Robinson, Schiffman, Li, Cui, and Whitcup are em-

ployees of Allergan, Inc.

Inclusion criteria:

Patients with a diagnosis of non-infectious intermediate or posterior uveitis were enrolled in this study if they were at least 18 years of age, had a vitreous haze score of at least +1.5 (on

a scale of 0-4), and a best-corrected visual acuity (BCVA) of 10 to 75 letters (20/630 to 20/32). Only 1 eye was designated as the study eye. If both eyes were eligible for the study, the

right eye was designated as the study eye. Patients were allowed to use the following medications under specified conditions: (1) topical corticosteroids and nonsteroidal anti-

inflammatory agents if doses were stable for at least 2 weeks prior to screening and remained stable through the treatment day on day 0, (2) systemic corticosteroids if doses were 20mg/d or less for oral prednisone (or equivalent for other corticosteroids), were stable for at least 1 month prior to screening, remained stable through the treatment day on day 0, and were expected to remain stable through week 8, and (3) systemic immunosuppressors (eg,cyclosporine and methotrexate) if doses

were stable for at least 3 months prior to screening, remained stable through the treatment day on day 0, and were expected to remain stable through week 8.

Exclusion criteria:

any active ocular disease or

infection; uveitis unresponsive to prior corticosteroid treatment; the use of IOP-lowering medications within the last month and a history of glaucoma, ocular hypertension, or clinically

significant IOP elevation in response to corticosteroid treatment; IOP more than 21 mm Hg at baseline; BCVA less than 34 letters in the nonstudy eye; or any uncontrolled systemic

disease. Patient participated in a previous clinical trial of the DEX implant, had used the FA implant in the study eye, had periocular corticosteroid injections in the study eye 8 weeks or less prior to the treatment

visit on day 0, had history of any intravitreal drug injection to the study eye 26 weeks or less prior to the treatment visit unless it was triamcinolone acetonide at the dose of 4 mg or less

injected 26 weeks or more prior to the treatment visit on day 0, or there was an anticipation to initiate or change current doses

of systemic corticosteroids or systemic immunosuppressors during the first 8 weeks of the study.

Group A: N=77

0.7 mg DEX implant

Group B: N=76

0.35 mg DEX implant

Group C: N=76

sham procedure

Study treatment:

Prior to each treatment, the study eye was anesthetized with topical and subconjunctival anesthetics and prepared according to standard clinical practice for eyes undergoing intravitreal injection. The DEX implant was inserted into the vitreous

cavity through the pars plana using a customized, single-use, 22-gauge applicator. The sham procedure followed the same protocol but used a needleless applicator.

All patients were treated with a topical ophthalmic antibiotic 4 times daily starting 3 days prior to the day of their study procedure (day 0) and

continuing for 3 days after the procedure.

Nonstudy treatments:

Nonstudy treatments considered necessary for the best care of

the patient could be given at the discretion of the investigator. Unless required for patient care, the use of systemic immunosuppressive therapy or corticosteroids (systemic, periocular, intravitreal, or topical) was prohibited. The criteria for the use of anti-inflammatory agents were an increase from baseline in vitreous haze score of 1 or more units from week 3 to just prior to

week 8 and a vitreous haze score of +1.5 or more from week 8

to week 26. The use of either of these therapies was recorded as

a rescue treatment. Other prohibited treatments included nonstudy procedures or surgery on the study eye and the use of anticoagulant agents within 2 weeks of receiving study treatment.

Length of follow-up:

26 weeks

Lost to follow-up:

Group A:

4/77=5.2%

Group B:

3/76=3.9%

Group C:

5/76=6.6%

Reasons for lost to follow-up:

N=2 adverse events in group A, N=1 lack of efficacy in group B, other reasons (not stated): N=9

Intention to treat analysis:

yes

Primary outcome measure:

Proportion of eyes with a vitreous haze score of 0 (=no inflammation) at week 8.

Secondary outcome measures:

- Proportion of eyes with a vitreous haze score of 0 at week 26

- Visual acuity

- IOP

-Adverse events

Results

% with vitreous haze score of 0 at week 8

At baseline, the mean vitreous haze score was approximately 2 in all treatment groups (p=0.427).

0.7 mg DEX : 36/77=47%

0.35 mg DEX : 27/76=36%

sham procedure: 9/76=12%

Statistically significant difference between the DEX groups and sham (p<0.001).

% with vitreous haze score of 0 at week 26

The percentage of eyes with a vitreous haze score of 0 was also significantly greater in the 0.7-mg DEX implant group than the sham group at weeks 6 through 26 (P≤0.014) and in the 0.35-mg DEX implant group at weeks 6 through 12 and weeks 20 and 26 (P≤0.030).

There was no statistically significant difference between the 0.7-mg and 0.35-mg DEX implant groups.

