Clinical trial NCT04505566: INflammatory MediatorS in the PathophysIology of Diabetic REtinopathy Study
Official title: INflammatory MediatorS in the PathophysIology of Diabetic REtinopathy (INSPIRE) Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Diabetic Retinopathy
Keywords: Topical Ketorolac
Acuvail
Prevention of Diabetic Retinopathy
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: Allergan
name: National Eye Institute (NEI)
First posted: 2020-08-10
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: PGE2 level during Diabetic Retinopathy progression
timeFrame: 1 year
measure: Vascular Endothelial Growth Factor (VEGF) level during Diabetic Retinopathy progression
timeFrame: 1 year
measure: Interleukin 6 (IL-6) level during Diabetic Retinopathy progression
timeFrame: 1 year
measure: Interleukin 8 (IL-8) level during Diabetic Retinopathy progression
timeFrame: 1 year
measure: Progression of Diabetic Retinopathy (DR)
timeFrame: 3 years
measure: Severity of Diabetic Retinopathy (DR)
timeFrame: 3 years
Secondary outcomes:
measure: Incidence of Diabetic Macular Edema
timeFrame: 3 years
measure: Progression of Diabetic Macular Edema
timeFrame: 3 years
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Stephen J Kim, MD
role: PRINCIPAL_INVESTIGATOR
References: