Dextromethorphan for Diabetic Macular Edema

Objective:

Diabetic retinopathy (DR) is one of the leading causes of blindness in the United States. A
frequent manifestation of DR is diabetic macular edema (DME) for which the only proven
treatment is laser photocoagulation. In the retina, microglia are capable of migrating
through the retina to sites of inflammation to associate closely with neurons and the
vasculature, and are key cellular players in the mediation of processes of chronic
inflammation implicated in DME. For these reasons, microglia represent a promising cellular
target for forms of therapy that limit the deleterious inflammatory changes found in DR. The
objective of this study is to investigate the safety and efficacy of dextromethorphan as a
microglia inhibitor in participants with DME.

Study Population:

Eligibility criteria include presence of diabetic retinopathy with retinal thickening due to
diabetic macular edema within 3000 μm of the center of the macula as measured by optical
coherence tomography (OCT), and visual acuity better than 20/200 in the study eye.

Design:

Five participants will be initially enrolled in this unmasked pilot study. However, up to an
additional three participants may be enrolled to account for participants who withdraw from
the study prior to receipt of six months of study treatment. Participants will take an oral
dose of 60 mg of dextromethorphan twice daily for 24 months. During each visit, participants
will have their visual acuity measured and will undergo OCT testing to measure retinal
thickness. Beginning at the Month 4 visit, participants will be assessed for worsening
disease defined as loss of ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters
of vision compared to baseline or a ≥ 50% increase in total central retinal thickness as
measured by OCT. Additionally, beginning at the Month 6 visit, participants will be eligible
for treatment, with either focal laser or anti-vascular endothelial growth factor (VEGF)
injections (such as bevacizumab or ranibizumab) if they have center-involving macular edema.

Outcome Measures:

The primary outcome is the change in retinal thickness measured by OCT at 6 months compared
to baseline. Secondary outcomes include the change in retinal thickness as measured by OCT
at 12, 18 and 24 months compared to baseline, change in best-corrected visual acuity (BCVA)
at 6, 12, 18 and 24 months compared to baseline, change in mean macular sensitivity as
measured by microperimetry at 6, 12, 18 and 24 months compared to baseline, as well as
changes in fluid leakage in the macula as demonstrated by fluorescein angiography at 6, 12,
18 and 24 months compared to baseline. Safety outcomes include the number and severity of
systemic and ocular toxicities, and adverse events.

Inclusion Criteria

1. Participant is 18 years of age or older.

2. Participant must understand and sign the protocol's informed consent document.

3. Female participants of childbearing potential must not be pregnant or breast-feeding,
must have a negative urine pregnancy test within 24 hours prior to initiation of
study medication and must be willing to undergo urine pregnancy tests throughout the
study.

4. Female participants of childbearing potential and male participants able to father
children must have (or have a partner who has) had a hysterectomy or vasectomy, be
completely abstinent from intercourse or must agree to practice two acceptable
methods of contraception throughout the course of the study and for one week after
study medication discontinuation. Acceptable methods of contraception include:

- hormonal contraception (i.e., birth control pills, injected hormones, dermal
patch or vaginal ring),

- intrauterine device,

- barrier methods (diaphragm, condom) with spermicide, or

- surgical sterilization (hysterectomy or tubal ligation).

5. Participant must agree to notify the study investigator or coordinator if any of
his/her doctors initiate a new medication during the course of this study.

6. Participant must agree not to take medications containing dextromethorphan during the
course of this study.

7. Participant must have normal renal function and liver function, or have mild
abnormalities no greater than grade 1 as defined by the Common Terminology Criteria
for Adverse Events v4.0 (CTCAE).

8. Participant has a diagnosis of diabetic mellitus (type 1 or type 2). Any one of the
following will be considered to be sufficient evidence that diabetes is present:

- Current regular use of insulin for the treatment of diabetes;

- Current regular use of oral anti-hyperglycemia agents for the treatment of
diabetes;

- Documented diabetes by American Diabetes Association (ADA) and/or World Health
Organization (WHO) criteria.

9. Participant has documented hemoglobin A1C 12% or less within one month of baseline.

- Participants with elevated hemoglobin A1C but within the 12% or less cutoff will
undergo appropriate evaluation, and unstable patients will be excluded according
to the investigator's best medical judgment.

- Participant agrees to refrain from consuming grapefruit juice, grapefruits and
Seville oranges at any time while s/he is enrolled in this study.

10. Participant has at least one eye that meets the study eye criteria listed below.

Exclusion Criteria

1. Participant is in another investigational study and actively receiving another study
medication for diabetic macular edema (DME).