Visual acuity

The proportion of eyes achieving at least a 15-letter improvement from baseline BCVA was 2- to 6-fold (statistically significant) greater in the DEX implant groups than the sham group throughout the study period.

The mean improvement from baseline BCVA was also significantly greater in the DEX implant groups than the sham group throughout the study period.

IOP

The percentage of eyes with intraocular pressure of 25mmHg or more peaked at 7.1% for the 0.7-mg DEX implant, 8.7%

for the 0.35-mg DEX implant, and 4.2% for the sham (P>0.05 at any visit).

Adverse events

The incidence of cataract reported

in the phakic eyes was 9 of 62 (15%) with the 0.7-mg DEX implant, 6 of 51 (12%) with the 0.35-mg DEX implant, and 4 of 55 (7%) with the sham (P>0.05).

Other common ocular adverse events included conjunctival hemorrhage (0.7-mg DEX implant group: 23 of 76, 30%; 0.35-mg DEX implant group: 12 of 74, 16%; sham group: 16 of 75, 21%), ocular discomfort (0.7-mg DEX implant group: 10 of 76, 13%; 0.35-mg DEX implant group: 3 of 74, 4%; sham group: 6 of 75, 8%), eye pain (0.7-mg DEX implant group: 9 of 76, 12%; 0.35-mg

DEX implant group: 8 of 74, 11%; sham group: 10 of 75, 13%), and iridocyclitis (0.7-mg DEX implant group: 7 of 76, 9%; 0.35-mg DEX implant group: 1 of 74, 1%; sham

group: 4 of 75, 5%). The between-group differences were not statistically significant for any of these adverse events.

Need for rescue medication

At the first study visit (week 3), the percentage of eyes requiring rescue medication in the sham and 0.35-mg and

0.7-mg DEX implant groups was 15%, 3%, and 1% (P=.002 vs sham), respectively. At week 26, the corresponding percentages were 38%, 25%, and 22% (P=.030 vs sham). Throughout the study, the percentage of eyes requiring rescue medication was greater in the 0.7-mg DEX implant group compared with the 0.35-mg DEX implant group, except for weeks 3 and 26.

This between-group difference, however, was not statistically significant.

Randomization was performed

centrally (using an interactive voice/web response system) by

the study sponsor and was stratified by baseline vitreous haze (scores of +1.5 or +2 in one stratum and scores of +3 or +4

in the other) by using balanced blocked randomization method.

The treatment investigator performed the implant placement and other treatment procedures and was responsible for the overall safety of study participants but kept all study medication information confidential and did not collect efficacy information.

Patients were masked with regard to study treatment, and the key efficacy variables were collected and evaluated by follow-up investigators who were also masked with regard to study treatment.

The primary efficacy analysis was performed using all patients

who were randomized to treatment (intention-to-treat analysis).

Nonstudy treatments considered necessary for the best care of the patient could be given at the discretion of the investigator (indirectness of effect)

Given the inclusion and

exclusion criteria for this clinical study, the vision-related

function results may not be generalizable to all patients with

noninfectious intermediate and posterior uveitis.

Patients were treated with only a single DEX implant and followed up for only a 6-month period, which limits the

ability to assess the risk of cataract.

Study was sponsored by Allergan who also participated in the design of the study, data analysis, and interpretation and supervised the preparation of the manuscript and approved the final version.

GRADE: moderate quality of evidence due to possible indirectness (strict in- and exclusion criteria) and possible competing interests.

Lightman, 2013

same RCT as Lowder, 2011; for details study: see Lowder 2011

Type of study: multicentre RCT

Country:

Competing interests:

Inclusion criteria:

Exclusion criteria:

Group A: N=77

0.7 mg DEX implant

Group B: N=76

0.35 mg DEX implant

Group C: N=76

sham procedure

Length of follow-up:

26 weeks

Lost to follow-up:

Group A:

4/77=5.2%

Group B:

3/76=3.9%

Group C:

2/76=2.6%

Intention to treat analysis:

Yes, but the NEI VFQ-25 analyses were performed using all patients who were randomized to treatment and who had at least a baseline and one follow-up assessment. Analytical sample for NEI VFQ-25 was 220/229=96%.

Primary outcome measure:

National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) score. Clinical

significance was predefined as a 5- to 10-point increase in the NEI VFQ-25 subscale and overall composite scores.

Results

Baseline scores

At baseline, significant differences were found between DEX implant 0.70 mg and

sham groups for overall composite score, colour vision, dependency, social functioning, and mental health and between DEX

implant 0.35 mg and sham groups for overall composite score , near vision, distance vision, role difficulties, and dependency (data not shown). For each subscale with significant differences in mean baseline NEI VFQ-25 scores between the three treatment groups, the sham group reported better vision-related functioning scores.

