“Intravitreal fluocinolone acetonide implant: a prospective, pilot study on patients with chronic diabetic macular edema”

doi:10.21203/rs.3.rs-2343565/v1

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“Intravitreal fluocinolone acetonide implant: a prospective, pilot study on patients with chronic diabetic macular edema”

https://doi.org/10.21203/rs.3.rs-2343565/v1

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OBJECTIVES: To analyze the clinical efficacy and safety profile of intravitreal 0.19 mg fluocinolone acetonide (FAc) implant (Iluvien®) in patients with chronic/ refractory diabetic macular edema (DME)
SUBJECTS/METHODS: This a prospective, cross-sectional pilot study enrolling patients with chronic DME, previously treated with intravitreal anti-vascular endothelial growth factors (VEGF) agents and/or intravitreal corticosteroids. The primary endpoints were the modifications in best-corrected visual acuity (BCVA) and central macular thickness (CMT) during the follow-up. Secondary endpoints were recurrence rate, the presence of systemic and/or ocular adverse events (AEs), including changes in intraocular pressure (IOP).

RESULTS: Fourteen eyes of 11 patients were enrolled in this study. Average follow-up period was 18.7 months ± 8.2. Baseline BCVA improved from 59.6 letters to 61.1 letters after 1 month (p=0.994), 63.1 letters after 3 months (p=0.819), 63.7 letters after 6 months (p=0.635), 68.7 letters after 12 months (p=0.07) and 67.7 letters after 18 months (p=0.505). Baseline CMT significantly decreased from 378 µm before Fac treatment to 336 µm after 1 month (p= 0.034), 320 µm after 3 months (p= 0.015), 329 µm after 6 months (p= 0.05), 314 µm after 12 months (p= 0.0025) and 271 µm after 18 months (p= 0.001). Eight eyes (57.1%) needed to be re-injected with anti-VEGF drugs within 12 months and only one (7.1%) was retreated with DEX implant.
No systemic and/ocular AES were reported, including significant variations in IOP.

CONCLUSIONS: FAc implant can be considered an effective and safe treatment option in patients with chronic/refractory DME.

Health sciences/Medical research/Drug development

Health sciences/Diseases

Health sciences/Health occupations

Health sciences/Medical research

Health sciences/Neurology

Health sciences/Pathogenesis

Health sciences/Risk factors

Health sciences/Signs and symptoms

Physical sciences/Optics and photonics

fluocinolone acetonide

Iluvien

diabetic macular edema

intravitreal injections

diabetic retinopathy

chronic macular edema

Diabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetic retinopathy (DR) and its management still represents a compelling issue (1). In fact, due to the growing prevalence of diabetes in the global population and the increased life expectancy, in the near future other effective and longer-lasting treatment options should be provided for patients with DME (2).

Anti-vascular endothelial growth factors (VEGF) drugs are generally the first-line treatment for DME (3); however, a non-negligible percentage of patients is insufficiently responsive to these agents and the frequent injections and close monitoring represent an important limitation (4) (5). Considering the increasing evidence of the role of inflammation behind the pathogenesis of DME, intravitreal corticosteroids have been developed with aim of reducing the overexpression of proinflammatory cytokines, inhibiting vascular permeability and neovascularizations (6). Currently, corticosteroids implants, including intravitreal dexamethasone (DEX) and fluocinolone acetonide (FAc), are commonly adopted as an important alternative treatment option for treating DME (7) (8). FAc intravitreal implant (ILUVIEN® Alimera Sciences, Inc., Alpharetta, GA, USA) was approved in 2014 by FDA and it consists of a non-degradable micro implant releasing in the vitreous 0.19 mg of the molecule with a durability of 36 months (9) (10). FAc implant has the clinical indication for the management of visual loss due to chronic/relapsing DME, which is insufficiently responsive to other first-line available therapies (11). After the pivotal FAME trial, other real-life studies provided promising results about FAc clinical efficacy and safety profile (12–18); however, despite the encouraging results documented, there is still need of further real-life evidence of Fac clinical outcomes.

