Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study

Abstract

Purpose: Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME.

Methods: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME who received oral minocycline 100 mg twice daily for 6 months. Main outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST), and central macular volume using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA).

Results: Findings indicated that the study drug was well tolerated and not associated with significant safety issues. In study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8 letters, respectively, while mean retinal thickness (CST) on OCT decreased by -2.9%, -5.7%, -13.9, and -8.1% for the same time points. At month 6, mean area of late leakage on FA decreased by -34.4% in study eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Improvements in outcome measures were not correlated with concurrent changes in systemic factors.

Conclusions: In this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with improved visual function, central macular edema, and vascular leakage, comparing favorably with historical controls from previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the inflammatory etiology of DME. (ClinicalTrials.gov number, NCT01120899.).

Conflict of interest statement

Disclosure: C.A. Cukras, None; P. Petrou, None; E.Y. Chew, None; C.B. Meyerle, None; W.T. Wong, None

Figures

Figure 1.

Change in BCVA from baseline in participants (n = 5) with DME. (A) Summary of visual acuity changes from baseline for study eyes (n = 5, top panel) and fellow eyes (n = 5, bottom panel) for all study visits. Each histogram column shows the change in visual acuity score (in ETDRS letters) for all study visits (month 1, month 2, month 4, and month 6) arranged in consecutive order. (B) Mean change in visual acuity score from baseline over time for study eyes (n = 5, solid symbols) and fellow eyes (n = 5, open symbols). (C) Mean change in visual acuity score from baseline over time for all eyes in the study (study eyes and fellow eyes combined, n = 10, solid symbols) and for qualifying eyes that met inclusion criteria at baseline (n = 8, open symbols). Error bars represent standard error.

Figure 2.

Change in macular thickness and edema in study eyes (n = 5) as evaluated by OCT analysis. Upper panel: Horizontal B-scans traversing the center of the central ETDRS circle at the fovea for all study visits. Consecutive images illustrate progressive anatomical changes at the same horizontal locus of the macula as a function of time. Lower panel: Topographic maps of the en-face view of the central macula, as constructed from 512 × 128 volume scans, at baseline and at month 6. The maps are overlaid with an ETDRS grid and the numbers in each sector of the grid represent mean retinal thickness in that sector in μm. All scans and topographical maps have been checked for alignment and correct delineation to allow accurate comparisons in corresponding retinal loci. Study eyes in participants 1, 2, and 5 demonstrated the highest CST at baseline, which decreased at month 6. Study eye in participant 4 decreased progressively in central macular edema up to month 4, which increased again at month 6. Study eye in participant 3 which had the smallest amount of central edema remained relatively unchanged across all study visits.

Figure 3.

Change in macular thickness and edema in fellow eyes (n = 5) as evaluated by OCT analysis. Upper panel: Horizontal B-scans traversing the center of the central ETDRS circle at the fovea for all study visits. Consecutive images illustrate progressive anatomical changes at the same horizontal locus of the macula as a function of time. Lower panel: Topographic maps of the en-face view of the central macula, as constructed from 512 × 128 volume scans, at baseline and at month 6. The maps are overlaid with an ETDRS grid and the numbers in each sector of the grid represent mean retinal thickness in that sector in μm. All scans and topographical maps have been checked for alignment and correct delineation to allow accurate comparisons in corresponding retinal loci. Fellow eyes in participants 3 and 5 did not meet enrollment criteria and are considered “non-qualifying eyes.” These participants showed five relatively mixed trends with time.

Figure 4.

Percentage change in CST from baseline in participants (n = 5) with DME as measured using OCT. (A) Summary of visual acuity changes from baseline for study eyes (n = 5, top panel) and fellow eyes (n = 5, bottom panel) for all study visits. Each histogram column shows the percentage change in CST for all study visits (month 1, month 2, month 4, and month 6) arranged in consecutive order. (B) Mean percentage change in CST from baseline over time for study eyes (n = 5, solid symbols) and fellow eyes (n = 5, open symbols). (C) Mean percentage change in CST from baseline over time for all eyes in the study (study eyes and fellow eyes combined, n = 10, solid symbols) and for “qualifying eyes” that met inclusion criteria at baseline (n = 8, open symbols). Error bars represent standard error.

Figure 5.

Percentage change in CMV from baseline in participants (n = 5) with DME as measured using OCT. Summary of change in CMV in eyes relative to baseline. (A) Mean percentage change in CMV from baseline over time for study eyes (n = 5, solid symbols) and fellow eyes (n = 5, open symbols). (B) Mean percentage change in CMV from baseline over time for all eyes in the study (study eyes and fellow eyes combined, n = 10, solid symbols) and for “qualifying eyes” that met inclusion criteria at baseline (n = 8, open symbols). Error bars represent standard error.

Figure 6.

Changes in vascular permeability from baseline in participants (n = 5) with DME as measured using FA. Example of angiographic changes in the early (1–3 minutes) and late (≈10 minutes) phases of the angiogram as seen in participant 2 as examined at baseline (top) and month 6 (bottom). (A) Study eyes. (B) Fellow eyes. Comparisons of matched frames in this participant demonstrate decreases in the number of leaking microaneurysms seen in the early frames and in the area of late leakage in the late frames at month 6 relative to baseline. Quantifications of the changes in the area of late leakage from baseline to month 6 for all participants demonstrate net decreases in 5/5 study eyes and 4/5 fellow eyes. (C) Absolute changes. (D) Percentage changes.