Mean change analyses

After 26 weeks, statistically significant changes from baseline were observed between the DEX implant 0.70 mg and

sham groups on NEI VFQ-25 overall composite, distance vision, vision-specific role difficulties, vision-specific dependency, vision-specific social functioning, and vision-specific mental health scores. The improvements in the overall composite scores were maintained at 26 weeks in the

DEX implant 0.70 mg group, with patients reporting improvement of 10.1 points compared with 2.8 points in the sham

group.

After 26 weeks, statistically significant changes from baseline were observed between the DEX implant 0.35 mg and

sham groups on NEI VFQ-25 overall composite score, near vision, and distance vision. The improvements in the DEX implant 0.35 mg group were maintained at 26 weeks, with patients reporting changes in the overall composite scores of 8.0 points compared with 2.8 points in the sham group.

Responder analysis

By 8 weeks, there were significantly more ≥ 5-point responders for the overall com-

posite score in the DEX implant 0.70 mg (54.8%; P < 0.001) and 0.35 mg (60.3%; P < 0.001) groups compared with the sham group (27.0%). These differences were maintained at 16 and 26 weeks, favouring the DEX implant treatment groups.

After 8 weeks, there were significantly more ≥ 10-point responders for the overall composite score in the DEX implant 0.70 mg (45.2%; P < 0.001) and 0.35 mg (39.7%; P < 0.001) groups compared with the sham group (14.9%).

Because the NEI VFQ-25 responses are based on vision in

both eyes, results are highly influenced by vision in the better-seeing eye. Results presented here are for all patients,

regardless of whether their study eye was the better- or

worse-seeing eye.

Study patients were treated in only one eye. BCVA and vision-related functioning outcomes may vary when both eyes are treated as is the case in clinical practice.

GRADE: moderate quality of evidence due to indirectness (outcome influenced by vision in the better-seeing eye, strict in- and exclusion criteria) and possible competing interests.

0.59-m FA implant vs. 2.1-mg FA implant

Jaffe, 2006

Type of study:

multicentre RCT

(26 centers in the U.S. and 1 in Singapore)

Country:

USA and Singapore

Competing interests:

Dr Pearson has a financial interest in Control Delivery Systems, has

received consulting fees from Bausch & Lomb, and is listed on patents concerning this technology. Drs Martin and Callanan have received con-

sulting fees from Bausch & Lomb, and Dr Jaffe has received research support from Control Delivery Systems and Bausch & Lomb. Drs Levy and

Comstock are employees of Bausch & Lomb.

Inclusion criteria:

males and nonpregnant females at least 6 years old, with at least one eye with a

history of recurrent noninfectious uveitis affecting the posterior segment for at least 1 year and were treated with at least one of the following: (1) systemic corticosteroid or other equivalent systemic therapy for at least 3 months before enrollment, (2) at least 2

sub–Tenon’s capsule corticosteroid injections for the management of uveitis during the 6 months before enrollment, or (3) either

systemic corticosteroid or sub–Tenon’s capsule corticosteroid injection therapy, required by at least 2 separate recurrences within

6 months before enrolment. Additionally, patients had ≤ 10 anterior chamber (AC) cells per high-power field and vitreous haze ≤

grade 2 at the time of implantation. A VA of ≥ +1.40 logMAR (20/500) in the study eye was required; however, for the Singapore

site only, patients had to have had a VA ≥ +1.00

logMAR (20/200) in the nonstudy eye due to institutional review board requirements. For patients with bilateral disease, only patients in whom the investigator felt that it would be possible to control the

fellow-eye ocular inflammation with local therapy (topical medication or periocular injection) were eligible for enrollment.

Exclusion criteria:

known allergy to FA or any component of the delivery system, history of posterior

uveitis not accompanied by vitritis or macular edema, or history of iridocyclitis only with no vitreous cells or vitreous haze. Addition-

ally, patients were excluded if they had vitreous hemorrhage, a toxoplasmosis scar in the study eye, peripheral RD in the planned area of implantation, media opacity precluding evaluation of the

retina and vitreous, or ocular surgery on the study eye within 3 months before enrollment. Patients with a history or presence of

uncontrolled IOP while on corticosteroid therapy resulting in loss of vision or IOP > 25 mmHg requiring

≥ 2 types of ocular antihypertensive medication to lower IOP to < 25 mmHg were excluded. Patients treated with chronic systemic corticosteroid therapy (> 15 mg of prednisone daily) or systemic immunosuppressive therapy to manage nonocular disease or those with HIV were also excluded.

Group A: N=110

0.59-mg fluocinolone acetonide (FA) implant

Group B: N=168

2.1-mg fluocinolone acetonide (FA) implant

Study treatment:

For patients with bilateral disease, the eye more severely affected received the implant.