The aim of this prospective study is to examine the real-world clinical efficacy and safety profile of the FAc implant in patients with chronic/relapsing DME.

Study Design

This prospective, observational, monocenter study was conducted at the University Eye Clinic of Genoa- IRCCS Polyclinic San Martino Hospital (Genoa, Italy) and it enrolled patients with chronic DME, which was defined by the presence of persistent and/or relapsing macular edema lasting for at least 2 years. A single injection of the 0.19 mg FAc micro-implant (Illuvien®; Alimera Sciences, Inc, Alpharetta, GA, USA) was delivered to the examined subjects. Inclusion criteria were the following: diagnosis of diabetic retinopathy assessed by optical coherence tomography (OCT) imaging with the presence of chronic DME, pseudophakia, previous treatment with intravitreal anti-VEGF and/or other corticosteroids (DEX) and/or laser photocoagulation, a wash-out period of at least 2 months since the previous anti-VEGF therapy or 6 months since the last DEX implant. In this study, patients who met the following criteria were excluded: phakia, a medical history of ocular hypertension and/or glaucoma, vitreomacular traction syndrome, previous ocular surgery including pars plan vitrectomy, active or previous ocular infections and pregnancy.

All the subjects underwent a complete ophthalmological examination, including best corrected visual acuity (BCVA) expressed in ETDRS letters, slit-lamp examination, intraocular pressure (IOP) measurement with Goldmann applanation tonometry, a indirect fundus biomicroscopy and structural OCT scans, measuring the central macular thickness (CMT) as a biomarker of disease activity.

After the baseline visit, all the study subjects were evaluated at months 1, 3, 6, 9, 12, 18 after the FAc intravitreal injection.

Optical coherence tomography device

All the subjects underwent swept-source OCT (SS-OCT) examinations, after pupil dilation with mydriatic tropicamide 1% ophthalmic drops. It was used a SS-OCT device (DRI OCT Triton; Topcon Corporation), which is characterized by a central wavelength of 1050 nm with an acquisition speed of 100.000 A-scans per second and an axial and transversal resolution of 7 and 20 µm in tissue, respectively. Each subject was analyzed with a 12-radial line (12 mm) acquisition centered on the fovea.

Statistical analysis

The SPSS statistical software (SPSS, Inc, Chicago, Illinois, USA) was adopted for data analysis. Values are expressed as mean ± standard deviation (SD). A one-way ANOVA test was performed to compare continuous variables among the different follow-up visits. Paired- samples t Test was used to compare the means between baseline and before treatment groups in subgroup analysis. Post hoc comparisons were done by using the Tukey’s test. Statistical significance was set at p < 0.05.

Demographic features

Overall, 14 eyes of 11 patients were included in this prospective study. Among them, 8 subjects were males (72.7%) and 3 were females (27.3%). 7 eyes (50%) were right, whereas the remaining 7 (50%) were left. The average age was 70.2 years ± 7.7. The mean duration of the chronic DME was 76.7 months ± 16.6. At baseline, the average BCVA was 59,6 letters ± 8,4 (ETDRS) and the mean CMT was 378 µm ± 53 in the study population. The average IOP was 16.2 mmHg ± 2.2 at baseline.

All the patients were previously treated with intravitreal anti-VEGF drugs and/or intravitreal corticosteroids (DEX implant). In particular, patients were previously treated with on average 4,9 ± 2,1 DEX implants and 8,5 ± 8,8 of anti-VEGF intravitreal injections. Among them, 10 eyes (71.4%) underwent combined therapy between anti-VEGF agents and DEX implants, while 4 eyes (28.6%) were treated with DEX implants only (Table 1). The mean follow-up period was 18.7 months ± 8.2. Among the treated eyes, 8 of them (57.1%) needed to be re-injected as soon as 6 months since FAc implant. On average, these eyes were retreated with 1.3 ± 0.8 anti-VEGF drugs, while only one eye (7.1%) of them was retreated with DEX implant.

