Effectiveness and safety of fluocinolone acetonide intravitreal implant in diabetic macular edema patients considered insufficiently responsive to available therapies (REACT): a prospective, non-randomized, and multicenter study

Objective To assess the effectiveness and safety of the intravitreal fluocinolone-acetonide implant (FAc-i) in patients with chronic diabetic macular edema who did not sufficiently respond to other available therapies. Methods This was a multicenter, prospective, non-randomized, and phase-IV observational study conducted on patients with recurrent-DME who were insufficient responders to currently available therapies (REACT-Study). The primary end-point was the mean change in best-corrected-visual-acuity from baseline to month-24 values. Results Thirty-one eyes from 31 patients were included in the study. Mean age was 68.0 ± 7.7 years, and 10 (32.3%) were women. Study patients had received 5.3 ± 7.3 previous DME treatments before starting the study. In the overall study sample, BCVA improved from 56.1 ± 12.3 letters at baseline to 62.4 ± 17.0 letters at month-24 (p = 0.0510). The eyes with a baseline BCVA < 70 ETDRS letters had a significant improvement in BCVA from 53.2 ± 10.2 letters at baseline to 61.5 ± 17.9 letters at month-24 (p = 0.0165). In the overall study population, central-subfoveal-thickness (CST) was significantly reduced from 474.0 ± 135.1 µm at baseline to 333.4 ± 135.6 at month-24 (p < 0.0001). Similarly, macular-volume (MV) was significantly reduced from 10.7 ± 2.7 mm3 at baseline to 9.6 ± 2.9 mm3 (p = 0.0027) at month-24. Among the 31 study eyes, 19 (61.3%) required an additional treatment for DME. Throughout the study, 9 (29.0%) eyes required ocular hypotensive medication for controlling their intraocular-pressure and 5 (16.1%) eyes underwent cataract surgery. Conclusions In DME eyes who did not sufficiently respond to previous therapies, the FAc-i was associated with an improvement in visual and anatomic outcomes. There were no unexpected adverse-events. Trial registration number EudraCT identifier: 2016-001680-37. Supplementary Information The online version contains supplementary material available at 10.1007/s10792-023-02864-2.


Introduction
Diabetic macular edema (DME) is a prevalent and disabling disease that directly impairs central vision of patients with diabetic retinopathy (DR), making diabetes the leading cause of severe vision impairment in working-age populations of developed countries [1].
Among the different treatment options currently available for patients with DME, vascular endothelial growth factor inhibitors (anti-VEGF) are considered first-line treatments [2].However, in those eyes who do not adequately respond to anti-VEGF therapy or in those patients with systemic contraindications to anti-VEGF, intravitreal corticosteroid implants may be considered the treatment of choice [2][3][4].
Fluocinolone acetonide sustained-release intravitreal implant (FAc-i) (ILUVIEN ® ; Alimera Sciences, Hampshire, UK) is a non-erodible implant, which can deliver a low daily dose (0.2 µg per day) sustainedly of fluocinolone acetonide over a 3-year period [5].The FAc-i was approved in different European countries for treating eyes with recurrent and recalcitrant DME, i.e., DME eyes which do not adequately respond to other therapies [6].Additionally, in Europe, it is also indicated for preventing the onset of relapse episodes in eyes with recurrent non-infectious uveitis [7,8].
The effectiveness and safety of FAc-i was first demonstrated in the pivotal phase-III randomized controlled FAME trials, which were conducted on patients with chronic DME who received, at least, one session of laser treatment [9,10].The results of these studies found that FAc-i provided a significant and sustained improvement in best corrected visual acuity (BCVA) [9,10].
Diverse multicenter, non-randomized, and phase 4 studies were designed to assess the effectiveness and safety of FAc-i n daily clinical practice conditions [11][12][13][14].The ILUVIEN Registry Safety Study (IRISS; NCT01998412) reported a significant improvement in BCVA, which was greater in eyes with a shorter duration of DME, with no unexpected adverse events appearing [13].Similarly, the PALA-DIN study found significant improvements in both visual and anatomic outcomes, with a favorable safety profile [14].Finally, the Retro-IDEAL study demonstrated a significant improvement of BCVA and reduction in central retinal thickness over a period of 3 years [11].In summary, these studies have evidenced the favorable, long-term benefit-to-risk profile of the FAc-i in eyes with DME who did not achieve an adequate response to previous therapies [11][12][13][14].
The evidence evaluating the effectiveness and safety of the FAc-i in the Spanish clinical setting is scarce and reflects the experience of retrospective and single center studies [15,16].
This study aimed to assess the effectiveness and safety of the FAc-i in patients with chronic DME who did not sufficiently respond to other available therapies.

Study design
Phase IV observational, prospective, non-randomized, multicenter, and national clinical trial conducted on eyes with chronic DME who were considered insufficiently responsive to available therapies (REACT).
This study was in accordance with the ICH guidelines and guidelines for Good Clinical Practice (GCP), with the Declaration of Helsinki (revised version, Fortaleza, October 2013) [17] and the local laws and guidelines of the countries in which the study is being conducted.
The study protocol was approved by the ethics committee of Bellvitge University Hospital and registered in the European Union Clinical Trials Register (EudraCT identifier: 2016-001680-37).