After implantation, uveitis medications were tapered. Systemic

corticosteroid doses were decreased by 30% per week to 2.5 mg/day for 1 week, then discontinued. Corticosteroid daily drop frequency was decreased by 1 drop at weekly intervals, then discontinued. Immunosuppressive agents were discontinued or tapered within a 6-week period at the investigator’s discretion.

Perioperative, the following medication was given: cyclopentolate hydrochloride 1% and phenylephrine 2.5% for dilation, balanced salt

irrigating solution used for injection through the pars plana to restore IOP at the end of surgery, if necessary, an antibiotic injected subcon-

junctivally at the end of surgery, and a postoperative regimen consisting of 1 drop of prednisolone acetate (or equivalent) at least 4 times daily, and 1 drop of a broad-spectrum

antibiotic 4 times daily (excluding corticosteroid combinations), and 1 drop of homatropine 5% (or equivalent) twice daily for 1 week after surgery.

If there was a clinical recurrence in either eye, patients were treated first with periocular corticosteroid injection and, if necessary, systemic corticosteroids. Once the recurrence was under control, therapy was tapered as indicated above. Oral, systemic, and topical corticosteroids and immunosuppressive agents other than those specified in the protocol were not permitted during the study unless required to treat uveitis recurrences

Length of follow-up:

34 weeks

Lost to follow-up:

No (not reported)

Intention to treat analysis:

NA

Primary efficacy outcome measure:

comparison of the recurrence rate in the implanted eye from the 34-week period before implantation to the 34-week period after implantation.

Recurrence defined as: (1) increase in

the number of cells in the AC per high-power field of ≥ 2 steps compared with baseline, (2) increase in vitreous haze of ≥ 2 steps compared with baseline, (3) deterioration in VA of at least +0.30 logMAR from screening/baseline (all 3 criteria could not be attributable to conditions other than noninfectious posterior segment uveitis), or (4) failure to be observed for clinical examination beyond the 24-week visit (to be conservative, these patients were deemed to have had a recurrence, because they could not be evaluated).

Secondary outcomes:

the comparison of the recurrence rates between the 2 dose levels (0.59 mg and 2.1 mg), within-patient recurrence rate (implant vs. fellow eye), need for adjunctive

therapy (preimplantation vs. postimplantation as well as within-patient), within-patient comparisons of VA, and CME measurements.

Results:

Recurrence rate pre- vs. post-implantation

implant eye:

0.59-mg FA: 54.6% vs. 6.4% (p<0.0001)

2.1-mg FA: 49.4% vs. 6.0% (p<0.0001)

both doses: 51.4% vs. 6.1%* (p<0.0001)

* 6 of 17 (6.1%) recurrences due to failure to be observed for clinical observation beyond week 24 (actual uveitic inflammation was not observed clinically).

fellow eye:

0.59-mg FA: 23.9% vs. 41.3% (p=0.0009)

2.1-mg FA: 18.0% vs. 42.5% (p<0.0001)

both doses: 20.3% vs. 42.0% (p<0.0001)

Visual acuity (VA)

Visual acuity stabilized or improved, defined as a < 1-line loss, in 87% of eyes after implantation. Although significantly more implanted eyes (21%) had a ≥ 3-line improvement in VA compared with fellow eyes (6.0%; P<0.0001), the percentage

of eyes that lost ≥3 lines of vision did not differ between the implanted and fellow eyes.

Need for adjunctive therapy 34 weeks after implantation

implant eyes:

77% decline in need for systemic medication, 97% decline in need for periocular injections, 54% decline in need for topical corticosteroids.

fellow eyes:

40% increase in need for periocular injections and 58% increase in need for topical corticosteroids.

IOP

During the 34-week postoperative period, increases of ≥ 10 mmHg were observed in 59% of implanted eyes (163/278),

compared with 11% of fellow eyes (30/276) (P<0.0001).

The proportion of eyes that required ocular antihypertensive agents increased from 13.6% at baseline to 49.1% at week 34 for

the 0.59-mg group, and from 14.2% to 52.4% for the 2.1-mg group. implant group. By comparison, 9.2% of fellow eyes at baseline and 15.2% of fellow eyes at week 34 required ocular antihypertensive

medications. Of the implanted eyes, 18 (6.5%) required surgical intervention to manage elevated IOP before the 34-week visit.

Cataracts

Cataracts were reported as a serious adverse event in 13.3% of implanted eyes, and 9.9% required cataract surgery (10.9% in the 0.59-mg group and 9.2% in the 2.1-mg group). In contrast, 2.7% of fellow eyes underwent cataract surgery during the same follow-up period.

Other adverse events

procedural complications (26%), eye pain (27%), and hypotony (IOP < 6 mmHg) (9.4%) of implanted eyes.