Table 1

Demographic features of the study population
Number of patients included	11	CMT at baseline (µm)	378 ± 53
Number of eyes included	14	BCVA at baseline (ETDRS letters)	59.6 ± 8.4
Mean Age	70.2 ± 7.7	Average number of previous anti-VEGF injections	8.5 ± 8.8
M/F	8/3	Average number of previous DEX implants	4.9 ± 2.1
BCVA = Best-corrected visual acuity; CMT = Central macular thickness; DEX = Dexamethasone

Central macular thickness (CMT)

During the follow-up period it was found a significant reduction in CMT in comparison with baseline. It was found a decrease in CMT from 378 ± 53 µm before Fac treatment to 336 µm after 1 month (p = 0.034), 320 ± 48 µm after 3 months (p = 0.015), 329 ± 52 µm after 6 months (p = 0.05), 314 ± 57 µm after 12 months (p = 0.0025) and 271 ± 59 µm after 18 months (p = 0.001) in comparison with baseline. (Fig. 1) (Table 2). Multiple comparisons with ANOVA test revealed a further significant decrease in CMT between the last follow-up visit after 18 months and those after 3 and 12 months, respectively (p = 0.03 and p = 0.019). In subgroup analysis, those 8 eyes which needed to be retreated with either anti-VEGF agents or DEX implants showed a not statistically decrease in CMT from 376 µm to 361 µm (p = 0.451)

Table 2

**Central macular thickness (CMT) modifications during the follow-up visits**
	Before treatment	1 month	3 months	6 months	12 months	18 months
Average CMT (µm)	378.31	335.76	320.16	329.30	314.66	271.25
P value	-	* 0.034	* p = 0.015 § p = 0.505	* p = 0.05 § p = 0.794 # p = 0.712	* p = 0.025 § p = 0.452 # p = 0.844 £ p = 0.616	* p = 0.001 § p = 0.03 # p = 0.098 £ p = 0.059 ^ p = 0.0192
* vs Before treatment; § vs 1st month; # vs 3rd month; £ vs 6t^h month; ^ vs 12th month

Best-corrected visual acuity (BCVA)

BCVA remained stable along all the follow-up visits, varying from baseline 59.6 ± 8.4 letters to 61.1 ± 8.1 letters after 1 month (p = 0.994), 63.1 ± 7.7 letters after 3 months (p = 0.819), 63.7 ± 7.8 letters after 6 months (p = 0.635), 68.7 ± 8.2 letters after 12 months (p = 0.07) and 67.7 ± 8.4 letters after 18 months (p = 0.505) (Fig. 2) (Table 3).

Table 3

**Best-corrected visual acuity (BCVA) modifications during the follow-up visits**
	Before treatment	1 month	3 months	6 months	12 months	18 months
Average BCVA (letters ETDRS)	59.6	61.1	63.1	63.7	68.7	67.7
P value	-	* 0.994	* p = 0.819 § p = 0.983	* p = 0.635 § p = 0.999 # p = 0.712	* p = 0.076 § p = 0.217 # p = 0.556 £ p = 0.758	* p = 0.505 § p = 0.802 # p = 0.986 £ p = 0.999 ^ p = 0.941
* vs Before treatment; § vs 1st month; # vs 3rd month; £ vs 6t^h month; ^ vs 12th month

No significant differences were also found in multiple comparisons between the different follow-up visits. In subgroup analysis, those 8 eyes which needed to be retreated with either anti-VEGF agents or DEX implants had a non-significant mean gain of + 3.0 letters after the intravitreal injection (from 63.4 to 66.4 ETDRS letters, p = 0.213)

Safety and tolerability

Overall, no severe ocular and/or systemic adverse events (AEs) were referred in the study population. The mean IOP at baseline was 16.8 mmHg ± 2.2, increasing to 19.2 mmHg ± 3.3 after 1 month and decreasing to 16.6 mmHg ± 2.3 after 6 months and 16.4 mmHg ± 2,1 after 12 months, showing no significant differences between the follow-up visits (p = 0.4).

