Clinical-Decision Criteria to Identify Recurrent Diabetic Macular Edema Patients Suitable for Fluocinolone Acetonide Implant Therapy (ILUVIEN^®) and Follow-Up Considerations/Recommendations

Figures & data

Table 1 Comparison of Available Intravitreal Corticosteroid Agents

Agent	Total Dose (Daily Release)	Formulation	Procedure	Duration of Action of 1 Injection	Primary Endpoint	Number of Treatments Over 36 Months in RCTs	Number of Treatments Over 12 Months in Real Life	Licensed DME Indication	Reference(s)
DEX	700 μg (~6.25 μg/day) OZURDEX^®	Biodegradable	Injectable 22 gauge needle/stepped incision	~4 months	% ≥15 letter gain in BCVA at year 3; 22% vs 12%; p<0.001 (OZURDEX vs sham group)	5.0	N/A	Adult patients with visual impairment due to DME who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for, non-corticosteroid therapy	[^Citation11,Citation57]
					Systematic review of real-life studies	N/A	2.6		[^Citation13]
IVTA	4 mg TA (unknown)	Preservative-free	Injectable 25 gauge needle/standard intravitreal injection	~3 months	3-year extension: mean BVCA = +5 with laser vs +0 with TA	4.1	N/A	Not licenced in the EU	[^Citation96]
FAc	190 μg (0.2 μg/day) ILUVIEN^®	Nonbioerodible (polyimide tube)	Injectable 25 gauge needle/standard intravitreal injection	Up to 3 years	≥15 letter gain (chronic DME) 34% vs 13%; p<0.001 (ILUVIEN vs sham group)	1.3	1	Vision impairment associated with chronic DME considered insufficiently responsive to available therapies	[^Citation7,Citation70]

Notes: Adapted from Kane et al, 2008.⁶⁶

Abbreviations: BCVA, best corrected visual acuity; DEX, dexamethasone; DME, diabetic macular edema; FAc, fluocinolone acetonide; IVTA, intravitreal triamcinolone acetonide; N/A, not applicable; RCT, randomized controlled trial; TA, triamcinolone acetonide.

Figure 1 FA levels in human aqueous humor in subjects receiving one ILUVIEN^® implant (FAMOUS Study).

Notes: Data from Campochiaro et al.¹² FAc, 0.2 μg/day fluocinolone acetonide (ILUVIEN).

Table 2 Key Clinical Trial and Real-World Studies Demonstrating Effectiveness of 0.19 Mg Fluocinolone Acetonide Implant

Study Name (Author)	Region (Study Type)	No. of Eyes	Mean no. Prior Intravitreal Injections	Follow-Up Period	Mean ETDRS Letter Gains	Mean Decrease in CRT	IOP-Lowering Medication	Mean Supplemental Therapies and Time to Administration
Phase III trials
Fluocinolone Acetonide in Diabetic Macular Edema studies; FAME A and B^Citation7,Citation75	USA, Canada, EU, India (Two multicenter, randomized double-blind, parallel group studies)	953	N/A – laser given as a prior therapy	36 months	At 36 months + 5.3 (full DME group) + 7.6 (chronic DME group)	At 36 months -181 μm (full DME group) -186.8 µm (chronic DME group)	At 36 months 38.4% (full DME group) 35.9% (chronic DME group)	At 36 months 40.7% laser and 13.4% including anti-VEGF and IVTA (chronic DME group)
European real-world studies (≥81 eyes, multicenter)
ILUVIEN® Registry Safety Study; IRISS^Citation38	UK, Germany, Portugal (Observational study)	593	5.3 ranibizumab (66.3%), 3.3 bevacizumab (28.8%), 4.0 aflibercept (5.2%), 1.4 dexamethasone implant (19.2%), 2.7 ocular corticosteroids (22.6%), (full group)	~15 months (471.2 days; range, 1–1269 days)	At 12 months +3.7 (all DME eyes) Chronic DME (pseudophakic eyes): s hort-standing chronic DME = +8.2; and, l ong-standing chronic DME = +1.7	Not recorded	Overall 23.3%	Overall Anti-VEGF, corticosteroid therapies, laser and ILUVIEN retreatment (31.0%) The mean time to additional treatment was 356.1±274.8 days.
MEDISOFT Audit Group^Citation39	UK (Retrospective analysis)	345	Mean: 7.36 intravitreal treatments including ranibizumab (68.4%), IVTA (29.0%), dexamethasone implant (5.5%) (full group)	~14.1 months (428 days; range, 0–919 days)	At 24 months +5.3 (all DME eyes) +5.8 (DME, pseudophakic eyes)	Overall -95.7 μm	Overall 13.9%	Overall Anti-VEGF, corticosteroid therapies (ILUVIEN retreatment) and laser (35.7%) A mean of 4.4 intravitreal therapies were administered
Retro-IDEAL^Citation94	Germany (Retrospective study)	81	4.3 ranibizumab (91.1%), 4.3 bevacizumab (91.1%), 5.0 aflibercept (6.3%), 1.5 dexamethasone implant (24.1%), 1.1 IVTA (41.8%) (full group)	30.8 months^Citation92	At 36 months +2.7 At 30 months (ie mean follow-up period) +4.3	At 36 months -158.0 μm At 30 months -111.0 μm	Overall 49.4% (27.2% were emergent IOP cases)	Overall Anti-VEGF and corticosteroid therapies (30.9%) 16% of supplemental treatments were given by Month 12 with a further 40% administered between 12 and 24 months
European real-world studies reporting 3 years of follow-up (n>1, single center)
Panos et al.^Citation76	UK	24	4.8 ranibizumab (58.3%); 1.1 IVTA (29.2%)	36 months (n=9/24)	At 36 months +7.5 letters (from 0.62 to 0.47 logMAR)	At 36 months -93.0 μm	Overall 20.8%	54.2% (n=13/24) patients received supplemental injections of anti-VEGF or corticosteroid. Mean time to supplementary treatment was 13.5 (range: 3–27) months
Rehak et al.^Citation77	Germany	49	6.74 anti-VEGF (100.0%); 1.27 dexamethasone implant (51.0%) (full group)	36 months (n=19/49)	At 36 months Group A: +10.6 (switched from anti-VEGF to ILUVIEN) (n=12) Group B: +9.7 (switched from anti-VEGF to dexamethasone and then to ILUVIEN) (n=7)	At 36 months Group A: −257.6 μm Group B: −245.6 μm	At 36 months 28.6%	Overall Group A: 37.5% including anti-VEGF, dexamethasone implant and a second ILUVIEN implant Group B: 36.0% including anti-VEGF and anti-VEGF Mean time to supplemental treatment was: Group A, 22.7 months; and, Group B, 21.8 months
Young et al.^Citation78	UK	21	4.7 bevacizumab (52.4%), 11.7 ranibizumab (66.7%), 7.7 aflibercept (14.3%), 1.3 dexamethasone implant (19.0), 1.4 IVTA (23.8%) (full group)	36 months (n=10/21)	At 36 months +9.3	At 36 months -157.8 μm	Overall 38.1%	At 36 months 13.1 anti-VEGF (30.0% [n=3/10])
Fusi-Rubiano et al.^Citation79	UK	29	4.3 bevacizumab (62.1%), 3.9 ranibizumab (58.6%), 2.3 IVTA (55.2%) (full group)	36 months (n=6/29)	At 36 months +11.0	At 36 months -137.0 μm	Overall 6.9%	At 36 months 5.0 anti-VEGF or laser (83.3% [n=5/6]) Mean time to supplementary treatment was 12.8 (range: 10–16 months)