Five eyes required explantation: 2 implants were removed for uncontrollable elevated IOP, 1 as a result of endophthalmitis, 1 due to an unrelated intraocular lymphoma, and 1 after severe late postoperative hypotony.

NB: There were no statistically significant differences in any of the parameters studied for the 0.59-mg implant, compared with the 2.1-mg implant.

No placebo/control group for comparison.

Randomisation method:

computer-generated randomization code. Treatment group assignment was stratified based on investigative site and method of uveitis management (systemic therapy or local injection before enrollment). Randomization of study drug was in the ratio of 2:3 (0.59 mg to 2.1 mg).

Blinding:

The investigator, patient,

and all personnel involved in the monitoring or conduct of the study were masked to the study drug codes and will remain masked until after the study is completed and the database is finalized.

No (reported) lost to follow-up.

Authors attribute stabilized VA observed in this study to

excellent control of intraocular inflammation, thereby pre-

venting secondary retinal complications such as macular

edema. Data indicate that reductions in the area of

macular hyperfluorescence, a surrogate for macular edema,

can largely account for eyes with improved VA.

Although the study entry criteria stated that all fellow eyes had to be stable and controlled (as defined in the protocol) by local therapy, this determination was made by individual investigators at each study site and, thus, was

subject to variability. Because all patients were tapered off of systemic corticosteroid and immunosuppressant therapy,

this may have resulted in an increased number of recurrences in the fellow eyes.

Unclear how many recurrences were due to failure to be observed for clinical observation beyond week 24 (actual uveitic inflammation was not observed clinically).

Authors had competing interests.

GRADE: low quality of evidence due to study limitations (no placebo/control group for comparison, number of recurrences due to failure to be observed for clinical observation beyond week 24 unknown, possible confounding) and possible competing interests.

Callanan, 2008

same RCT as Jaffe 2006; for details study: see Jaffe 2006

Type of study:

Country:

Competing interests:

Inclusion criteria:

Exclusion criteria:

Group A: N=110

0.59-mg FA implant

Group B: N=168

2.1-mg FA implant. 70 subjects received the original 2.1-mg implant and 98 received the redesigned 2.1-mg implant

Study treatment:

Approximately 9 months after commencement of this study,

a release rate higher than the upper limit specified for the 2.1-mg

implant was reported to the study sponsor by the manufacturer of the clinical trial materials. Study enrollment was then suspended and the 2.1-mg implant was redesigned, following which enrollment into the study resumed. The redesigned 2.1-mg implant is similar in structure to the 0.59-mg implant, which was unchanged throughout the study.

Length of follow-up:

3 years

Lost to follow-up:

Group A: 12/110=10.9%

Group B: 25/168=14.9%

Reasons:

adverse events (7 in each group), lost (3 in group A and 7 in group B), other (2 in group A and 11 in group B).

Intention to treat analysis:

yes, included

all of the enrolled subjects who received an implant and attended at least 1 postimplantation examination.

Primary efficacy outcome measure

Difference in uveitis recurrence rate before and after implantation in the implanted eye. Recurrences were defined as: (1) an increase of 2 or more steps in the number of anterior chamber cells compared with baseline; (2) an increase of 2 or more steps in vitreous haze compared with baseline; or (3) a deterioration of at least 0.30 log-MAR in VA from screening or baseline without an obvious alternate cause.

Secondary outcomes:

VA, need for adjunctive treatment, IOP, adverse events

Results:

(cumulative) Recurrence rate 1 year before implantation and 1,2,3 years after implantation

implanted eyes:

0.59-mg: 62% vs. 4%, 10%, 20% (p<0.01)

2.1-mg: 58% vs. 7%, 17%, 41% (p<0.01)

fellow eyes:

0.59-mg: 30% vs. 44%, 52%, 59% (p<0.01)

2.1-mg: 22% vs. 47%, 51%, 55% (p<0.01)

No statistically significant differences between the 0.59-mg and 2.1-mg (original and redesigned combined) dose groups over the 1-and 2-year postimplantation periods. But

a significant difference between dose groups over the 3-year postimplantation period with a higher recurrence rate in

the 2.1-mg group (P<0.01).

Visual acuity

Improvement > 3 lines at 3 years:

23% (22 of 94) of 0.59-mg implants and 18% (26 of 141) of 2.1-mg implants vs. 6% (5 of 90) and 4% (6 of 137) of nonimplanted fellow eyes (P<0.01 for both).

Deterioration > 3 lines at 3 years:

13% (12 of 94) of 0.59-mg implants and 21% (29 of 141) of 2.1-mg implants vs. 19% (17 of 90) and 18% (25 of 137) of nonimplanted fellow eyes (P>0.05).