The management of DME can be challenging in a non-negligible percentage of patients, in which the repeated administration of anti-VEGF drugs to avoid edema recurrence has not been effective or in some cases is not possible for their compliance and/or willingness (19). In these patients, corticosteroids represent a viable option and, among them, Fac implant is an excellent long-acting agent whose clinical activity has been reported to last until 36 months (20).

In this study, we found that FAc led to a rapid and significant reduction in CMT after the first month, which was maintained thinner than baseline during all the follow-up visits until 18 months. Interestingly, there was a mean reduction of 107 µm in the CMT after the 18-month follow-up period. In terms of functional outcomes, we found a stability of BCVA during all the follow-up visits, with a mean gain of + 8.1 letters.

Our morphological results are in line with previous studies, in which CMT has been proven to rapidly decrease of roughly 150–200 µm after 1 month post-FAc implantation and then these reductions are reported to be stable after 1 year and 2 years of follow-up, respectively (21) (13, 22). In particular, in our study the decrease in CMT was more limited after the first month post-FAc implantation (42 µm) and then it reached its zenith after 18 months (107 µm), which is slightly lower than the average reductions reported in previous studies probably due to the long-standing course of DME (76.7 months ± 16.6).

In regard with BCVA, the mean visual gain obtained (+ 8.1 letters) was stable (even if not statistically significant) and 14.2% (n = 2/14) of the eyes had a visual gain of 15 letters or more. Some previous clinical studies have reported more significant improvements in BCVA (21) (13) (22). In fact, in the FAME pivotal trial 28.7% of the FAc-treated patients showed an improvement of 15 letters or more after 2 years (23). In another real-life study, about 17% and 33% of Fac-treated patients with DME had an improvement of 15 letters or more at 3 and 12 months, respectively (15). Other studies reported percentages of patients achieving 15 letter or more varying from 18% and 25% (21) (13). By contrast, a real-life UK study revealed an average gain of + 5.1 letters after 12 months from FAc implantation (24), showing poorer visual outcomes in comparison with our study. Moreover, other real-life studies provided lower visual outcomes, with BCVA gains ranging from + 3.8 to 5.0 letters after 12 months (25). In our study, the long-standing course of the chronic DME in association with the multiple injections before FAc implant may have led to a higher percentage of disorganization of the inner retinal layer (DRIL) in comparison with previous studies, in which an early-switch to Fac has been performed (15). In this regard, it is known that the presence of DRIL is predictive for visual function recovery (26).

All the eyes included in this study were previously treated with at least one DEX implant, showing a good clinical answer (functional and morphological) in comparison with baseline. These findings are in line with prior consistent evidence of Fac clinical efficacy after previous DEX implant (27, 28).

FAc safety and tolerability profile is well-established, and this present study showed no presence of severe ocular and/or systemic AEs. Moreover, no significant variations in IOP were reported, without the need to adopt a IOP-lowering treatment in our patients. We deem that the pre-selection due to previous DEX implant has allowed us to avoid IOP rises in the subgroup of patients with a medical history of ocular hypertension and/or glaucoma.

This study has some limitations, including the relatively small sample size of the study population e the short follow-up period. Further evidence is needed with a larger sample size and longer follow-up periods (more than 2 years).

In conclusion, FAc implant showed a favorable clinical efficacy profile, leading to a consistent and long-lasting morphological improvement and moderate visual gain and stability; nonetheless, FAc implant had an optimal safety and tolerability profile.