Study participants
Patients ≥ 18 years of age; diagnosed with DME according to investigator's clinical evaluation and demonstrated using fundoscopic photography and spectral domain optical coherence tomography (SD-OCT); who were considered as insufficiently responsive to currently available therapies; and willing to comply with the investigators and protocol indications were included in the study.
The main inclusion/exclusion criteria are listed in Table S1.

Study treatment
All eligible patients with a signed informed consent received a 190 µg FAc-i (ILUVIEN ® ; Alimera Sciences, Hampshire, UK) in applicator with an initial release rate of 0.2 µg per day.The implant was administered by injection according to the method of administration defined in the Summary of Product Characteristic [18].Topical antibiotic was prescribed for all patients for 3-5 days following the day of implantation.

Outcomes
The primary end-point was the mean change in BCVA from baseline values.
The secondary end-points included the mean changes in central subfield thickness (CST) and macular volume (MV) assessed using SD-OCT; the incidence of adverse events; and the results of a Qualityof-Life Analysis (VFQ-25 questionnaire).

Statistical analysis
A standard statistical analysis was performed using SAS/STAT software, Version 9.4 of the SAS System for Windows.Copyright © 2023 SAS Institute Inc.
Prior to the study, it was planning to include 40 patients, 5 patients in each clinical center.Because it was a pilot study, no sample size was estimated.
Continuous variables were described by mean; median; standard deviation (SD); inter-quartile range (IqR); minimum; and maximum, as appropriate, while categorical variables were summarized by number and percentages.
No data were excluded due to protocol violations.Intent-to-treat analysis included all patients who received study medication.
The two-tailed paired sample t test or the Wilcoxon test, as appropriate, were used to assess changes in BCVA, CST, MV, and intraocular pressure (IOP).
Categorical variables were compared using a Chisquare test and a Fisher`s exact test, as needed.p value of less than 0.05 was considered significant.
In order to evaluate the influence of the initial BCVA on the treatment effectiveness, the eyes were stratified according to their baseline BCVA (BCVA < 50 ETDRS letters versus BCVA ≥ ETDRS 50 letters).

Results
Thirty-one eyes from 31 patients were included in the study.Eleven patients were lost of follow-up 10 for personal reasons (due to the lockdown measures taken during the SARS-COV-2 pandemic) and one patient due to an adverse event (Vitreous hemorrhage).The study flowchart is shown in Figure S1.
Study patients had received 5.3 ± 7.3 previous DME treatments before starting the study.
The main demographic and clinical characteristics are summarized in Table 1.

Best corrected visual acuity
In the overall study sample, BCVA improved from 56.1 ± 12.3 letters at baseline to 62.4 ± 17.0 letters at Vol:. (1234567890) month-24, although such improvement was not statistically significant (p = 0.0510) (Fig. 1A).Although baseline BCVA increased after FAc-i treatment at all the different time-point measured, such increase was not statistically significant (Figure S2A).
As compared to baseline values, BCVA improvement was statistically significant at months 9, 12, and 15 in the eyes with baseline BCVA < 50 ETDRS letters.Whereas, in those eyes with a baseline BCVA ≥ 50 ETDRS letters, BCVA remained stable throughout the study follow-up (Table S2).

Anatomic outcomes
In the overall study population, CST was significantly reduced from 474.0 ± 135.3A).
An analysis of the anatomical response based on the baseline BCVA revealed that, in the eye with a baseline BCVA ≥ 50 letters, CST was significantly reduced from 464.30 ± 133.4 µm at baseline to 321.05 ± 121.7 µm at month-24 (p = 0.0014) (Figure S3).
Although in eyes with a baseline BCVA < 50 letters the CST was reduced from 501.75 ± 145.3 µm at baseline to 375.40 ± 185.6 µm at month-24, such a difference was not statistically significant (p = 0.0625) (Figure S3).

Safety
Over the course of the study, 33 adverse events (AEs) were reported in 17 patients.Among them, 8 (24.2%)AEs were possible-definitive related to the study medication.
Six (18.2%)AEs were classified as serious, namely one retinal detachment, one colorectal cancer, one patient who underwent intestinal surgery, and 3 eye who developed cataract in the treated eye.Fifteen (45.5%)AEs were considered as moderate-to-severe.Additionally, 6 (19.4%) patients underwent cataract surgery throughout the study, 5 (16.1%) of them in the study eye.
An overview of the different AEs is shown in Table 2.

