PCME Prevention in Patients With NPDR

Study Overview
=================
Brief Summary
-----------------
Pseudophakic cystoid macular edema (PCME), or Irvine-Gass syndrome, is retinal thickening of the macula, which usually develops within 3 months after surgery, with a peak incidence between 4 and 6 weeks. Despite recent improvements in surgical techniques, PCME remains one of the most common causes of visual decline following an uneventful cataract surgery. Symptoms of PCME usually are blurred vision, metamorphopsia, loss of contrast sensitivity, and central scotomas. PCME usually responds well to medical therapy or may resolve spontaneously but carries a risk of permanent vision loss or loss of contrast sensitivity. There is wide discrepancy in opinions about the most effective antiinflammatory drops for the prevention of PCME. Patients with diabetes mellitus (DM) have attracted special interest because of higher incidence of cataract and increased risk for developing CME after cataract surgery. The optimum antiinflammatory prophylaxis for PCME in patients with nonproliferative diabetic retinopathy (NPDR) remains unknown. Purpose of this study is to determine the efficacy of topical bromfenac and topical dexamethasone on intraocular concentration of interleukin-6 (IL6) and the incidence of pseudophakic cystoid macular edema (PCME) after cataract surgery in patients with nonproliferative diabetic retinopathy (NPDR).

Detailed Description
-----------------
There is no standardized, widely-acceptable, evidence-based prophylaxis and treatment protocols to prevent macular edema after cataract surgery (PCME). Current leading theory of pathogenesis of PCME (Irvine Gass) involves inflammation caused by surgical trauma which induces the release of inflammatory mediators like cytokines, prostaglandins and other vasopermeability factors, which disrupt the blood-retinal barrier and cause leakage from perifoveal retinal capillaries and accumulation of extracellular fluid in outer plexiform and inner nuclear layers of the retina. Diabetes is significant risk factor for developing PCME and grows proportionately with the severity of the diabetic retinopathy (DR). DR is common complication of diabetes mellitus (DM) and affects one in three persons with DM. Interleukin-6 (IL6) is associated with many intraocular inflammatory diseases such as diabetic retinopathy and macular edema acting as a pro-inflammatory cytokine. Levels of IL6 in aqueous humor are correlated with the severity of DR and the severity of DME. IL6 probably plays a crucial role in the development of inflammation after cataract surgery. Macular edema is usually monitored by spectral domain optical coherence tomography (SD-OCT) which is suitable for detecting subtle macular changes as well as follow up after treatment. OCT provides an objective measurement of macular thickness that correlates well with visual impairment and can be useful in standardizing definitions of PCME. Prevention of PCME after cataract surgery in patients with NPDR include preoperative treatment with steroids, intravitreal injections of anti-vascular endothelial growth factors, laser treatment and topical nonsteroidal anti-inflammatory drugs (NSAIDs). This randomized, double blinded, placebo-controlled trial will be conducted at Clinic of Ophthalmology, University Hospital Center Zagreb, Croatia. Ninety (90) eyes with mild to moderate NPDR (EDTRS classification) and cataract grade II nuclear/cortical or posterior subcapsular (Lens Opacities Classification System III) who will undergo phacoemulsification with intraocular lens implantation will be divided into three groups. Group 1 will receive topical bromfenac, group 2 will receive topical dexamethasone and group 3 will receive topical placebo, 7 days preoperatively and 3 weeks postoperatively. All patients will receive standard regimen of topical steroid-antibiotic drops postoperatively. Macular edema is defined as central foveal subfield thickness (CFT) increase of 40% from baseline. On the day of the surgery aqueous humor samples (0.1-0.2 mL) will be taken and IL6 concentration will be analyzed. Central foveal subfield thickness (CFT) will be measured with spectral domain optical coherence tomography (SD-OCT) and analyzed 7 days prior to surgery, on the day of the surgery and on 1, 7, 30 and 90 postoperative day.