2. Participant is unable to comply with study procedures or follow-up visits.

3. Participant has a known hypersensitivity to sodium fluorescein dye.

4. Participant has a condition that, in the opinion of the investigator, would preclude
participation in the study (e.g., unstable medical status including blood pressure
and glycemic control).

• Patients in poor glycemic control who, within the last four months, initiated
intensive insulin treatment (a pump or multiple daily injections) or plan to do so in
the next four months should not be enrolled.

5. Participant has a history of chronic renal failure requiring dialysis or kidney
transplant.

6. Participant has a history of hepatitis or liver failure.

7. Participant has an allergy or hypersensitivity to dextromethorphan or levorphanol.

8. Participant is taking or has taken within the last 14 days any medication that could
adversely interact with dextromethorphan such as selective serotonin reuptake
inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs) including but not limited
to the following: almotriptan; amitriptyline; amoxapine; bromocriptine; buspirone;
cabergoline; citalopram; clomipramine; desipramine; desvenlafaxine;
dihydroergotamine; doxepin; duloxetine; eletriptan; ergoloid mesylates; ergotamine;
escitalopram; fluoxetine; fluvoxamine; frovatriptan; imipramine; isocarboxazid;
linezolid; lithium; maprotiline; meperidine; methylergonovine; milnacipran;
mirtazapine; moclobemide; naratriptan; nefazodone; nortriptyline; paroxetine;
phenelzine; procarbazine; promethazine; protriptyline; rasagiline; rizatriptan; SAMe
(S-adenosylmethionine); selegiline; sertraline; sibutramine; St. Johns wort;
sumatriptan; tapentadol; tramadol; tranylcypromine; trazodone; trimipramine;
tryptophan; venlafaxine; vilazodone; zolmitriptan.

9. Participant has a blood pressure of > 180/110 (systolic above 180 OR diastolic above
110).

• If blood pressure is brought below 180/110 by anti-hypertensive treatment, a
patient can become eligible.

10. Participant has a history of treatment with systemic anti-vascular endothelial growth
factor (VEGF) agents or steroids within three months prior to study entry.

Study Eye Inclusion Criteria

1. Best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study
(ETDRS) score of 34 letters or better (i.e., 20/200 or better).

2. Definite retinal thickening due to diabetic macular edema, based on clinical
examination, that is not refractory to further therapy as based on the investigator's
clinical judgment.

3. Retinal thickening due to DME within 3000 μm of the center of the macula, as measured
by Spectral optical coherence tomography (OCT).

4. Media clarity, pupillary dilation and patient cooperation sufficient for adequate
fundus photographs.

Study Eye Exclusion Criteria

1. Macular edema is considered to be due to a cause other than diabetic macular edema.

An eye should not be considered eligible if:

- The macular edema is considered to be related to cataract extraction; or

- Clinical exam and/or OCT suggest that vitreoretinal interface disease (e.g., a
taut posterior hyaloid or epiretinal membrane) is the primary cause of the
macular edema.

2. An ocular condition is present such that, in the opinion of the investigator, visual
acuity would not improve from resolution of macular edema (e.g., foveal atrophy,
pigmentary changes, dense subfoveal hard exudates, non-retinal condition).

3. An ocular condition is present (other than diabetic retinopathy (DR) that, in the
opinion of the investigator, might affect macular edema or alter visual acuity during
the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory
disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.).

4. Substantial cataract that, in the opinion of the investigator, is likely to be
decreasing visual acuity by three lines or more (i.e., cataract would be reducing
acuity to 20/40 or worse if eye was otherwise normal).

5. History of panretinal scatter photocoagulation (PRP) within four months prior to
study entry.

6. History of prior pars plana vitrectomy within six months prior to study entry.

7. History of major ocular surgery (including cataract extraction, scleral buckle, any
intraocular surgery, etc.) within three months prior to study entry.

8. History of Yttrium aluminium garnet (YAG) capsulotomy performed within two months
prior to study entry.

9. History of treatment within three months prior to enrollment with any drug that has
not received regulatory approval at the time of study entry, such as intravitreal or
periocular steroids or intravitreal anti-VEGF agents.

Choice of Study Eye in Cases of Bilateral Disease

If both eyes of a participant meet the criteria described above, the following will be
used to determine the study eye:

1. If one eye is treatment-naïve and the other is not, the treatment-naïve eye will be
chosen as the study eye.

2. If both eyes are treatment-naïve, the eye with the better visual acuity will be
chosen as the study eye.

3. If both eyes are treatment-naïve and are equivalent, the choice of study eye will be
determined at the investigator's discretion after consultation with the participant.

4. If both eyes have been previously treated, the choice of study eye will be determined
at the investigator's discretion after consultation with the participant.