Dextromethorphan for Diabetic Macular Edema

Phase 1

Completed

Conditions: Diabetic Macular Edema

Interventions: Drug: Dextromethorphan hydrobromide

Registration Number: NCT01441102

Lead Sponsor: National Eye Institute (NEI)

Brief Summary: Background: Many people with diabetes have macular edema (swelling) at the back of the eye. Macular edema can cause loss of vision. Studies suggest that inflammation may be involved in the swelling. A drug called dextromethorphan may help prevent the inflammation and the swelling. Dextromethorphan is approved for use as a cough medicine, but it has not been studied to see if it can help in diabetic macular edema.

Objectives: To see if dextromethorphan can help treat diabetic macular edema.

Eligibility: Individuals at least 18 years of age who have diabetic macular edema in at least one eye.

Design:

* This study lasts 2 years, and will require at least 14 visits to the National Eye Institute outpatient clinic. Study visits will be every month for the first 2 months and then every other month. Each visit will take about 2 to 4 hours.

* Participants will be screened with a physical exam, medical history, eye exam, and blood tests. One eye with macular edema will be chosen as the study eye for testing.

* Participants will take dextromethorphan twice a day, about 12 hours apart, for 2 years. A study diary will help keep track of the date, time, and number of pills taken.

* Participants will have study visits once a month for the first 2 months and then every other month for the rest of the study. Each study visit will involve eye exams and blood and urine tests.

* Four months after starting the study medication, participants may have laser surgery or other treatments for the macular edema, if it is needed.

Detailed Description: 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. Individual participants deemed to have worsening disease may stay on the study and continue to receive study medication, but will be allowed to receive focal laser therapy for any amenable leaking microaneurysms and/or anti-vascular endothelial growth factor (VEGF) intravitreal injections (such as bevacizumab or ranibizumab) at the discretion of the treating physician. Additionally, beginning at the Month 6 visit, participants will be eligible for treatment, with either focal laser or anti-VEGF injections 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dextromethorphan hydrobromide	Dextromethorphan hydrobromide	-

Primary Outcome Measures

Name	Time	Method
Percentage Change in Retinal Thickness in the Study Eye at 6 Months Compared to Baseline	Baseline and 6 months	Retinal thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria. The eye not chosen as the study eye is referred to as the "fellow eye."

Secondary Outcome Measures

Name	Time	Method
Percentage Change in Retinal Thickness in the Study Eye at 12 Months Compared to Baseline	Baseline and 12 Months	Retinal thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. Changes in OCT will be calculated using the ETDRS grid. Attention will be directed to changes in retinal thickness as measured by OCT in each of the 9 subfields of the grid.
Percentage Change in Retinal Thickness in the Study Eye at 18 Months Compared to Baseline	Baseline and 18 Months	Retinal thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. Changes in OCT will be calculated using the ETDRS grid. Attention will be directed to changes in retinal thickness as measured by OCT in each of the 9 subfields of the grid.
Percentage Change in Retinal Thickness in the Study Eye at 24 Months Compared to Baseline	Baseline and 24 Months	Retinal thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. Changes in OCT will be calculated using the ETDRS grid. Attention will be directed to changes in retinal thickness as measured by OCT in each of the 9 subfields of the grid.
Change in Best-corrected Visual Acuity (BCVA) in the Study Eye at 6 Months Compared to Baseline	Baseline and 6 Months	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.
Change in Best-corrected Visual Acuity (BCVA) in the Study Eye at 12 Months Compared to Baseline	Baseline and 12 Months	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.
Change in Best-corrected Visual Acuity (BCVA) in the Study Eye at 18 Months Compared to Baseline	Baseline and 18 Months	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.
Change in Best-corrected Visual Acuity (BCVA) in the Study Eye at 24 Months Compared to Baseline	Baseline and 24 Months	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.
Number of Study Eyes Demonstrating a Decrease in the Area of Late Leakage, as Measured by Fluorescein Angiography (FA), at 6 Months Compared to Baseline	Baseline and 6 Months	Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA) at baseline and at Month 6, Month 12, Month 18, and Month 24. Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD).
Number of Study Eyes Demonstrating a Decrease in the Area of Late Leakage, as Measured by Fluorescein Angiography (FA), at 12 Months Compared to Baseline	Baseline and 12 Months	Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA) at baseline and at Month 6, Month 12, Month 18, and Month 24. Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD).
Changes in Mean Macular Sensitivity in the Study Eye at 6 Months Compared to Baseline	Baseline and 6 Months	Microperimetry was used to assess macular sensitivity.
Number of Study Eyes Demonstrating a Decrease in the Area of Late Leakage, as Measured by Fluorescein Angiography (FA), at 18 Months Compared to Baseline	Baseline and 18 Months	Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA) at baseline and at Month 6, Month 12, Month 18, and Month 24. Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD).
Changes in Mean Macular Sensitivity in the Study Eye at 12 Months Compared to Baseline	Baseline and 12 Months	Microperimetry was used to assess macular sensitivity.
Number of Study Eyes Demonstrating a Decrease in the Area of Late Leakage, as Measured by Fluorescein Angiography (FA), at 24 Months Compared to Baseline	Baseline and 24 Months	Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA) at baseline and at Month 6, Month 12, Month 18, and Month 24. Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD).
Changes in Mean Macular Sensitivity in the Study Eye at 18 Months Compared to Baseline	Baseline and 18 Months	Microperimetry was used to assess macular sensitivity.
Changes in Mean Macular Sensitivity in the Study Eye at 24 Months Compared to Baseline	Baseline and 24 Months	Microperimetry was used to assess macular sensitivity.
Number of Participants Withdrawn From the Study Therapy Due to Vision Loss or Adverse Events	Duration of the study, up to 24 months