Effectiveness of Periocular Drug Injection in CATaract Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The ESCRS EPICAT Study: Effectiveness of Periocular Drug Injection in CATaract Surgery

Conditions
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Macular Edema, Cystoid Macular Edema, Retinal Disease, Cataract, Lens Diseases, Eye Diseases

Intervention / Treatment
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* Drug: Bromfenac
* Drug: Dexamethasone
* Drug: Triamcinolone Acetonide
* Drug: Ketorolac-Phenylephrine Ophthalmic 0.3%-1% Intraocular Solution


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: topical bromfenac & dexamethasone<br>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. | Drug: Bromfenac<br>* Bromfenac topical eye drops (Yellox)<br>* Other names: Product code: EU/1/11/692;Drug: Dexamethasone<br>* Dexamethasone topical eye drops<br>* Other names: Product code (NL): RVG 56003;|
| Active Comparator: subconjunctival triamcinolone acetonide<br>one subconjunctival injection of 10 mg triamcinolone acetonide during cataract surgery (TA, Triesence/Vistrec) in the inferotemporal quadrant, 6mm from the limbus. | Drug: Triamcinolone Acetonide<br>* 0.25ml of 40mg/ml (10mg) triamcinolone acetonide (Triesence/Vistrec) will be injected subconjunctivally<br>* Other names: Product code (NL): RVG 106092;|
| Active Comparator: intracameral ketorolac<br>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. | Drug: Ketorolac-Phenylephrine Ophthalmic 0.3%-1% Intraocular Solution<br>* 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.<br>* Other names: Omidria;|
| Active Comparator: subconjunctival triamcinolone acetonide & intracameral ketorolac<br>one subconjunctival injection of 10 mg triamcinolone acetonide & intracameral injection of ketorolac tromethamine solution (Omidria; 0.023mg/mL) during cataract surgery. | Drug: Triamcinolone Acetonide<br>* 0.25ml of 40mg/ml (10mg) triamcinolone acetonide (Triesence/Vistrec) will be injected subconjunctivally<br>* Other names: Product code (NL): RVG 106092;Drug: Ketorolac-Phenylephrine Ophthalmic 0.3%-1% Intraocular Solution<br>* 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.<br>* Other names: Omidria;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in central subfield mean macular thickness as a measurement of efficacy | 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) | Baseline, 6 weeks postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in central subfield mean macular thickness as a measurement of efficacy | Measured using OCT | Baseline, 12 weeks postoperatively | 
| No. of subjects developing clinically significant macular edema as a measurement of efficacy | The occurrence of postoperative clinically significant macular edema (CSME) within 12 weeks postoperatively | Until 12 weeks postoperatively | 
| Change in parafoveal retinal thickness in the central inner circle (1.0 - 3.0mm) as a measurement of efficacy | Measured using OCT | Baseline, 6 weeks and 12 weeks postoperatively | 
| Change in perifoveal retinal thickness in the central outer circle (3.0 - 6.0mm) as a measurement of efficacy | Measured using OCT | Baseline, 6 weeks and 12 weeks postoperatively | 
| Change in macular volume in the central 6.0mm area as a measurement of efficacy | Measured using OCT | Baseline, 6 weeks and 12 weeks postoperatively | 
| Change in corrected distance visual acuity (CDVA) as a measurement of efficacy | CDVA measurements will be taken using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts (logMAR) | Baseline, 1 week, 6 weeks, and 12 weeks postoperatively | 
| Change in Intraocular pressure (IOP) as a measurement of safety | IOP (in mmHg) will be measured by Goldmann applanation tonometry (preferred), Non-Contact Tonometry, or iCare tonometry | Baseline, 1 week, 6 weeks, and 12 weeks postoperatively | 
| Anterior chamber inflammation as a measurement of safety | using the Standardization of Uveitis Nomenclature (SUN) classification | Baseline, 1 week , 6 weeks, and 12 weeks postoperatively | 
| No. of subjects with Adverse Events as a measurement of safety and tolerability | 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. | Until 12 weeks postoperatively | 
| Patient reported outcome measures (PROMs): NEI VFQ-25 | Patient satisfaction and vision-specific quality of life as measured by National Eye Institute Visual Function Questionnaire (NEI VFQ-25). | Baseline and 12 weeks postoperatively | 
| Patient reported outcome measures (PROMs): Catquest | Patient satisfaction and vision-specific quality of life as measured by Catquest questionnaire. | Baseline and 12 weeks postoperatively | 
| Patient reported outcome measures (PROMs): HUI3 | Health-related quality of life as measured by HUI3 (Health Utility Index Mark 3) questionnaire. | Baseline and 12 weeks postoperatively | 
| Patient reported outcome measures (PROMs): EQ-5D-5L | Health-related quality of life as measured by EQ-5D-5L questionnaire. | Baseline and 12 weeks postoperatively | 
| Quality Adjusted Life Years (QALYs) | Calculated based on generic health-related quality of life, using the EQ-5D-5L and HUI-3 questionnaires | Baseline until 12 weeks postoperatively | 
| Costs per patient | Cost per patient, including valuation of resource use by using the Dutch guidelines for cost-analyses or cost prices provided by the medical center. | Baseline until 12 weeks postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): QALY | Evaluation of cost-effectiveness by using calculated costs per quality-adjusted life years (QALYs) | Baseline until 12 weeks postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): NEI VFQ-25 | Calculated costs per clinically improved patient on the NEI VFQ-25 questionnaire | Baseline until 12 weeks postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): Catquest | Calculated costs per clinically improved patient on the Catquest questionnaire | Baseline until 12 weeks postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): Visual acuity | Calculated costs per patient with clinical improvement in (un)corrected distance visual acuity | Baseline until 12 weeks postoperatively | 
| Budget impact | 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). | Baseline until 12 weeks postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention