Pilot and Phase 2 Study of the Efficacy of a Treatment Protocol With Dexamethasone Implant Loading Dose in Patients With Diabetic Macular Edema (LOADEX)

Study Overview
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Brief Summary
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Nowadays, steroids and anti-VEGF are the first line treatment for diabetic macular edema. Ozurdex is the most frequently used steroid and has label for both first and second line treatment. Ozurdex treatment paradigm for patients with diabetic macular edema is to inject patient only in case of huge recurrence. The risk of this scheme is a progressive loss of vision due to photoreceptors loss. A more pro-active regimen, as it already exists for anti-VEGF treatment, would allow a better patient management. A new treatment paradigm consisting in a loading dose of 2 injections within 12 weeks, followed by a PRN (Pro Re Nata) regimen with strict retreatment criteria and minimal time limit of 12 weeks between two injections should result in a better visual acuity gain and a limited augmentation of the number of injections (which will remain lower than the number observed for anti-VEGF treatment). The investigators have therefore chosen a pilot study to investigate the impact on efficacy and on the number of intravitreal injections (IVI) of such a scheme.

Official Title
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Pilot and Phase 2 Study of the Efficacy of a Treatment Protocol With Dexamethasone Implant Loading Dose in Patients With Diabetic Macular Edema

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Dexamethasone with 2 loading doses followed by PRN regimen.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient > 40 years old Patients with a significant DME : Macular thickening secondary to DME involving the center of the fovea, as measured by SD-OCT, with Central Subfield Thickness (CST) ≥ 285 μm measured on Spectralis or ≥ 275 μm, as measured on Cirrus, at screening and VA between 20/32 and 20/320 (between 23 and 78 letters ETDRS) using the ETDRS protocol at the initial testing distance of 4 meters at inclusion Patient for which a dexamethasone implant is chosen 100% naive eyes (no history of steroids or anti-VEGF) Pseudophakic for at least 6 months HBA1c < 10% Blood pressure < 160/95 Patient who give voluntary signed informed consent Patient affiliated with the French universal health care system or similar Patient able to participated in all visits and medical examinations during the study If both eyes have to be treated, only one eye will be included : the eye with the lowest visual acuity at the baseline Exclusion Criteria: Aphatic eye without posterior lens capsule. Study eye with implant anterior chamber of the eye or intraocular implant with iris fixated or transsclerally or ruptured posterior lens capsule. Study eye with lens implant ARTISAN® Ocular or periocular infection active or suspected in the study eye including most viral diseases of the cornea and conjunctiva, epithelial keratitis active Herpes simplex (dendritic keratitis), vaccinia, chickenpox, mycobacterial infections and mycoses At inclusion, delay after cataract surgery < 3 months in the study eye Delay after last session of panretineal Photocoagulation laser < 1 month in the study eye Delay after last focal laser session of the posterior pole < 1 month in the study eye Vitreomacular traction syndrome, associated ERM in the study eye History of macular grid laser in the study eye Focal laser only if the scars are located within 750 microns of the center (1/2 Papillary Diameter) in the study eye Ischemic maculopathy (increase of more than 2 times the surface of the central avascular zone) Proliferative diabetic Retinopathy in the study eye Hypertension or Open Angle Glaucoma (OAG) treated by dual therapy eye drops or more Patients with a systemic pathology that could interfere in the evolution of the Diabetic Macular Edema and treated by with immunosuppressive drugs, systemic steroids, anti-aldosterone or systemic anti-VEGF. Patients with systemic treatment with a toxic effect on the lens, retina or optic nerve: deferoxime, chloroquine / hydroxychloroquine, tamoxifen, phenothiazines and ethambutol; in progress or within 6 months of inclusion Hypersensitivity to the active substance or to any of the excipients and to anesthetic or hypotonizing eye drops History of any pathology, metabolic disease, or any serious suspicion of disease at clinical or laboratory examination that contraindicates the use of the intra-retinal dexamethasone implant, could affect the interpretation of the results of the study or cause significant risks of complication for the subject Infectious conjunctivitis and/or active or suspected appendix infection Any eye condition or condition that the investigator believes may require intraocular surgery within 12 months Eye contralateral that studied with visual acuity < 23 letters Pregnant and breastfeeding woman Female of reproductive age, sexually active, who does not want to commit to using adequate and highly effective contraception during the study and up to 6 months after the last administration of the study treatment: Combined hormonal contraception (containing estrogens and progestins) aimed at inhibiting ovulation (oral, intravaginal or transdermal); Hormonal contraception containing only a progestin intended to inhibit ovulation (oral, injectable or implantable); Intrauterine device (IUD); Intrauterine Hormone Release System (IUS); Ovariectomy with hysterectomy, bilateral tubal obstruction or total hysterectomy for at least 6 weeks before inclusion (for women included) or vasectomy for at least 6 months before inclusion (for partners of a patient included); Sexual abstinence. A woman will be considered to be of childbearing age from her first period and until the menopause, unless she is sterile or has had an oophorectomy type surgery with hysterectomy, bilateral tubal obstruction or hysterectomy total at least 6 weeks before inclusion. A post-menopausal state is defined as the absence of spontaneous menstruation (that is to say without any other medical treatment, in particular of the hormonal contraceptive type or hormone replacement therapy) for 12 months Major patient protected under the terms of the law (Public Health Code) Patient's ongoing participation in another interventional clinical trial (study eye and/or untreated eye) Follow-up impossible for 24 months, the judgment of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ozurdex®, 700µg dexamethasone intravitreal injection<br>Intravitreal injection of dexamethasone (Ozurdex®) | Drug: Dexamethasone with 2 loading doses followed by PRN regimen.<br>* Loading dose with 2 systematic intravitreal injections (IVI) of ozurdex at the baseline and 12 weeks.Followed by a PRN regimen with strict retreatment criteria (already used and published in the Prediamex study, Bellocq,Kodjikian et al Ophthalmology Retina 2017) Retreatment criteria: Reduction in VA ≥ 5 ETDRS Letters; and/or CSMT ≥ 275 microns by OCT-Cirrus® or ≥ 285 microns by OCT Spectralis®; and/or increase of CSMT > 50 microns; and/or onset of recurrent retinal cysts; and/or residual edema considered by the practitioner to be clinically significant. Minimal time limit between two IVI : 12 weeks Visits: monthly during 1 year (to check efficacy and safety) and then for the 2nd-year only at Month18 (M18) and Month 24 (M24)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum BCVA (Best Corrected Visual Acuity) change (best improvement) from baseline (during one year of treatment) | Best Corrected Visual Acuity (BCVA) is measured on the ETDRS scale at an initial distance of 4 meters. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time required to obtain the best BCVA | average, standard deviation, median, minimum and maximum | 52 weeks | 
