The Role of Prostaglandins in the Progression of Diabetic Retinopathy

Phase 1

Withdrawn

• Conditions: Inflammation
• Interventions: Other: Placebo; Drug: Acuvail

• Registration Number: NCT01609881
• Lead Sponsor: Vanderbilt University

Brief Summary

Objective of the research study:

1. To measure anterior chamber and vitreous ketorolac (Acuvail®) concentrations after topical administration in patients undergoing routine vitrectomy to determine the ability of the medication to penetrate into the anterior chamber and vitreous cavity, and to compare these levels to the IC50 for the cyclooxygenase-1 and -2 enzymes (COX-1 and COX-2)

2. To measure vitreous concentrations of prostaglandin subtypes (PGE, PGD, PGF) and other inflammatory mediators (Interleukin-1β \[IL-1β\], IL-6, IL-8, tumor necrosis factor \[TNF\]-α, VEGF) in both diabetic and nondiabetic patients undergoing vitrectomy

3. To determine if topical ketorolac (Acuvail®) can penetrate the anterior chamber and vitreous cavity sufficiently to decrease levels of intraocular inflammatory mediators that have been shown to be elevated in diabetic patients

4. To serve as a precursor to a 5-year longitudinal clinical trial to determine if chronically administered topical ketorolac (Acuvail®) can prevent, delay or slow diabetic retinopathy.

Research hypothesis

1. Ketorolac (Acuvail®) will penetrate the anterior chamber and vitreous cavity sufficiently to achieve levels above the IC50 for COX-1 and COX-2

2. Prostaglandin and other inflammatory mediator levels in the anterior chamber and vitreous cavity will be significantly higher among diabetic patients than nondiabetic controls

3. Acuvail® can significantly lower anterior chamber and vitreous cavity levels of prostaglandins and other inflammatory mediators in diabetic patients

Detailed Description

Patients who require vitrectomy for any indication and those meeting the inclusion/exclusion criteria will be included. Patients will be consented to participate in the study and for surgery.

Nondiabetic patients will be included in one of two groups. Twenty will receive topical ketorolac (Acuvail®) preoperatively for 3 days and then samples will be taken at the time of surgery. Twenty other patients will serve as controls for intraocular prostaglandin and cytokine levels (to be compared to diabetic patients). This group will not receive preoperative ketorolac (Acuvail®).

Diabetic patients will be included in one of two groups. Twenty patients will have intraocular prostaglandin and cytokine levels measured. Twenty other patients will be in the interventional group to determine if topical ketorolac (Acuvail®) can successfully lower intraocular prostaglandin and inflammatory cytokine levels.

In all cases, patients are undergoing vitreoretinal surgery as the surgical treatment of choice for their condition. For this study, undiluted samples will be drawn from the vitreous cavity and anterior chamber at the beginning of the vitrectomy. These samples will be stored, analyzed and frozen.

Samples will be tested for prostaglandin levels, in addition to other inflammatory cytokines, and ketorolac levels.

Three days of Acuvail® given four times per day was chosen, as previous studies have shown that one dose of ketorolac 0.4% achieves a peak aqueous concentration of 57.5 ng/mL,1 and that 12 doses over two days achieves an aqueous concentration of 1079 ng/mL.2 Both values are well above the IC50 for COX-1 (5.3 to 7.5 ng/mL) and COX-2 (33.9-45.2 ng/mL). The upper end of this dosing spectrum was chosen, as more doses and a longer duration of therapy is likely required to achieve sufficient vitreous levels to inhibit COX-1 and COX-2. This dosing regimen was also used in another clinical study that assessed ketorolac levels and prostaglandin levels in the vitreous cavity after topical administration four times a day for three days preoperatively.3

Study Timeline

• Study Start: 2012-03
• Study First Submitted: 2012-03-27
• Study First Submitted QC: 2012-05-29
• Study First Posted: 2012-06-01
• Primary Completion: 2016-10-19
• Study Completion: 2016-10-19
• Status Verified: 2017-02
• Last Update Submitted: 2017-02-20
• Last Update Posted: 2017-02-23

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Adult patients aged 18 years or older who present for vitrectomy surgery for any indication.
2. Diabetic and non-diabetic patients will be included.

Exclusion criteria:

1. Patients under the age of 18 years of age.
2. Pregnant women.
3. Patients with a history of vitrectomy surgery.
4. Current topical, periocular, intraocular or systemic corticosteroid use
5. Co-existent macular, retinovascular or ocular inflammatory disease (age-related macular degeneration, retinal venous occlusive disease, uveitis, etc.)

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo using artificial tear drops
Acuvail	Acuvail	Acuvail as preventive for inflammation and possible decrease or prevent diabetic retinopathy. The study has four arms - diabetic ketorolac, diabetic control, normal eyes ketorolac, normal eyes control. patients are randomized to ketorolac or control.

Primary Outcome Measures

Name	Time	Method
Vitreous and anterior chamber levels of prostaglandins, other cytokines, and Acuvail	3 days	Vitreous and anterior chamber levels of prostaglandins, other cytokines, and Acuvail

Secondary Outcome Measures

Name	Time	Method
Primary Outcome	7 days	The primary outcomes include drug and prostaglandin concentrations on the anterior chamber and vitreous.
Secondary Outcome	14 days	The secondary outcome will include cytokine levels in the vitreous.

Trial Locations

Locations (1)

Vanderbilt Eye Institute; 🇺🇸 Nashville, Tennessee, United States