STATEMENT OF ETHICS

This study adhered to the tenets of Helsinki’s declaration. This study has been granted an exemption from requiring ethics approval by the IRCCS San Martino Polyclinic Hospital Ethics Committee, because the investigated drug is already approved and has the indication for patients with DME.

CONSENT TO PARTECIPATE CONSENT

A written informed consent to participate in the study has been obtained from all the study subjects

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

FUNDING SOURCES

This article was not funded and/or sponsored.

AUTHOR CONTRIBUTION STATEMENT

All the authors contributed to the conception and design of the work. MN, LFD, RR, AV, AC contributed to acquisition, PC, CET and DM contributed to analysis and MN, LFD and CET to interpretation of data for the work. MN, LFD and AV contributed to drafting and revising the work.
All the authors contributed to final approval.

DATA AVAILABILITY STATEMENT

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Bandello F, Battaglia Parodi M, Lanzetta P, Loewenstein A, Massin P, Menchini F, et al. Diabetic Macular Edema. Dev Ophthalmol. 2017;58:102-38.
Koye DN, Magliano DJ, Nelson RG, Pavkov ME. The Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic Kidney Dis. 2018;25(2):121-32.
Diabetic Retinopathy Clinical Research N, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-203.
Gonzalez VH, Campbell J, Holekamp NM, Kiss S, Loewenstein A, Augustin AJ, et al. Early and Long-Term Responses to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Analysis of Protocol I Data. Am J Ophthalmol. 2016;172:72-9.
Nicolo M, Morlacchi A, Cappelli F, Ferro Desideri L, Colombo V, Musetti D, et al. Real-Life Data in the Treatment of Neovascular Age-Related Macular Degeneration: Results from the Imaculaweb Registry Evaluated in a Single Italian Medical Retina Center. Ophthalmologica. 2020;243(6):453-60.
Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of Corticosteroids for Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018;59(1):1-12.
Szymanska M, Mahmood D, Yap TE, Cordeiro MF. Recent Advancements in the Medical Treatment of Diabetic Retinal Disease. Int J Mol Sci. 2021;22(17).
Boyer DS, Yoon YH, Belfort R, Jr., Bandello F, Maturi RK, Augustin AJ, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-14.
Campochiaro PA, Brown DM, Pearson A, Chen S, Boyer D, Ruiz-Moreno J, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125-32.
Augustin AJ, Bopp S, Fechner M, Holz F, Sandner D, Winkgen AM, et al. Three-year results from the Retro-IDEAL study: Real-world data from diabetic macular edema (DME) patients treated with ILUVIEN((R)) (0.19 mg fluocinolone acetonide implant). Eur J Ophthalmol. 2020;30(2):382-91.
Saedon H, Anand A, Yang YC. Clinical utility of intravitreal fluocinolone acetonide (Iluvien((R))) implant in the management of patients with chronic diabetic macular edema: a review of the current literature. Clin Ophthalmol. 2017;11:583-90.
Soubrane G, Behar-Cohen F. [Fluocinolone acetonide (ILUVIEN(R)) micro-implant for chronic diabetic macular edema]. J Fr Ophtalmol. 2015;38(2):159-67.
Figueira J, Henriques J, Amaro M, Rosas V, Alves D, Cunha-Vaz J. A Nonrandomized, Open-Label, Multicenter, Phase 4 Pilot Study on the Effect and Safety of ILUVIEN(R) in Chronic Diabetic Macular Edema Patients Considered Insufficiently Responsive to Available Therapies (RESPOND). Ophthalmic Res. 2017;57(3):166-72.
Pessoa B, Coelho J, Correia N, Ferreira N, Beirao M, Meireles A. Fluocinolone Acetonide Intravitreal Implant 190 mug (ILUVIEN(R)) in Vitrectomized versus Nonvitrectomized Eyes for the Treatment of Chronic Diabetic Macular Edema. Ophthalmic Res. 2018;59(2):68-75.