Notes: For the group “European real-world studies reporting 3 years of follow-up”, data is presented at the 36-month time point if it was reported in the paper, otherwise the overall numbers are reported and refer to the full group analysed.

Abbreviations: CRT, central retinal thickness; DEX, dexamethasone; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; IOP, intraocular pressure; IVTA, intravitreal triamcinolone acetonide; N/A, not applicable; SD, standard deviation; VEGF, vascular endothelial growth factors.

Figure 2 Percentage of subjects with ≥15 letter improvement from baseline in best corrected visual acuity (BCVA) at 24 and 36 months in patients with DME treated with 0.2 μg/day FAc implant versus sham injection.

Notes: Data from Campochiaro et al.⁷, and ILUVIEN^® Spanish Summary of Product Characteristics.⁷⁰ *P = 0.002 FAc vs sham at Month 24; **P < 0.018 FAc vs sham at Month 36; ***P < 0.001 FAc vs sham for both at Month 24 and 36. Full study population, N= 376 (FAc), N = 185 (sham); Chronic DME subgroup, N = 207 (FAc), N = 111 (sham).

Abbreviation: DME, diabetic macular edema; FAc, 0.2 μg fluocinolone acetonide (ILUVIEN).

Figure 3 Mean gains in best corrected visual acuity (BVCA) from baseline at 24 and 36 months in patients with chronic DME treated with 0.2 μg/day FAc implant.

Notes: *P = 0.35 vs sham at Month 24; **P = 0.04 vs sham at Month 36.; FAc, 0.2 μg fluocinolone acetonide.

Abbreviations: DME, diabetic macular edema; FAc, 0.2 μg fluocinolone acetonide (ILUVIEN^®).

Figure 4 Mean central foveal thickness (CFT) change in patients with chronic DME treated with 0.2 μg/day FAc implant.

Notes: Data from Campochiaro et al.⁷, and ILUVIEN^® Spanish Summary of Product Characteristics.⁷⁰ *P = 0.005 vs sham at Month 24.

Abbreviation: DME, diabetic macular edema; FAc, 0.2 μg fluocinolone acetonide (ILUVIEN).

Figure 5 ILUVIEN^® indication and follow-up pathway.

Figure 6 Algorithm for the management of IOP elevation by retinal specialists: pre- (top panels) and post-corticosteroid injection (bottom panels).

Note: Adapted from Goni et al.⁹³

Table 3 General Pre- and Post-Injection Action Protocol for FAc Implant Treatment

Medical Exam (Pre-injection)

An OCT examination should be performed to detect signals of ellipsoid zone integrity, hyperreflective dots, DRIL and intraretinal or subretinal fluid, and to generate an image of what the patient’s prognosis could be.

Goldmann applanation tonometry and retinal nerve fiber layer OCT analysis, as well as visual field examination (optional), should be performed in order to obtain baseline information about the IOP level, optic disc anatomy and cup-to-disc ratio. This baseline information will be useful to compare with future follow-up information.

The use of the FAc implant in aphakic patients should be analyzed according to the benefit–risk assessment because of the risk of migrating the implant into the anterior chamber.

Comment from the group of experts: Most physicians adhere to the published summary of product characteristics (SmPC) showing that glaucoma is considered a contraindication for the use of the FAc implant.^Citation70

Follow-up checks for 36 months (post-injection)

Check at one week post-injection to exclude any adverse effects related to the intravitreal injection, and then follow the patient every 3 months (eg, using information from the SmPC).^Citation70

In the follow-up visits, the anatomical efficacy of the treatment should be tested using OCT to look at central macular thickness (CMT) and macular volume. The functional efficacy (ie, BCVA) should be checked. Fundus and diabetic retinopathy status/progression should also be checked.

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