IOP during 3-year follow-up

78% of implanted eyes (both dose groups combined) required IOP-lowering eyedrops compared with 36% of fellow eyes

(P<0.01), and 40% of implanted eyes (both dose groups combined) required IOP-lowering surgery compared with

2% of fellow eyes (P<0.01). Six implants were removed during the course of the study due to elevated IOP

Cataracts during 3-year follow-up

93% (132 of 142) of phakic implanted eyes underwent cataract surgery compared with only 20% (37 of 186) of phakic non-implanted fellow eyes (P<0.01).

Other ocular adverse events

Ocular adverse events (e.g. eye pain, conjunctival hyperemia, conjunctival hemorrhage, blurred vision, reduced VA) were reported in 98% (273 of 278) of implanted study eyes and 86% (239 of 278) of fellow

nonimplanted eyes.

The incidence of hypotony (IOP < 6 mmHg) was significantly higher in eyes in the 0.59-mg group (34% [37 of 110]) and 2.1-mg group (46% [78 of 168]) compared with fellow nonimplanted eyes (15% [41 of 275]; both dose groups combined) at any time during the 3-year follow-up (P<0.01 for both).

1 case of endophthalmitis due to incom-

plete wound closure following 0.59-mg implantation.

Explants

Overall, a total of 22 subjects had the FA implant surgically removed over the course of the 3-year postimplantation follow-up period (8 subjects in the 0.59-mg FA implant group and 14 in the 2.1-mg FA implant group).

Reasons:

6 for uncontrolled elevated IOP, 6 for sus-

pected depletion of study medication (5 of these subjects were reimplanted with new Fai mplants), 3 for spontaneous dissociation of the implant from its anchoring strut (these implants were produced prior to the adoption of an improved adhesive process), 1 each for: spontaneous expulsion of the implant (this subject was reimplanted with a new FA implant), inadvertent lysis of the anchoring suture, endophthalmitis, necrotizing scleritis (in the area of the implant in a subject with sarcoidosis), unassociated intraocular lymphoma, cytomegalovirus infection, and hypotony.

The protocol-required withdrawal of systemic medications following implantation may have contributed in part to the difference in uveitis recurrence rates between implanted eyes and nonimplanted fellow eyes (ie,by contributing to an increase in uveitis recurrences in the fellow nonimplanted eyes of subjects with bilateral uveitis).

GRADE: low quality of evidence due to study limitations (no placebo/control group for comparison, possible confounding) and possible competing interests.

0.59-mg FA implant vs. standard of care therapy

Pavesio, 2010

Type of study:

multicentre RCT (37 centers in 10 countries)

Country:

France, Germany, Israel, Italy, Portugal, Saudi Arabia, Spain, Switzerland, Turkey, UK

Competing interests:

Sponsored by Bausch & Lomb, Inc., Rochester, New York. Four authors consultant or employee of Bausch & Lomb

Inclusion criteria:

Noninfectious posterior uveitis; quiet eyes at the time of treatment (only eye randomized to implant had to be quiet at the time of surgery); male or nonpregnant female aged ≥ 6 years; ≥ 1-year history of recurrent or recrudescent unilateral or asymmetric NIPU not associated with significant systemic activity of any underlying disease; more severely affected eyes with ≥ 2 separate recurrences of NIPU and the last episode occurring within 8 months of enrolment; more severely affected eyes were treated with systemic therapy (and immunosuppressive agents) for ≥ 1 month; less severely affected eyes with: VA of ≥ 0.7 logMAR (6/30) and uveitis requiring only periocular injections or no therapy; study eyes at time of enrollment: VA of ≥ 1.4 logMAR (6/150) and ≤ 10 anterior chamber cells/ high-power field and a vitreous haze grade ≤ 2

Exclusion criteria:

History of retinal detachment, retinoschisis in the area of implantation; media opacity precluding evaluation of the retina and vitreous; presence or history of uncontrolled IOP while receiving steroid therapy resulting in loss of vision; IOP > 25 mmHg requiring at least 2 antiglaucoma

medications to be reduced to < 25 mmHg; known allergy or contraindication to fluocinolone acetonide, systemic corticosteroids, or immunosuppressive agents; history of NIPU only or iritis only with no vitreitis, macular edema, vitreous cells, or vitreous haze; infectious cause; vitreous hemorrhage or a toxoplasma scar in the study eye; ocular surgery, trauma affecting the study eye, or both within 3 months before enrollment, or trabeculoplasty or yttrium–aluminum–garnet laser within 1 month of enrolment; monocularity for reasons other than uveitis; positive HIV test results, pregnancy or lactation; potential for noncompliance, or participation in other clinical studies within 1 month of enrolment.