Official Title
-----------------
The Effect of Topical Corticosteroids and Topical NSAIDs Perioperatively on IL6 Levels in Aqueous Humor and on Incidence of PCME in Patients With NPDR

Conditions
-----------------
Cystoid Macular Edema Following Cataract Surgery

Intervention / Treatment
-----------------
* Drug: Bromfenac Ophthalmic 0.09% Ophthalmic Solution
* Drug: Dexamethasone Ophthalmic
* Drug: Placebo
* Procedure: Phacoemulsification surgery (PHACO)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: clinical diagnosis of mild to moderate nonproliferative diabetic retinopathy (EDTRS) and senile cataract grade II nuclear/cortical or posterior subcapsular (LOCS III) Exclusion Criteria: anterior segment pathology (pseudoexfoliation syndrome, corneal opacities), posterior segment pathology (diabetic macular edema, previous diabetic macular edema treatment, previous retinal photocoagulation therapy, age related macular degeneration, retinal vascular diseases or history of uveitis) intraoperative complications (posterior capsular rupture, vitreus loss, intraocular lens not implanted in the capsular bag), postoperative complications (leaking incision, increased intraocular pressure, corneal edema or inflammation), therapy for glaucoma, patients on antihypertensive therapy, topical or systemic NSAIDs or steroids, previous steroid responders or hypersensitivity to the NSAID drug class, previous ocular trauma and intraocular surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bromfenac<br>Group 1 will receive topical bromfenac (0.9 mg/mL) 2x daily, 7 days before the surgery | Drug: Bromfenac Ophthalmic 0.09% Ophthalmic Solution<br>* topical bromfenac (0.9 mg/mL) 2x daily 7 days before the surgery<br>* Other names: Bromfenac;Procedure: Phacoemulsification surgery (PHACO)<br>* About 0.1-0.2 mL of aqueous humor will be collected at the beginning of the cataract surgery (PHACO) through paracentesis, aqueous will then be transported in dry ice with a dedicated box to the laboratory and stored at -80C until the analysis. IL6 concentration will be analyzed with Human IL6 Quantikine Elisa kit (R&D System).<br>|
| Experimental: Dexamethasone<br>Group 2 will receive topical dexamethasone (1mg/mL) 2x daily before the surgery | Drug: Dexamethasone Ophthalmic<br>* topical dexamethasone (1 mg/mL) 2x daily 7 days before the surgery<br>* Other names: Dexamethasone;Procedure: Phacoemulsification surgery (PHACO)<br>* About 0.1-0.2 mL of aqueous humor will be collected at the beginning of the cataract surgery (PHACO) through paracentesis, aqueous will then be transported in dry ice with a dedicated box to the laboratory and stored at -80C until the analysis. IL6 concentration will be analyzed with Human IL6 Quantikine Elisa kit (R&D System).<br>|
| Placebo Comparator: Placebo<br>Group 3 will receive topical placebo (artificial tears substitute) 2x daily before the surgery | Drug: Placebo<br>* topical placebo (artificial tears substitute) 2x daily before the surgery<br>Procedure: Phacoemulsification surgery (PHACO)<br>* About 0.1-0.2 mL of aqueous humor will be collected at the beginning of the cataract surgery (PHACO) through paracentesis, aqueous will then be transported in dry ice with a dedicated box to the laboratory and stored at -80C until the analysis. IL6 concentration will be analyzed with Human IL6 Quantikine Elisa kit (R&D System).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin 6 concentration | IL6 concentration in aqueous humor will be analyzed with Human IL6 Quantikine Elisa kit R&D System | up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central foveal subfield thickness (CFT) measured by optical coherence tomography (OCT) | Macular thickness will be reported according to the EDTRS thickness map. Central foveal subfield thickness (CFT) corresponds to the mean macular thickness in the central 1.0 mm area measured by optical coherence tomography (OCT). | 7 days before the surgery, on the day of the surgery, on 1, 7, 30 and 90 postoperative day | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pseudophakic cystoid macular edema (PCME), Interleukin-6 (IL6), Central foveal subfield thickness (CFT), Spectral domain Optical coherence tomography (SD-OCT)