Oral Dextromethorphan for the Treatment of Diabetic Macular Edema: Results From a Phase I/II Clinical Study

Abstract

Purpose: The activation of microglia, the primary innate immune cell resident in the retina, produces inflammatory mediators, which underlie changes in diabetic retinopathy including increased vascular permeability. This study evaluates the safety and efficacy of dextromethorphan, a drug capable of inhibiting microglial activation, in the treatment of diabetic macular edema (DME).

Methods: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with macular involving DME who received oral dextromethorphan 60 mg twice daily for 6 months as monotherapy. Main outcome variables included central retinal subfield thickness (CST), best-corrected visual acuity (BCVA), macula sensitivity, and late leakage on fluorescein angiogram (FA).

Results: The study drug was well tolerated. At the primary end point of 6 months, mean CST decreased by -6.3% ± 6.8% and BCVA increased by +0.6 ± 5.11 (mean ± SEM) letters. Late leakage on FA was scored as improved in four of five study eyes. These findings were not correlated with changes in hemoglobin A1c (HbA1c), creatinine, or blood pressure.

Conclusions: In this proof-of-concept study, dextromethorphan administration as the primary treatment for DME was associated with decreased vascular leakage, suggesting possible therapeutic effects. Additional studies investigating the modulation of microglial activation is warranted.

Translational relevance: These findings highlight microglial modulation as a potentially useful therapeutic strategy in the treatment of diabetic macular edema.

Keywords: diabetes; diabetic retinopathy; microglia; retina.

Figure 1

Longitudinal record of central macular thickness in study eyes (n = 5) as evaluated by SD-OCT. (Upper panels) Horizontal B-scans traversing the center of the fovea are shown for all study visits from baseline to month 6. (Lower panels) Topographic maps of macular thickness at baseline and month 6 with a superimposed ETDRS grid centered on the fovea. The numbers in the grid depict mean retinal thickness in each subfield in micrometers. Study eyes in participants 1, 3, and 5 demonstrated a decrease in overall macular thickness at month 6 relative to baseline. The study eye in participant 2 showed in redistribution in the position of macular edema, while that in participant 4 showed an increase in central edema.

Figure 2

Longitudinal record of central macular thickness in fellow eyes (n = 3) as evaluated by SD-OCT. (Upper panels) Horizontal B-scans traversing the center of the fovea are shown for all study visits from baseline to month 6. (Lower panels) Topographic maps of macular thickness at baseline and month 6 with a superimposed ETDRS grid centered on the fovea. The numbers in the grid depict mean retinal thickness in each subfield in micrometers. Relative to baseline, the qualifying eyes changed at month 6 in the following ways: participant 3, a slight improvement in macular thickness; participant 4, slight worsening; participant 5, worsening macular edema.

Figure 3

Longitudinal record of noncentral temporal macular thickness in two study eyes as evaluated by SD-OCT. (Upper panels) Horizontal B-scans traversing the center of the area of temporal edema are shown for the study eyes of participants 2 and 4. The ETDRS circle was repositioned to center on the area of temporal edema. A scan in the temporal location was not obtained for participant 2 at the month 2 study visit. The numbers in the grid depict mean retinal thickness in each subfield in micrometers. (Lower panels) Topographic maps of the temporal macular thickness; the area of temporal macular edema in the study eye of participant 2 demonstrated clear improvement, while that in participant 4 showed mild reductions in thickness.

Figure 4

Changes in macular thickness measurements from baseline in study and qualifying fellow eyes. (A) Percentage changes in CST (measured in the 1-mm diameter central subfield) from baseline are shown for individual study eyes (left, n = 5) and qualifying fellow eyes (right, n = 3). Each histogram column shows the percentage change in CST at all study visits (months 1, 2, 4, and 6) arranged in consecutive order. (B) Mean percentage change in CST for all study eyes (left, n = 5) and all qualifying eyes (right, n = 8) at all study visits. (C) CST (measured in the 1-mm diameter central subfield) are shown for individual study eyes (left, n = 5) and qualifying fellow eyes (right, n = 3). Each histogram column shows the CST at all study visits (baseline, months 1, 2, 4, and 6) arranged in consecutive order. (D) Mean percentage change in CMV (measured in the 3-mm diameter central subfields) for all study eyes (left, n = 5) and all qualifying eyes (right, n = 8) at all study visits. Column heights indicate means and error bars indicate standard error.

Figure 5

Change in BCVA from baseline in study and qualifying fellow eyes. (A) Changes in BCVA (letters) from baseline are shown for individual study eyes (left, n = 5) and qualifying fellow eyes (right, n = 3). Each histogram column shows the percentage change in CST at all study visits (months 1, 2, 4, and 6) arranged in consecutive order. (B) Mean change in BCVA for all study eyes (left, n = 5) and all qualifying eyes (right, n = 8) at all study visits. Column heights indicate means and error bars indicate standard error.

Figure 6

Changes in macular sensitivity measured using MP-1 microperimetry. (A) Changes of mean sensitivity from baseline to month 6 for each study eye (central radius 10°, dark column; central 5°, white columns). (B) The average change in macular sensitivity from baseline to month 6 for all study eyes (central radius 10°, dark column; central 5°, white columns).

Figure 7

Changes in retinal vascular leakage in late phase fluorescein angiograms from baseline and month 6 in study and qualifying fellow eyes. Late phases fluorescein angiograms in (A) study eyes (n = 5) and (B) qualifying fellow eyes (n = 3) were obtained and compared at baseline and month 6.