Intervention: N=72

0.59-mg FA implant

Subjects in the implant group received the implant in only 1 eye (most severey affected in case of bilateral uveitis), followed by tapering of the steroids or other agents

Control: N=74

Standard of care (SOC) therapy

For patients treated with steroids alone at inclusion, the level of steroids was considered unsatisfactory so an immunosuppressive agent was added to lower the level of steroid

doses (4–6 weeks later to a minimum dose of 0.1 mg/kg daily). If

an immunosuppressive agent was not recommended, the SOC patients were managed by maintaining the level of systemic steroids at a higher level of > 0.2 mg/kg daily of prednisolone equivalent or by increasing steroids in case of activity. This would then be followed by a slow taper to a minimal dose of 0.2 mg/kg

daily or 10 mg/day for patients whose weight was more than 50 kg

This standardized therapy was maintained for at least 6 months.

For the SOC patients already treated with steroids plus immunosuppressive agents, steroids were maintained at a minimum dose of 0.1 mg/kg daily for at least 6 months, and then the treatment doses were tapered.

Concomitant medications

Medications allowed before, during, and immediately after the surgery included anesthetics, cyclopentolate hydrochloric acid 1% and phenylephrine 2.5% for dilation (administered 2 to 4 times beginning 30 minutes to 2 hours before surgery), balanced salt irrigating solution injected during surgery and to restore intraocular pressure (IOP) after surgery, and an antibiotic and a steroid to be injected subconjunctivally at the end of surgery. Medications prohibited during the study included oral, systemic, and ocular

steroids and immunosuppressive agents other than the study agents

Length of follow-up:

24 months

Lost to follow-up:

15/146=10.3%

n=6 (implant group) discontinued before treatment and were excluded from the intent-to-treat population.

Discontinuation before 2-year follow-up: AE (n=4 in implant group), withdrawal of consent (n=1 in SOC group), and loss to follow-up (n=1 for implant group, n=2 for SOC group).

Intention to treat analysis:

All randomized subjects who underwent at least 1 assessment after randomization were included in the intent-to-treat population, and all efficacy and safety summaries were based on the intent-to-treat population.

Primary efficacy outcome measure:

Time to first recurrence of uveitis in the study eye occurring in the 24 months after

randomisation for the SOC group and in the 24 months after the week 12 visit for the implant group.

Uveitis recurrence was defined as a 2-step

increase or more in the number of anterior chamber cells from baseline per high-powered field (1.6X using 1-mm beam), an

increase in the vitreous haze of 2 steps or more from baseline (graded with reference photographs provided to each study center), or deterioration in VA of 0.3 or more logMAR units from the best improved VA

since screening without alternate causes.

Secondary outcomes

recurrence rate (≥ 1 recurrence in 2-year treatment period), visual acuity (>15 letters on ETDS charts from baseline), CME, adverse events

Results:

Time to first recurrence

implant group: mean of 6.4 ± 7.0 months

SOC group: mean of 7.1 ± 7.2 months

The survival distribution was significantly better with implanted eyes than with SOC eyes (P < 0.01).

Recurrence rate

implant group: 18.2%

SOC group: 63.5%

p<0.01

Visual acuity (≥ 3 lines improvement)

implant group: 17.2%

SOC group: 14.3%

p=0.66

CME (> 1 mm² reduction in area by fluorescein angiography)

implant group: 86.5%

SOC group: 74.4%

p=0.003

Ocular adverse events (implant vs. SOC group)

Ocular adverse events related to treatment

95.5% vs. 39.2%

Cataract extraction

43/49 (87.8%) vs. 11/57 (19.3%); p<0.01

IOP lowering medication

41/66 (62.1%) vs. 15/74 (20.3%); p<0.01

IOP lowering surgery

14/66 (21.2%) vs. 2/74 (2.7%); p<0.01

Hypotony

13/66 (19.7%) vs. 1/74 (1.4%); p=0.0003

Other serious AE

endophthalmitis: n=3 vs. n=0

retinal detachment: n=1 vs. n=2

Randomisation method:

randomization code with

treatment randomization numbers assigned by a centrally administered randomization procedure. They were stratified by treatment site and according to the type of treatment being used at study entry: monotherapy (corticosteroid only), bitherapy (corticosteroid and 1 immunosuppressant), or tritherapy (corticosteroid and 2 immunosuppressants). A weighting factor was used, based on the

number of subjects previously assigned to each treatment group for each of the strata.

Blinding:

It was not possible to mask study treatments. Treatment allocation was masked to both the investigator and the subject through the use of an interactive voice response system that informed the investigator of the treatment group only after confirmation of inclusion of the subject. In addition, some assessments, including fluorescein angiography, fundus photogra-

phy, and laboratory parameters, were masked.

Study power criteria not met (A sample size of 75 subjects per treatment was determined to

have 85% power to detect a difference with respect to the primary end point in a 2-tailed test ( α= 0.05).

