The OPTIMISE Study

Study Overview
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Brief Summary
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Rationale: The cornea is the most transplanted tissue in the Netherlands, with more than 1,500 procedures performed each year. A minimally invasive technique called Descemet Membrane Endothelial Keratoplasty (DMEK) has become the preferred method in the past decade. The main advantage of DMEK over previous techniques is a low graft rejection rate (1-2% per year). Despite this, rejection prophylaxis after DMEK follows the same high potency regimen as previous techniques in the first year, and patients are burdened with indefinite immunosuppression. The current project, OPTIMISE, aims to establish an evidence-based, cost-effective regimen that effectively prevents rejection and minimizes side effects. Corticosteroid eye drops are the mainstay of ocular immunomodulatory therapy. Their main side effect is a steroid-induced increase in intraocular pressure (IOP). It manifests in about one-fourth of patients within the first year after surgery and can lead to irreversible optic nerve damage and vision loss. Patients with IOP elevation require additional medications and hospital visits resulting in reduced quality of life and increased costs. The optimal dosing regimen in the first year after DMEK and whether patients may safely stop steroids after one year remains unknown. As a result, protocols in the Netherlands vary considerably from surgeon to surgeon. Patients are potentially over-treated in the short and long-term, resulting in undue burden for the patient and increased costs. Consequently, the Dutch Ophthalmology Society (NOG) identified the optimal short- and long-term immunosuppressive protocol for corneal transplantation as one of its Top 10 knowledge gaps, underscoring relevance for clinical practice. With this work, the investigators expect to address this knowledge gap to the benefit of our patients and society. Objective: The OPTIMISE study aims to establish an evidence-based, cost-effective regimen that effectively prevents rejection and minimizes side effects. The hypothesis of this study is that Fluorometholone 0.1% in the first year and discontinuing medication in the second year is a cost-effective treatment strategy after DMEK. Study design: The design of this study is a randomized, controlled multicentre trial with a duration of 24 months. Study population: The study population will consist of 342 patients aged 21 years or older undergoing DMEK surgery in one eye. Intervention: All patients will receive Descemet's Membrane Endothelial Keratoplasty. Following this procedure, patients will be randomized into the following post-operative regime in two stages: STEP-I (Year 1): Control group: DMS 0.1% 6 times a day for 1 month tapered off to once daily within 6 months and then once a day for 6 months. Intervention group: DMS 0.1% 6 times a day for 1 month followed by FML 0.1% 4 times a day for two months tapered off to once daily within four months and then once a day for 6 months. STEP-II (Year 2): Control Group: Half the patients in each study arm will use FML 0.1% daily. Intervention Group: Half the patients in each study arm will discontinue steroids. Main study parameters/endpoints: Primary outcomes: Step-I: IOP elevation compared to baseline Step-II: Endothelial cell loss (ECL) compared to pre-surgical baseline Secondary outcomes are: Rejection free graft survival. Patient reported outcome measures. Incremental cost-effectiveness ratios, including a short term trial-based economic evaluation (TBEE) and a life-long model-based economic evaluation (MBEE) Structural outcomes including corneal, central macular and retinal nerve fibre layer thicknesses, and optic nerve head imaging.

Official Title
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Optimized Immunosuppression for Corneal Transplantation: A Multi-center Randomized Controlled Clinical Trial

Conditions
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Pseudophakic Bullous Keratopathy, Fuchs' Endothelial Dystrophy, Intraocular Pressure

Intervention / Treatment
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* Drug: Fluorometholone 0.1% Oph Susp
* Drug: Dexamethasone 0.1% ophthalmic suspension
* Other: Stop steroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Patients aged 21 years or older registered on the NOTR as candidates for DMEK corneal transplantation Exclusion Criteria: Inability to complete follow up or comply with study procedures Previous corneal graft in the study eye Known sensitivity or contraindication to the ingredients in the study medications History of uveitis or herpetic keratitis Human Leukocyte Antigen (HLA) typed allograft Pregnancy (current and planned) or lactation Use of other local or systemic immunosuppressive drugs

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention STEP I (Year 1 after DMEK)<br> | Drug: Fluorometholone 0.1% Oph Susp<br>* Year 1: DMS 0.1% 6 times a day for 1 month followed by FML 0.1% 4 times a day for two months tapered off to once daily within four months and then once a day for 6 months. Year 2: Half the patients in each study arm will use FML 0.1% daily.<br>Drug: Dexamethasone 0.1% ophthalmic suspension<br>* Year 1: DMS 0.1% 6 times a day for 1 month tapered off to once daily within 6 months and then once a day for 6 months.<br>|
| Active Comparator: Control STEP I (Year 1 after DMEK)<br> | Drug: Dexamethasone 0.1% ophthalmic suspension<br>* Year 1: DMS 0.1% 6 times a day for 1 month tapered off to once daily within 6 months and then once a day for 6 months.<br>|
| Experimental: Intervention STEP II (Year 2 after DMEK)<br> | Other: Stop steroids<br>* Half the patients in each study arm will discontinue steroids.<br>|
| Active Comparator: Control STEP II (Year 2 after DMEK)<br> | Drug: Fluorometholone 0.1% Oph Susp<br>* Year 1: DMS 0.1% 6 times a day for 1 month followed by FML 0.1% 4 times a day for two months tapered off to once daily within four months and then once a day for 6 months. Year 2: Half the patients in each study arm will use FML 0.1% daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of intraocular pressure elevation between the two arms |  | Year 1 | 
| Difference of endothelial cell loss (ECL) compared to pre-surgical baseline between arms |  | Year 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of rejection free graft survival between arms |  | 1-2 years | 
| Differences of patient reported outcome measures between groups |  | 1-2 years | 
| Differences of incremental cost-effectiveness ratios, including a short term trial-based economic evaluation (TBEE) and a life-long model-based economic evaluation (MBEE) |  | 1-2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cornea, Descemet Stripping Endothelial Keratoplasty