Diabetic Retinopathy
Conditions
Keywords
Topical Ketorolac, Acuvail, Prevention of Diabetic Retinopathy
Brief summary
The central hypothesis is that inflammation mediators are biomarkers of both systemic diabetes and Diabetic Retinopathy (DR) progression in the aqueous and that sustained topical ketorolac application reduces/suppresses those inflammatory mediators thereby reducing the progression of Diabetic Retinopathy.
Detailed description
Study goals include confirming inflammation mediators are biomarkers of both systemic diabetes and DR progression in the aqueous. Like the vitreous humor, the aqueous reflects localized ocular inflammation, however, is technically easier to collect with less risk. The investigators will also determine the long-term effects of sustained ketorolac application on intraocular cytokine levels, DR progression, and diabetic macular edema (DME) incidence. The proposal is the first to use a cornea-permeable Nonsteroidal anti-inflammatory drug (NSAID) for the treatment of DR. It is believed local inflammation control in the eye will transform future treatment options for diabetic patients facing blindness. Tracking and inhibiting local inflammatory mediators through all DR stages has the capacity to reduce or prevent disability in millions of patients per year. 164 adult type II diabetic mellitus (T2DM) patients, aged 18 years or greater will be enrolled to measure aqueous PGE2 and inflammatory cytokines. Because the pathophysiology of type I disease and the population it effects are different, type I diabetic patients will be excluded. Diabetic retinopathy is broadly categorized as nonproliferative (NPDR) and proliferative (PDR). The international Clinical Disease Severity Scale is a standard classification system consisting of two categories and five stages: the nonproliferative category, stage 1-4 and proliferative category, stage 5. Stage 1 is characterized as "no apparent retinopathy." The nonproliferative stage is further grouped into stage 2 (mild), stage 3 (moderate), and stage 4 (severe). Stage 5 is final stage, PDR. Of the 164 patients enrolled for aqueous PGE2 and inflammatory cytokine measurements, the diabetic participants corresponding to stages 1, 3, and 5 will be classified as patients with no DR (23 patients), with PDR (23 patients), and with moderate NPDR (118 patients). The 118 participants with moderate NPDR will be randomized for Aim 2 described below. In addition, 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole will be enrolled as controls. Aim 1 of this project is to measure aqueous PGE2 and inflammatory cytokines during DR progression. Aim 2 of this project is two-fold: 1. Investigate the long-term effects of daily topical application of ketorolac on PGE2 and cytokine levels. 2. Determine how topical application of ketorolac influences DR progression and development of DME.
Interventions
DRUGKetorolac 0.45% ophthalmic solution
Ketorolac 0.45% ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.
DRUGPlacebo - Preservative-free artificial tears
Preservative free artificial tears ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.
OTHERAqueous PGE2 and inflammatory cytokines measurements
After topical anesthetic, antibiotic and 5% povidone-iodine application, a 30 gauge needle on a 1 ml tuberculin syringe will be inserted into the anterior chamber and used to collect 0.1 ml of aqueous fluid from each eye. Aqueous PGE2 and Inflammatory cytokines will be measured
Sponsors
Stephen J. Kim, MD
Allergan
National Eye Institute (NEI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Masking description
At the baseline visit, only patients from the moderate NPDR group will be randomized into one of 2 groups, using a red cap database for randomization in a block manner to ensure near equal randomization in both groups. A report is generated every 4 months for assessment of the number of patients in each randomized category. Patients in this group will have both eyes randomized to either Acuvail or placebo-control (preservative-free artificial tear) in double-masked fashion.
Intervention model description
This is a 2 aim, randomized and double-masked Phase I study on topical Ketorolac for the prevention of diabetic retinopathy. 164 adult type II diabetic patients, aged 18 years or greater will be enrolled in addition to 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole will also be enrolled.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aim 1 Diabetic Arm Inclusion Criteria: Adult patients age 18 years or greater with type II diabetes. * Aim 1 Nondiabetic Control Arm Inclusion Criteria: age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole. * Aim 2 Inclusion Criteria: Adult patients age 18 years or older with type II diabetes, with baseline moderate NPDR and HbA1c ≥ 8.
Exclusion criteria
* Aim 1 Diabetic Arm
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PGE2 level during Diabetic Retinopathy progression | 1 year | Aqueous samples will be analyzed using liquid chromatography electrospray ionization tandem mass spectrometry to measure all PGE2 levels. PGE2 will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis. |
| Vascular Endothelial Growth Factor (VEGF) level during Diabetic Retinopathy progression | 1 year | Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure VEGF levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis. |
| Interleukin 6 (IL-6) level during Diabetic Retinopathy progression | 1 year | Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure IL-6 levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis. |
| Interleukin 8 (IL-8) level during Diabetic Retinopathy progression | 1 year | Aqueous samples will be analyzed using a microparticle bead-based multiplex assay will be used to measure IL-8 levels. VEGF will be measured every 4 months during 1 year of study to determine whether their mean mediator levels associate with DR severity stage using a linear mixed effects model. The DR severity stage will be included as a continuous or categorical variable, and potential confounding factors as well as baseline measurements for each inflammatory mediator, will be adjusted in the analysis. |
| Progression of Diabetic Retinopathy (DR) | 3 years | To determine progression of DR, we will analyze data from the 118 diabetic patients randomized to either Ketorolac or placebo. Diabetic retinopathy progresses in discrete steps defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale (15-step scale: minimum value of 10 and maximum value of 65, with higher scores meaning a worse outcome). With each advancing level, the risk of developing DME and/or PDR increases. A 2-stage or more worsening on the ETDRS severity scale is associated with an increased risk of vision loss. |
| Severity of Diabetic Retinopathy (DR) | 3 years | A blinded sub-investigator will grade DR by utilizing the 15-step severity scale established by the ETDRS. A 2-step or more increase or decrease in severity scale, observed on 2 consecutive follow-up appointments, will define a change in DR (progression or improvement). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Diabetic Macular Edema | 3 years | To determine incidence of Diabetic Macular Edema, we will analyze data from the 118 diabetic patients. An increase in macular thickness (determined by OCT as ≥ 40%) will determine development of DME. |
| Progression of Diabetic Macular Edema | 3 years | To determine progression of Diabetic Macular Edema, we will analyze data from the 118 diabetic patients. An increase in macular thickness (determined by OCT as ≥ 40%) will determine progression of DME. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephen J Kim, MD
Vanderbilt University Medical Center
Outcome results
None listed