Effectiveness of Periocular Drug Injection in CATaract Surgery (EPICAT)

Cystoid macular edema (CME) is a major cause of suboptimal postoperative visual acuity after cataract surgery. Topical steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to prevent CME. However, noncompliance with eye drops may compromise the effectiveness of treatment. Dropless periocular drug delivery during cataract surgery may improve the outcomes and cost-effectiveness of cataract surgery, and may alleviate the burden on homecare organizations.

In a recent European multicentre study (PREvention of Macular EDema after cataract surgery; PREMED), it was demonstrated that the combination of topical corticosteroids and NSAIDs results in the lowest risk of developing CME after cataract surgery. However, noncompliance with eye drops may compromise the effectiveness of treatment. Noncompliance is often unintentional and related to forgetfulness or incorrect instillation, particularly in the elderly cataract surgery population. The objective of this study is to evaluate the effectiveness of different treatments to prevent CME after cataract surgery, using either topical drugs (control group) or intra-/periocular injections (intervention groups). The hypothesis of this study is that intra-/periocular anti-inflammatory drug delivery during cataract surgery is effective in preventing CME, with better health-related quality of life and improved cost-effectiveness compared to standard topical drug delivery. The primary outcome measure is the change in central subfield mean macular thickness (CSMT) at 6 weeks postoperatively as compared to baseline. Secondary outcome measures are the incidence of CME; the incidence of clinically significant macular edema (CSME); mean corrected distance visual acuity (CDVA); para- and perifoveal thickness and total macular volume (TMV); intraocular pressure (IOP); anterior chamber inflammation; vision-related quality of life; and cost-effectiveness. The design of this study is a European randomised controlled multicenter trial. The study population will consist of 808 patients aged 21 years or older who require cataract surgery in at least one eye. Patients with a foreseen increased risk of developing CME or ophthalmic disorders other than cataract will be excluded. Follow-up duration is 12 weeks. The study will be conducted over a period of 36 months.

A block randomization procedure will be followed to acquire equal number of subjects in every treatment group. Patients are randomly allocated to 1 of 4 treatment groups in a 1:1:1:1 ratio. The various study centres will be taken into account during randomization.

Masking will be achieved as much as possible. As there is an objective primary outcome, it will not be necessary to replace medicines by sham injections or placebo eye drops. Moreover, the ophthalmologist who performs the cataract surgery will not be blinded for treatment allocation of the subject. The study statistician, the data safety monitoring group, optometrists who perform the examinations (especially visual acuity) and observers who evaluate the examinations and OCTs will be masked when possible for treatment allocation.

bromfenac 0.09% eye drops twice daily starting two days before surgery and continuing 2 weeks postoperatively & dexamethasone 0.1% eye drops four times daily starting two days before surgery and continuing four times daily during the first postoperative week and one drop less per day every following week.

one subconjunctival injection of 10 mg triamcinolone acetonide during cataract surgery (TA, Triesence/Vistrec) in the inferotemporal quadrant, 6mm from the limbus.

intracameral injection of ketorolac tromethamine solution during cataract surgery (Omidria). A 4ml vial of Omidria (ketorolac concentration 2.88mg/ml) is added to 500ml of the irrigation solution used during cataract surgery, resulting in a ketorolac concentration of 0.023mg/ml. At the end of the surgery, the anterior chamber will be filled with the ketorolac solution.

one subconjunctival injection of 10 mg triamcinolone acetonide & intracameral injection of ketorolac tromethamine solution (Omidria; 0.023mg/mL) during cataract surgery.

0.25ml of 40mg/ml (10mg) triamcinolone acetonide (Triesence/Vistrec) will be injected subconjunctivally

Omidria is added to the irrigation fluid used during cataract surgery. At the end of surgery, the anterior chamber will be filled with the ketorolac solution.

The primary endpoint is the change in central subfield mean macular thickness in the 1 mm area (central subfield macular thickness, CSMT) as compared to baseline within the first 6 weeks postoperatively, measured using Optical Coherence Tomography (OCT)

The occurrence of postoperative clinically significant macular edema (CSME) within 12 weeks postoperatively

Change in parafoveal retinal thickness in the central inner circle (1.0 - 3.0mm) as a measurement of efficacy

Change in perifoveal retinal thickness in the central outer circle (3.0 - 6.0mm) as a measurement of efficacy

CDVA measurements will be taken using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts (logMAR)

IOP (in mmHg) will be measured by Goldmann applanation tonometry (preferred), Non-Contact Tonometry, or iCare tonometry

An adverse event (AE) is defined as any undesirable experience occurring to a subject during the study, whether or not considered related to the investigational product. All adverse events reported spontaneously by the subject or observed by the principal investigator or his staff will be recorded. Most frequently reported adverse events which might occur while using the study medication: abnormal sensation in the eye, pain or irritation, redness or headache while using eye drops; increased IOP and masking of infections while using corticosteroids; abnormal sensation in the eye, pain or irritation, conjunctival hyperaemia, inflammation and corneal edema after intracameral injection with phenylephrine/ketorolac.

Patient satisfaction and vision-specific quality of life as measured by National Eye Institute Visual Function Questionnaire (NEI VFQ-25).

Calculated based on generic health-related quality of life, using the EQ-5D-5L and HUI-3 questionnaires

Cost per patient, including valuation of resource use by using the Dutch guidelines for cost-analyses or cost prices provided by the medical center.

Reported as a difference in costs. Different scenario's will be compared to investigate the impact of various levels of implementation (e.g. 25%, 50%, 75% of eligible patients).

Inclusion Criteria: who are undergoing routine phacoemulsification (one eye per patient); who are 21 years or older; who should be able to communicate properly and understand instructions. willing and/or able to comply with the scheduled visits and other study procedures. Exclusion Criteria: patients who already participated with their contralateral eye; combined surgery (e.g. combined phacoemulsification and trabeculectomy); patients with an increased risk of developing cystoid macular edema (CME) in the study eye (e.g. diabetes mellitus, previous retinal venous occlusion, or a history of uveitis, macular edema, epiretinal membrane, or previous retinal surgery); patients who developed CME after cataract surgery in the contralateral eye; patients with cystoid macular changes in the study eye at baseline; patients with an increased risk of developing perioperative complications (e.g. Fuchs' endothelial dystrophy); patients with permanent moderate visual impairment in the contralateral eye (decimal visual acuity less than 0.3); patients with a history of steroid induced IOP rise or glaucomatous visual field loss; patients using drugs that reduce or increase the risk of macular edema (e.g., periocular or intraocular corticosteroid, NSAID, or antivascular endothelial growth factor (VEGF) injection; topical corticosteroid or NSAID use; systemic corticosteroids (>= 20mg prednisolon), methotrexate, biologicals, or acetazolamide), or in the previous 4 months; patients with a contraindication for any of the investigated drugs; patients who are cardiovascular unstable; patients who have a history of hyperthyroidism.