Study sponsored by Bausch & Lomb, Inc., Rochester. Four authors with competing interests.

GRADE: moderate quality of evidence due to lack of blinding, possible indirectness (strict in- and exclusion criteria) and possible competing interests.

0.59-mg FA implant vs. systemic therapy

MUST, 2011

Type of study:

multicentre RCT

(23 centres)

Country:

USA, Australia, UK

Competing interests:

Authors are consultant for several pharmaceutical companies (e.g. Alcon, Allergan, Sanofi, GSK, GenenTech, Medtronic, Roche)

Inclusion criteria:

age 13 years or older; diagnosis of non-infectious intermediate uveitis, posterior uveitis, or panuveitis by a MUST-certified ophthalmologist; active uveitis of a degree for which systemic corticosteroid therapy is indicated or such uveitis active within the last 60

days; uveitis with or without an associated systemic disease is acceptable if not interfering with therapy; BCVA of hand motions or better in at least one eye with uveitis; baseline intraocular pressure 24 mm Hg or less in all eyes with uveitis; collection of required baseline data within 10 days prior to randomization

Exclusion criteria:

Use of a fluocinolone acetonide implant within the last 3 years; DM inadequately controlled; known allergy to study medication; uncontrolled glaucoma; advanced glaucomatous optic nerve injury; history of scleritis; presence of an ocular toxoplasmosis scar; pregnancy or current breastfeeding; known HIV or other immunodeficiency disease for which corticosteroid therapy would be contraindicated; patients for whom participation in the trial would constitute a risk exceeding the potential benefits of study participation; medical problems or drug or alcohol dependence problems sufficient to prevent adherence to treatment and study procedures

Intervention: N=129 (245 eyes)

0.59-mg FA implant

Implant therapy began by using topical, periocular, or systemic

corticosteroids to suppress any anterior chamber inflammation. Implantation followed in the first eye within 28 days of randomization and in the second eye (if indicated)

within 28 additional days. The protocol dictated tapering and discontinuation of any systemic corticosteroids and immunosuppressive drugs initially in use after implant placement. Second eyes for which implantation was not indicated could be managed using nonsystemic treatments.

Control: N=126 (234 eyes)

Systemic therapy

Patients with active inflammation at baseline received 1 mg/kg/day up

to 60 mg/day of prednisone until either the uveitis was controlled

or 4 weeks had elapsed. After control was achieved, prednisone

was tapered per study guidelines.

Cases already suppressed at

baseline began by tapering from their initial prednisone dose.

Immunosuppression indicated for 1) failure to initially control inflammation using corticosteroids; (2) corticosteroid-sparing in cases consistently reactivating before reaching a prednisone dose of 10 mg/day; and (3) specific high-risk uveitis syndrome.

Length of follow-up:

24 months

Lost to follow-up:

implant group: 11/129=8.5%

systemic group:

12/126=9.5%

Intention to treat analysis:

yes

Primary outcome measure:

Change in BCVA from baseline to

24 months

Other outcome measures

uveitis activity/control, complications, patient-reported vision- and general health-related quality of life

Results:

Change in BCVA

implant group: +6.0 letters

systemic group: +3.2 letters

p=0.16

Uveitis control rate

implant group: 88%

systemic group: 71%

p=0.001

CME

implant group: 22%

systemic group: 30%

p=0.071

IOP lowering therapy / surgery

implant group: 61.1% / 26.2%

systemic group: 20.1% / 3.7%

p<0.0001

Cataract / cataract surgery

implant group: 90.7% / 80.4%

systemic group: 44.9% / 31.3%

p<0.0001

Other serious adverse events (implant vs systemic)

Glaucoma

17% vs 4.0%

vitreous haemorrhage

16% vs 5%

hypotony

8.4 vs 6.1%

endophthalmitis

1.3% vs 0%

retinal detachment

2.1% vs 0.44%

Vision related QoL (mean change)

implant group: 11.44

systemic group: 6.80

p=0.043

By 24 months both groups had improved, leaving a modest 4.6-unit advantage for the implant group (P=0.04), on the order of the

reported minimally important difference (4–6 units).

Randomisation method:

Randomization (1:1 ratio) was by variable length, permuted blocks within 2 strata (clinical center, intermediate vs posterior or panuveitis), with assignments produced by Stata 11.0

Blinding:

Patients, clinicians, and coordinators were not masked. Visual acuity examiners were masked, except for the 1- and 3-month visits, when postoperative

signs were expected to be visible. Reading Center image evaluations for ocular sequelae

of uveitis and of therapy, and glaucoma assessments all were

masked.

The protocol was modified during early enrolment, broadening eligibility to improve recruitment and make results more generalizable.

GRADE: moderate quality of evidence due to lack of blinding, possible indirectness (modified in- and exclusion criteria) and possible competing interests.