| The number of injections required to obtain the best BCVA | average, standard deviation, median, minimum and maximum | 52 weeks | 
| the maximum best corrected visual acuity (BCVA) change (best improvement) measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale | Best Corrected Visual Acuity (BCVA) is measured on the ETDRS scale at an initial distance of 4 meters. | between the baseline and 1,5 years and between the baseline and 2 years | 
| values of Visual Acuity (VA) at each visit |  | all visits during 2 years | 
| Area under the curve (AUC) of VA | AUC calculated with the values of VA at each visit | between the baseline and 52 weeks and between the baseline and 2 years | 
| Description of Visual acuity (VA) | categorized change of VA (>=+15 ; +10 -> +15 ; +5 -> +10 ; -5 -> +5 (stable) ; -5 -> -10 ; -10 -> -15 ; > -15) | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| Number of IVI |  | 1 year | 
| Number of IVI |  | 2 years | 
| OCT parameters: Central Subfield Mean Thickness (CSMT) | average, standard deviation, median, minimum and maximum | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters: Central Fovea Thickness | average, standard deviation, median, minimum and maximum | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : presence of interruptions of the ellipsoid line |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : presence of continuous external limiting membrane |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the which obtained the BCVA | 
| OCT parameters : presence of disorganization of the internal retinal layers |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : presence of intraretinal cysts |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : presence of vitreomacular traction |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtain the BCVA | 
| OCT parameters : presence of epiretinal membrane |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : presence of macular exudates |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : persistance of foveolar depression |  | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 years, 2 years and the visit which obtained the BCVA | 
| OCT parameters : presence of intraretinal fluid |  | at each visit | 
| Proportion of patients with macular edema resolution | A macular edema resolution will be defined as absence of intraretinal fluid for at least 6 months after the last | at 1 year | 
| Proportion of patients with macular edema resolution | A macular edema resolution will be defined as absence of intraretinal fluid for at least 6 months after the last | at 2 years | 
| Retinopathy parameters : presence of intraretinal or subretinal macular hemorrhage | on stereoscopic 7-field color fundus photographs | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Retinopathy parameters: presence of microaneurisms | on stereoscopic 7-field color fundus photographs | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Retinopathy parameters : presence of macular exudates | on stereoscopic 7-field color fundus photographs | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Severity evolution (improvement, no change, worsening) of diabetic retinopathy graded by 2 evaluators on stereoscopic 7-field color fundus photographs | Using the Stadification Diabetic Retinopathy Severity Scale (DRSS), 5 levels: No apparent retinopathy, Mild Non Proliferative Diabetic Retinopathy (NPDR), Moderate NPDR,severe NDPR and Proliferative Diabetic Retinopathy (PDR) | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Quantitative OCT-angiography analysis : the size of non-perfusion zones | The mean (and standard deviation) the median (minimum-maximum) of the size of non-perfusion | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Quantitative OCT-angiography analysis : the size of central avascular zones | The mean (and standard deviation) the median (minimum-maximum) of the size of central avascular zones compared with baseline | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Qualitative OCT-angiography analysis : presence of macular ischemia | the number of macular ischemia | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Qualitative OCT-angiography analysis : Evolution of macular ischemia compared to the baseline | Types of evolution compared to baseline : appearance / disappearance / stability of the macular ischemia. | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Qualitative OCT-angiography analysis : presence of preretineal neovessels | the number of preretineal neovessels, | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Qualitative OCT-angiography analysis : evolution of preretineal neovessels compared to the baseline | Types of evolution : appearance / disappearance / stability. | Baseline, 12 weeks, 24 weeks,36 weeks,52 weeks, 1.5 year and 2 years | 
| Biomicroscopy: the number and the percentage by categories of the condition of the implant | conditions : clear, opacified , integrity, open, performed capsulotomy | all visits during 2 years | 
| Biomicroscopy: presence of the state of the posterior capsule | absence or presence of the posterior capsule | all visits during 2 years | 
| Variation of the intraocular pressure |  | all visits during 2 years | 
| proportion of patients using hypotonic eye treatment |  | all visits during 2 years | 
| Number of adverse events | All adverse events will be coded using the Meddra system organ class and cases of patients stopping or switching drugs will be described (causes, new drugs,..) | all visits during 2 years | 
| Level of discomfort felt by the patient | Discomfort felt by the patient measured by a visual analog scale (EVA between 0 and 10 (0 = no discomfort)) | all visits during 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dexamethasone,, loading dose,, diabetic macular edema, pseudophakic