Elsevier

Ophthalmology

Volume 118, Issue 4, April 2011, Pages 626-635.e2
Ophthalmology

Original article
Long-term Benefit of Sustained-Delivery Fluocinolone Acetonide Vitreous Inserts for Diabetic Macular Edema

https://doi.org/10.1016/j.ophtha.2010.12.028Get rights and content

Objective

To assess the efficacy and safety of intravitreal inserts releasing 0.2 μg/day (low dose) or 0.5 μg/day (high dose) fluocinolone acetonide (FA) in patients with diabetic macular edema (DME).

Design

Two parallel, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trials.

Participants

Subjects with persistent DME despite at least 1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393).

Methods

Subjects received study drug or sham injection at baseline and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year.

Main Outcome Measures

The primary outcome was the percentage of patients with improvement from baseline best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Trial (ETDRS) letter score of 15 or more at month 24. Secondary outcomes included other parameters of visual function and foveal thickness (FTH).

Results

The percentage of patients with improvement from baseline ETDRS letter score of 15 or more at month 24 was 28.7 and 28.6 in the low- and high-dose insert groups, respectively, compared with 16.2 in the sham group (P = 0.002 for each). Benefit occurred for both doses compared with sham at 3 weeks and all subsequent time points. The mean improvement in BCVA letter score between baseline and month 24 was 4.4 and 5.4 in the low- and high-dose groups, respectively, compared with 1.7 in the sham group (P = 0.02 and P = 0.016). At all time points compared with sham, there was significantly more improvement in FTH. Subjects requiring cataract surgery were more frequent in the insert groups, and their visual benefit was similar to that of subjects who were pseudophakic at baseline. Glaucoma requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the low-dose, high-dose, and sham groups, respectively.

Conclusions

Both low- and high-dose FA inserts significantly improved BCVA in patients with DME over 2 years, and the risk-to-benefit ratio was superior for the low-dose insert. This is the first pharmacologic treatment that can be administered by an outpatient injection to provide substantial benefit in patients with DME for at least 2 years.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Patients and Methods

The Fluocinolone Acetonide for Macular Edema (FAME) studies A and B were performed under a single protocol (C-01-05-001, sponsored by Alimera Sciences, Inc.) as randomized, double-masked, sham injection-controlled, parallel-group, multicenter studies conducted over a 36-month period. The FAME study A was conducted at 49 sites in the United States, Canada, 4 countries in the European Union, and India. The FAME study B was conducted at 52 sites in the United States, India, and 3 countries in the

Baseline Characteristics and Patient Disposition

Treatment groups were balanced with respect to age, race, the mean duration of diabetes (16.1–17.1 years), the mean duration of DME (3.5–3.9 years), the mean BCVA (52.9–54.7 ETDRS visual acuity score), and FTH (451.3–485.1 μm; Table 2). Almost all patients received their assigned treatment (99.5%–100%; Table 2). The percentage of patients that failed to remain in the study until the month 24 primary end point was 19.0% in the high-dose group, 19.9% in the low-dose group, and 22.7% in the sham

Discussion

Diabetic macular edema is a major public health problem. It causes loss of vision in a large number of patients during their working years, resulting in lost productivity and a large expenditure of health care dollars and manpower. After 20 years of diabetes, the prevalence of DME is 28%.1 The high prevalence is compounded by the chronicity of DME, requiring patients and physicians to deal with it for years. Chronic diseases are managed best by treatments that exert a therapeutic effect for a

Acknowledgments

The authors thank the Data Safety Monitoring Board—Frederick L. Ferris III (chair), Stanley Chang, Matthew Davis, Michele Melia, and Richard Parrish—for overseeing the trial.

References (31)

  • Q.D. Nguyen et al.

    Supplemental inspired oxygen improves diabetic macular edema: a pilot study

    Invest Ophthalmol Vis Sci

    (2003)
  • H. Ozaki et al.

    Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression

    Invest Ophthalmol Vis Sci

    (1999)
  • B.D. Kelly et al.

    Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1

    Circ Res

    (2003)
  • Q.D. Nguyen et al.

    Vascular endothelial growth factor is a critical stimulus for diabetic macular edema

    Am J Ophthalmol

    (2006)
  • Q.D. Nguyen et al.

    Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) study

    Ophthalmology

    (2009)
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    Manuscript no. 2010-1629.

    The complete list of the FAME Study Group is available at http://aaojournal.org.

    Financial Disclosure(s): The author(s) have made the following disclosure(s):

    Peter A. Campochiaro - Consultant - LPath, Inc., Pfizer, Bristol Meyers Squib, and is on the Data and Safety Monitoring Committee for the Regeneron View 1 Trial; Member of Expert Panels - Genentech, Inc., GlaxoSmithKline, for which Johns Hopkins University receives compensation; Financial support - Alimera Sciences, Genentech, GlaxoSmithKline, Genzyme, Molecular Partners

    David M. Brown - Consultant - Genentech, Regeneron, Alcon, Allergan, Novartis; Lecturer - Genentech, Alcon; Financial support - Alimera Sciences, Genentech, Regeneron, Alcon, Allergan, Molecular Partners, Novartis

    Andrew Pearson - Consultant - Alimera Sciences; Equity owner - pSividia

    Thomas Ciulla - Financial support - Regeneron, Genentech, Acuity, Allergan, Macusight

    David Boyer - Consultant - Allergan, Alcon, Genentech, Regeneron, Novartis, Pfizer, EyeTech, iCo; Financial support - Allergan, Genentech, Regeneron, Alimera Sciences, iCo, Novartis

    Frank G. Holz - Consultant - Novartis, Pfizer, Alimera Sciences; Lecturer - Novartis

    Michael Tolentino - Consultant - GlaxoSmithKline, Eyetech, Pfizer, Allergan, Alimera Sciences, OPKO, Promedior, Notal Vision, Acuity Dynamic, Genentech, Ophthotec, Novartis, Regeneron; Lecturer - GlaxoSmithKline, Eytech, Pfizer, Allergan, Alimera Sciences, Novartis, QLT, Genentech, Regeneraon; Financial support - GlaxoSmithKline, Alcon, Eyetech, Pfizer, Allergan, Alimera Sciences, Regeneron, Genentech, Ophthotec, Novartis; Equity owner - OPKO Health, Acuity Dynamics, Cryotooth

    John Gonder - Financial support - Eli Lilly, Regerneron, Aventis Pharma, Astra Zeneca, Allergan, Novartis, Alcon, Alimera Sciences

    Amod Gupta - Financial support - Alimera Sciences

    Lilianne Duarte - Financial support - Alimera Sciences

    Steven Madreperla - Financial support - Alimera Sciences

    Frances E. Kane - Employee - Alimera Sciences

    Barry Kapik - Employee - Alimera Sciences

    Kathleen Billman - Employee - Alimera Sciences

    Supported by Alimera Sciences, Inc., Atlanta, Georgia, and Psivida, Inc., Watertown, Massachusetts.

    Group members listed online (available at http://aaojournal.org).

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