Purpose

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.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts 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 Exclusion Criteria: Patients with a history of previous vitrectomy in either eye; prior intravitreal injection within 3 months; co-existent macular, retinovascular, or inflammatory disease; history of ocular trauma; aphakia; presence of an anterior chamber intraocular lens; current use of prescription systemic NSAIDs or regular use of nonprescription NSAIDs including aspirin (defined as 4 days or more a week for at least 2 weeks a month); blood pressure > 180/110 mmHg; risk for corneal melting; and inability to comply with follow-up. - Aim 1 Nondiabetic Control Arm Exclusion Criteria: Patients who are unable to comply with testing and follow-up. - Aim 2 Exclusion Criteria: Patients with a history of previous vitrectomy in either eye; prior intravitreal injection within 3 months; co-existent macular, retinovascular, or inflammatory disease; history of ocular trauma; aphakia; presence of an anterior chamber intraocular lens; current use of prescription systemic NSAIDs or regular use of nonprescription NSAIDs including aspirin (defined as 4 days or more a week for at least 2 weeks a month); blood pressure > 180/110 mmHg; risk for corneal melting; and inability to comply with follow-up.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
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.
Primary Purpose
Prevention
Masking
Double (Participant, 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.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Adult Type II Diabetics - Moderate NPDR - Ketorolac
59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy and HbA1c ≥ 8 randomized to Ketorolac treatment.
  • Drug: Ketorolac 0.45% ophthalmic solution
    Ketorolac 0.45% ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.
    Other names:
    • Acuvail
  • Other: Aqueous 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
Placebo Comparator
Adult Type II Diabetics - Moderate NPDR - Placebo
59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy randomized to placebo treatment.
  • Drug: Placebo - 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.
    Other names:
    • Refresh
  • Other: Aqueous 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
Other
Adult Type II Diabetics - No Diabetic Retinopathy (DR)
23 Adult type II diabetic patients with no diabetic retinopathy as a control group.
  • Other: Aqueous 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
Other
Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR)
23 Adult type II diabetic patients with proliferative diabetic retinopathy as a control group.
  • Other: Aqueous 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
Other
Age-matched Non-diabetics
We will also enroll 100 age-matched patients without diabetes who are undergoing unilateral vitrectomy surgery for non-inflammatory conditions such as epiretinal membrane or macular hole. Removed aqueous fluid that is typically discarded will instead be collected and stored at -80° C. Aqueous fluid will be tested for inflammatory markers as detailed below to provide a reference level for cross-comparison analysis.
  • Other: Aqueous 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

Recruiting Locations

Vanderbilt University Medical Center
Nashville, Tennessee 37232

More Details

Status
Recruiting
Sponsor
Stephen J. Kim, MD

Study Contact

Crystal Nicholson
615-936-0971
crystal.nicholson@vumc.org

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.