INflammatory MediatorS in the PathophysIology of Diabetic REtinopathy Study

NCT04505566 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2014335R01EY031315-02
• Study Type: interventional
• Target: 164
• Locations: 1 country
• Sites: 1

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.

Conditions

Diabetic Retinopathy

Keywords

Topical Ketorolac; Acuvail; Prevention of Diabetic Retinopathy

Outcome Measures

Primary Outcomes (6)

• PGE2 level during Diabetic Retinopathy progression

  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.

  1 year

• Vascular Endothelial Growth Factor (VEGF) level during Diabetic Retinopathy progression

  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.

  1 year

• Interleukin 6 (IL-6) level during Diabetic Retinopathy progression

  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.

  1 year

• Interleukin 8 (IL-8) level during Diabetic Retinopathy progression

  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.

  1 year

• Progression of Diabetic Retinopathy (DR)

  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.

  3 years

• Severity of Diabetic Retinopathy (DR)

  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).

  3 years

Secondary Outcomes (2)

• Incidence of Diabetic Macular Edema

  3 years

• Progression of Diabetic Macular Edema

  3 years

Study Arms (5)

Adult Type II Diabetics - Moderate NPDR - Ketorolac

EXPERIMENTAL

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; Other: Aqueous PGE2 and inflammatory cytokines measurements

Adult Type II Diabetics - Moderate NPDR - Placebo

PLACEBO COMPARATOR

59 Adult type II diabetic patients with baseline moderate non-proliferative diabetic retinopathy randomized to placebo treatment.

Drug: Placebo - Preservative-free artificial tears; Other: Aqueous PGE2 and inflammatory cytokines measurements

Adult Type II Diabetics - No Diabetic Retinopathy (DR)

OTHER

23 Adult type II diabetic patients with no diabetic retinopathy as a control group.

Other: Aqueous PGE2 and inflammatory cytokines measurements

Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR)

OTHER

23 Adult type II diabetic patients with proliferative diabetic retinopathy as a control group.

Other: Aqueous PGE2 and inflammatory cytokines measurements

Age-matched Non-diabetics

OTHER

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

Interventions

Aqueous PGE2 and inflammatory cytokines measurements OTHER

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

Adult Type 2 Diabetics-Proliferative Diabetic Retinopathy(PDR); Adult Type II Diabetics - Moderate NPDR - Ketorolac; Adult Type II Diabetics - Moderate NPDR - Placebo; Adult Type II Diabetics - No Diabetic Retinopathy (DR); Age-matched Non-diabetics

Ketorolac 0.45% ophthalmic solution DRUG

Ketorolac 0.45% ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.

Also known as: Acuvail

Adult Type II Diabetics - Moderate NPDR - Ketorolac

Placebo - Preservative-free artificial tears DRUG

Preservative free artificial tears ophthalmic solution 1 drop instilled in both eyes twice daily for 3 years in double-masked fashion.

Also known as: Refresh

Adult Type II Diabetics - Moderate NPDR - Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

Sponsors & Collaborators

• Stephen J. Kim, MD: lead
• Allergan: collaborator
• National Eye Institute (NEI): collaborator

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• Kim SJ, Gangaputra S, Sheng J, Patel S, Nair AA, Al Hussein Al Awamlh S, Fitzpatrick J, Cherney E, Veach L, Nicholson C. Analysis of 24 pro-inflammatory cytokines in aqueous and serum of 94 patients without diabetes. Br J Ophthalmol. 2025 Nov 20;109(12):1357-1362. doi: 10.1136/bjo-2025-327421.

  PMID: 40695570 DERIVED

MeSH Terms

Conditions

Diabetic Retinopathy

Interventions

Ketorolac; Ophthalmic Solutions

Condition Hierarchy (Ancestors)

Retinal Diseases; Eye Diseases; Diabetic Angiopathies; Vascular Diseases; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Indomethacin; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pharmaceutical Solutions; Solutions; Pharmaceutical Preparations; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals

Study Officials

• Stephen J Kim, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Ophthalmology

Model Details: 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.

Study Record Dates

• First Submitted: July 31, 2020
• First Posted: August 10, 2020
• Study Start: November 9, 2020
• Primary Completion: May 1, 2026
• Study Completion: May 1, 2026
• Last Updated: January 21, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)