The Role of Prostaglandins in the Progression of Diabetic Retinopathy
Objective of the research study:
- 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)
- 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
- 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
- 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.
- Ketorolac (Acuvail®) will penetrate the anterior chamber and vitreous cavity sufficiently to achieve levels above the IC50 for COX-1 and COX-2
- Prostaglandin and other inflammatory mediator levels in the anterior chamber and vitreous cavity will be significantly higher among diabetic patients than nondiabetic controls
- Acuvail® can significantly lower anterior chamber and vitreous cavity levels of prostaglandins and other inflammatory mediators in diabetic patients
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
|Official Title:||The Role of Prostaglandins in the Progression of Diabetic Retinopathy and the Therapeutic Efficacy of Topical Ketorolac (Acuvail)|
- Vitreous and anterior chamber levels of prostaglandins, other cytokines, and Acuvail [ Time Frame: 3 days ] [ Designated as safety issue: No ]Vitreous and anterior chamber levels of prostaglandins, other cytokines, and Acuvail
- Primary Outcome [ Time Frame: 7 days ] [ Designated as safety issue: No ]The primary outcomes include drug and prostaglandin concentrations on the anterior chamber and vitreous.
- Secondary Outcome [ Time Frame: 14 days ] [ Designated as safety issue: No ]The secondary outcome will include cytokine levels in the vitreous.
|Study Start Date:||March 2012|
|Estimated Study Completion Date:||January 2016|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
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.
Dosing of drug 3 days prior to surgery
Other Name: Ketorolac 0.45%
Placebo Comparator: Placebo
Placebo using artificial tear drops
Artificial tears qid for 3 days preoperatively
Other Name: tears
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
|Contact: Stephen J Kim, MDemail@example.com|
|Contact: Sandy A Owingsfirstname.lastname@example.org|
|United States, Tennessee|
|Vanderbilt Eye Institute||Recruiting|
|Nashville, Tennessee, United States, 37232-8808|
|Contact: Sandy A Owings 615-936-1474 email@example.com|
|Contact: Lisa Pate 615-936-3465 firstname.lastname@example.org|
|Sub-Investigator: Scott D Schoenberger, MD|
|Principal Investigator:||Stephen J Kim, MD||Vanderbilt Eye Institute|