Discussion
Although DME is a disabling disease, which significantly impacts on patients' quality of life, there are currently diverse therapeutic strategies for its management [2].The advent of anti-VEGF meant a change in the paradigm of DME treatment [2].However, there is a proportion, which can reach 40% of cases, that does not respond adequately to this treatment [19].Moreover, many patients received suboptimal anti-VEGF treatment in real-life conditions [20].
The increasingly relevance that inflammation plays in the pathophysiology of DME has led to corticosteroids gaining importance as an alternative therapeutic strategy, particularly in recurrent DME and in patients resistant to anti-VEGF treatment [21,22].
Sustained-release corticoid formulations have emerged as a therapeutic strategy that allows a gradual corticoid release, with the subsequent reduction in the patient's treatment burden [2].
The current study aimed to evaluate the effectiveness and safety of the FAc-i in eyes with chronic DME who had an insufficient respond to other available therapies.
As far as we know, the REACT study is the first prospective, non-randomized, multicenter, national, and observational phase IV clinical trial evaluating the visual, anatomic, and safety outcomes of the FAc-i in Spain.
According to the results of this study, mean BCVA improved after FAc-i treatment at all the different time-point measured, although such increase was not statistically significant in the overall study sample.This fact was mainly due to the lockdown measures taken during the SARS-COV-2 pandemic for reducing the risk of infection spreading, which disrupted dramatically the provision of health care resulting of deferral of routine ophthalmic procedures [23,24].
Furthermore, after stratifying patients by baseline BCVA, a significant improvement in BCVA was observed at months 9, 12, and 15 in the eyes with baseline BCVA < 50 ETDRS letters.While in those eyes with a baseline BCVA ≥ 50 ETDRS letters, BCVA remained stable throughout the study follow-up.
Despite the anatomic improvement observed in both groups after FAc-i treatment, this improvement was greater in the eyes with a baseline BCVA ≥ 50 letters.It might be hypothesized that eyes with a worse baseline BCVA would present more severe structural anatomical abnormalities, which would justify the differences in BCVA throughout the study between both groups [25,26].These findings clearly suggest a positive benefit to risk profile in patients treated earlier with the FAc-i.
Regarding the anatomic outcomes, as compared to baseline values, both CST and MV were significantly reduced at all the different time-points measured in the overall study population.
Regarding visual outcomes, there does not seem to be a big difference between the real-life studies [36] and the FAME studies [9,10] and the current study.
In the current study, BCVA improved by 4.5 letters at month-24, while the FAME study reported a BCVA improvement of 4.4 letters at month-24 [9] and a meta-analysis of real-world studies observed a visual acuity improvement of 4.5 letters at month-24 [36].
Nineteen (61.3%) eyes required an additional treatment for DME during the study.This result was greater than that reported by the FAME study (15.2%) [9,10] and the meta-analysis (30% and 39%, respectively) [35,36].This finding might be related to the SARS-COV-2 pandemic, since the different measured adopted for controlling virus spreading led to deferral of routine ophthalmic procedures [23,24].
Regarding safety, the REACT study has found no unexpected adverse events.Throughout the study, 33 adverse events (AEs) were reported in 17 patients, with 6 AEs considered as serious.
Over the course of the study, 8 (25.8%) eyes started ocular hypotensive medication for controlling their IOP, although none of them required IOP-lowering surgery.
This study has some limitations that need to be considered when interpreting its results.The main one was the sample size.Although it was originally planned to include 40 eyes (5 eyes per center), only 31 eyes were included in the study.This could have motivated the lack of statistical significance in the BCVA improvement of the BCVA achieved at 24 months.

Conclusions
FAc-i was associated with a trend toward improvement in BCVA at month 24 in the overall study sample.Moreover, in those eyes with a baseline BCVA < 70 ETDRS letters, there was a statistically significant improvement on BCVA at month 24 after FAc-i injection.
The anatomic outcomes, both the CST and the MV, improved significantly after the administration of the FAc-i.
Regarding safety, no unexpected adverse events were reported.Five (16.7%) eyes required cataract surgery, and 8 (25.8%) eyes started ocular hypotensive medication for controlling their IOP.

Fig. 1 Fig. 2 AFig. 3
Fig. 1 Mean best corrected visual acuity throughout study follow-up in the overall study population (A) and in the eyes with a baseline BCVA < 70 ETDRS letters (B).Statistically significance was calculated by using paired sample two-tailed t test

Table 1
Main demographic and clinical characteristics of the study population * The total sum may be greater than 100%, since patients may have more than one systemic pathology ** Early Treatment Diabetic Retinopathy Study (ETDRS) letters SD Standard deviation; IqR Interquartile range; DM Diabetes Mellitus; DME Diabetic macular edema; DR Diabetic retinopathy; PRP Panretinal photocoagulation; CVD Cardiovascular disease; BPH Benign prostatic hyperplasia; CKD Chronic kidney disease; anti-VEGF Vascular endothelial growth factor inhibitors; BCVA Best corrected visual acuity; CST Central subfoveal thickness; MV Macular volume; VFQ Visual Function Quality

Table 2
Overview of the different adverse events that occurred throughout the study * Number of events/number of patients AEs Adverse events; COVID Coronavirus disease; BPH Benign prostatic hyperplasia