Pacella F, Pacella E, Trovato Battagliola E, Malvasi M, Scalinci SZ, Turchetti P, et al. Efficacy and safety of intravitreal Fluocinolone Acetonide microimplant (ILUVIEN((R))) in patients with chronic diabetic macular edema: 1 year follow-up. Eur J Ophthalmol. 2021:11206721211020203.
McCluskey JD, Kaufman PL, Wynne K, Lewis G. Early adoption of the fluocinolone acetonide (FAc) intravitreal implant in patients with persistent or recurrent diabetic macular edema (DME). Int Med Case Rep J. 2019;12:93-102.
Bailey C, Chakravarthy U, Lotery A, Menon G, Talks J, Medisoft Audit G. Extended real-world experience with the ILUVIEN(R) (fluocinolone acetonide) implant in the United Kingdom: 3-year results from the Medisoft(R) audit study. Eye (Lond). 2021.
Chakravarthy U, Taylor SR, Koch FHJ, Castro de Sousa JP, Bailey C, Group IRSSI. Changes in intraocular pressure after intravitreal fluocinolone acetonide (ILUVIEN): real-world experience in three European countries. Br J Ophthalmol. 2019;103(8):1072-7.
Ghanchi F, Bourne R, Downes SM, Gale R, Rennie C, Tapply I, et al. An update on long-acting therapies in chronic sight-threatening eye diseases of the posterior segment: AMD, DMO, RVO, uveitis and glaucoma. Eye (Lond). 2022.
Panos GD, Arruti N, Patra S. The long-term efficacy and safety of fluocinolone acetonide intravitreal implant 190 mug (ILUVIEN((R))) in diabetic macular oedema in a multi-ethnic inner-city population. Eur J Ophthalmol. 2021;31(2):620-9.
Eaton A, Koh SS, Jimenez J, Riemann CD. The USER Study: A Chart Review of Patients Receiving a 0.2 microg/day Fluocinolone Acetonide Implant for Diabetic Macular Edema. Ophthalmol Ther. 2019;8(1):51-62.
Elbarky AM. Effectiveness and tolerability of the fluocinolone acetonide implant in patients with diabetic macular edema in UAE: 12-Month results. Eur J Ophthalmol. 2021;31(6):3196-202.
Campochiaro PA, Brown DM, Pearson A, Ciulla T, Boyer D, Holz FG, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-35 e2.
El-Ghrably I, Steel DHW, Habib M, Vaideanu-Collins D, Manvikar S, Hillier RJ. Diabetic macular edema outcomes in eyes treated with fluocinolone acetonide 0.2 microg/d intravitreal implant: real-world UK experience. Eur J Ophthalmol. 2017;27(3):357-62.
Holden SE, Kapik B, Beiderbeck AB, Currie CJ. Comparison of data characterizing the clinical effectiveness of the fluocinolone intravitreal implant (ILUVIEN) in patients with diabetic macular edema from the real world, non-interventional ICE-UK study and the FAME randomized controlled trials. Curr Med Res Opin. 2019;35(7):1165-76.
Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol. 2014;132(11):1309-16.
Rehak M, Busch C, Unterlauft JD, Jochmann C, Wiedemann P. Outcomes in diabetic macular edema switched directly or after a dexamethasone implant to a fluocinolone acetonide intravitreal implant following anti-VEGF treatment. Acta Diabetol. 2020;57(4):469-78.
Rittiphairoj T, Mir TA, Li T, Virgili G. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2020;11:CD005656.

No competing interests reported.

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“Intravitreal fluocinolone acetonide implant: a prospective, pilot study on patients with chronic diabetic macular edema”

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Abstract

Figures

Introduction

Matherial And Methods

Study Design

Optical coherence tomography device

Statistical analysis

Results

Demographic features

Central macular thickness (CMT)

Best-corrected visual acuity (BCVA)

Safety and tolerability

Discussion

Declarations

References

Additional Declarations

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