A Pilot Study Evaluating Photobiomodulation Therapy for Diabetic Macular Edema

Study Overview
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Brief Summary
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Randomized clinical trial evaluating the effect of photobiomodulation compared with sham on central subfield thickness (CST) in eyes with central-involved DME and good vision.

Detailed Description
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This study is being conducted to assess the effects of photobiomodulation on CST compared with sham in eyes with central-involved DME and good vision. Photobiomodulation is irradiation by light in the 630-900 nanometer region of the spectrum. Furthermore, this pilot study is being conducted to determine whether the conduct of a pivotal trial has merit based on an anatomic outcome and provide information on outcome measures needed to design a pivotal trial.

Official Title
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A Pilot Study Evaluating Photobiomodulation Therapy for Diabetic Macular Edema

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Device: Retilux
* Device: Sham Light Device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Diagnosis of diabetes 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 and/or the World Health Organization criteria. Able and willing to provide informed consent. Atleast one eye meeting the following criteria: Best corrected E-ETDRS visual acuity letter score ≥ 79 (i.e., 20/25 or better) Ophthalmoscopic evidence of central-involved DME, confirmed by CST on spectral domain OCT: Zeiss Cirrus: ≥290µm in women, and ≥305µm in men, Heidelberg Spectralis: ≥305µm in women, and ≥320µm in men Media clarity, pupillary dilation, and study participant Exclusion Criteria: History of chronic renal failure requiring dialysis or kidney transplant. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status that might preclude completion of follow-up). Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months. Participation in an investigational trial that involved treatment within 30 days of randomization with any drug/device that has not received regulatory approval for the indication being studied. Note: study participants cannot participant in another investigational trial that involves treatment with an investigational drug or device while participating in the study. Systolic blood pressure above 180 or diastolic blood pressure above 110. If blood pressure is brought below 180 systolic and 110 diastolic by anti-hypertensive treatment, individual can become eligible. Systemic anti-vascular endothelial growth factor (anti-VEGF) or pro-VEGF treatment within 4 months prior to randomization. These drugs should not be used during the study. For women of child-bearing potential: pregnant or intending to become pregnant within the next 8 months. Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed. Individual is expecting to move out of the area during the 8 months of the study. A participant will be excluded if the study eye meets any of the following criteria: Macular edema is considered to be due to a cause other than DME. An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or investigator assessment of OCT suggests that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are contributing to the macular edema. An ocular condition is present such that, in the opinion of the investigator, any visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition). An ocular condition is present (other than DME) that, in the opinion of the investigator, might affect visual acuity during the course of the study or require intraocular treatment (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.) Cataract is present that, in the opinion of the investigator, may alter visual acuity during the course of the study. History of major ocular surgery (including cataract, scleral buckle, any intraocular surgery, etc.) within prior 4 months or major ocular surgery anticipated during the study period. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME or DR (such as panretinal photocoagulation, focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, or anti-VEGF) within the prior 12 months. If treatment was given more than 12 months prior, no more than 4 prior intraocular injections. Enrollment will be limited to a maximum of 15 percent of the planned sample size with any history of anti-VEGF treatment and a maximum of 15% with any history of PRP. Anticipated need to treat DME or DR during the study period History of topical steroid or non-steroidal anti-inflammatory drug treatment within 30 days prior to randomization. History of YAG capsulotomy performed within 2 months prior to randomization Any history of vitrectomy. Aphakia Uncontrolled glaucoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Random assignment (1:1) to photobiomodulation (PBM) or sham
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Photobiomodulation (PBM)<br>670nm wavelength device twice a day for 90 seconds through 4 months. At the 4-month visit, participants who have not already received alternative treatments for DME will return the original device and receive the alternative treatment group device (i.e. the sham group will receive an active treatment device and the active treatment group will receive a sham device). | Device: Retilux<br>* 670nm wavelength light<br>* Other names: Photobiomodulation;|
| Sham Comparator: Placebo<br>Broad spectrum light device twice a day for 90 seconds through 4 months. At the 4-month visit, participants who have not already received alternative treatments for DME will return the original device and receive the alternative treatment group device (i.e. the sham group will receive an active treatment device and the active treatment group will receive a sham device) | Device: Sham Light Device<br>* Broad spectrum light device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Optical Coherence Tomography Central Subfield Thickness From Baseline to 4 Months | Only eyes that completed the 4-month visit were included in calculation of descriptive statistics of optical coherence tomography (OCT) data. For eyes that received alternate DME treatment prior to 4 months (N=3 [PBM]; N = 1 [placebo]), the last OCT measurements prior to alternative diabetic macular edema (DME) treatment were used in place of the 4-month measurements. All analyses followed the intent-to-treat principle. Multiple imputation (m = 100) was used for missing values of central subfield thickness and retinal volume change, with imputation models that included variables for treatment group, baseline values, and change from baseline at all monthly interim visits up to the primary outcome visit and the randomization stratification factor of recent or planned intravitreous treatment in the non-study eye. Multiple imputation was not performed for center-involved DME given the thresholds are gender and machine specific. OCT CST change was truncated to the mean ± 3 SD (13 ± 3 × 5 | Baseline to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Retinal Volume on Optical Coherence Tomography From Baseline to 4 Months | CST = central subfield thickness, OCT = optical coherence tomography, PBM = photobiomodulation | Baseline to 4 months | 
| Number of Eyes With Center-involved Diabetic Macular Edema on Optical Coherence Tomography at 4 Months | DME = diabetic macular edema, OCT = optical coherence tomography | baseline to 4 months | 
| Number of Eyes Receiving Alternative Treatment for Diabetic Macular Edema |  | 4 months | 
| Change in Visual Acuity From Baseline to 4 Months | Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart. Visual acuity (VA) change truncated to mean ±3 SD (-0.3 ± 3 × 5.3). Eyes that received alternative treatment for DME before primary outcome visit (3 PBM, 1 placebo); last measurements taken before DME treatment was initiated were the pre-specified outcome data. Missing data for eyes that didn't get alternative treatment for DME imputed with multiple imputation. | baseline to 4 months | 
| Change in Optical Coherence Tomography Central Subfield Thickness From 4 to 8 Months | Only eyes that completed the 4-month visit were included in calculation of descriptive statistics of OCT data. For eyes that received alternate DME treatment prior to 4 months (N = 3 [PBM]; N = 1 [placebo]), the last OCT measurements prior to alternative DME treatment were used in place of the 4-month measurements. All analyses followed the intent-to-treat principle. Multiple imputation (m = 100) was used for missing values of central subfield thickness and retinal volume change, with imputation models that included variables for treatment group, baseline values, and change from baseline at all monthly interim visits up to the primary outcome visit and the randomization stratification factor of recent or planned intravitreous treatment in the non-study eye. Multiple imputation was not performed for center-involved DME given the thresholds are gender and machine specific. OCT CST change was truncated to the mean ± 3 SD (13 ± 3 × 58) | 4 to 8 months |