Laser Therapy Combined With Intravitreal Aflibercept vs Intravitreal Aflibercept Monotherapy (LADAMO)

Study Overview
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Brief Summary
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This will be a 24 month phase IV, randomised, prospective, multicentre, clinical trial of laser therapy to areas of peripheral retinal ischaemia combined with intravitreal aflibercept versus intravitreal aflibercept monotherapy. Both arms will have 2mg intravitreal aflibercept according to a treat and extend protocol. The specific aim of the study is to test whether laser therapy of peripheral retinal ischaemia reduces the overall number of intravitreal aflibercept injections required to control DMO over a 24 month period.

Detailed Description
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Diabetic retinopathy is the most common cause of blindness in individuals between the ages of 20 and 65 years in developed countries. Swelling of the central retina, or macular oedema, is the commonest cause of visual loss in diabetic retinopathy. Recent studies have suggested peripheral retinal ischaemia contributes to macula oedema in diabetes and retinal vein occlusions. Intravitreal anti-Vascular Endothelial Growth Factor (VEGF) therapy, such as Aflibercept (Eylea) has shown encouraging results in managing Diabetic Macular Oedema (DMO). There is evidence that regular treatment with anti-VEGF drugs reduces DMO and improves vision on average. Previous research at this institution has shown that an average of between 7 and 11 injections are required in the first year to stabilise the disease. However, there is a significant burden to patients in terms of frequent visits to the eye specialist, time off work and repeated injections into the eye. The purpose of this study is to see whether targeted peripheral retinal laser therapy to areas of the retina with impaired blood supply can reduce the number of intravitreal aflibercept injections required over 2 years to stabilise DMO.

Official Title
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A Phase IV Randomised Clinical Trial of Laser Therapy for Peripheral Retinal Ischaemia Combined With Intravitreal Aflibercept (Eylea®) Versus Intravitreal Aflibercept Monotherapy for Diabetic Macular Oedema

Conditions
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Diabetic Retinopathy

Intervention / Treatment
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* Drug: Aflibercept
* Procedure: Targeted laser therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At screening, the study eye must have DMO with retinal thickness > 300 microns in central 1mm subfield on Spectral domain OCT Age >= 18 years Diagnosis of diabetes mellitus Best corrected visual acuity of 35-79 LogMAR letters at 4 meters (approximately 6/7.5-6/60) in the study eye Women of childbearing potential must have a negative urine pregnancy test at the screening visit and prior to treatment. A woman is considered of childbearing potential unless she is postmenopausal and without menses for 12 months or is surgically sterilised Peripheral retinal ischaemia affecting an area greater than 10 disc diameters of the wide-field fundus fluorescein angiogram (as per the Central Vein Occlusion Study) Centre involving DMO, which in the opinion of the investigator, would not benefit from focal macular laser treatment (e.g. diffuse leak from the capillary bed, disruption of the foveal avascular zone or perifoveal capillary dropout, complete macular grid laser). Written informed consent has been obtained Exclusion Criteria: Known allergy to aflibercept or agents used in the study Women who are pregnant, nursing, or planning a pregnancy, or who are of childbearing potential and not using reliable means of contraception Loss of vision due to other causes (e.g. age related macular degeneration, myopic macular degeneration, retinal vein occlusion) in the study eye. Macular oedema due to other causes in the study eye. Macula hole, vitreo-macular traction or significant epiretinal membrane in the study eye. An ocular condition that would prevent visual acuity improvement despite resolution of oedema (such as foveal atrophy or substantial premacular fibrosis) Treatment with intravitreal triamcinolone acetonide (IVTA) within the last 6 months or peribulbar triamcinolone within the last 3 months, or anti-VEGF drugs (bevacizumab, ranibizumab or aflibercept) within the last 2 months in the study eye. Cataract surgery within the last 3 months in the study eye Previous PRP laser treatment in the study eye Previous vitrectomy in study eye Media opacity including cataract that already precludes adequate macular photography or cataract that is likely to require surgery within 12 months Intercurrent severe disease such as septicaemia, any condition which would affect follow-up or photographic documentation (e.g. geographical, psycho-social) History of chronic renal failure requiring dialysis or renal transplant Blood pressure >180/110 Patient has a condition or is in a situation that in the investigator's opinion may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aflibercept Monotherapy<br>Intravitreal aflibercept injections according to a treat and extend regimen. | Drug: Aflibercept<br>* Aflibercept is a soluble decoy receptor and is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which are then fused to the Fc region of human IgG-1. By binding to VEGF-A, aflibercept prevents activation of the native VEGF receptors, VEGFR-1 and VEGFR-2. The study sites will be supplied by Bayer with aflibercept. Intravitreal injection of 2mg in 0.05 ml aflibercept will be administered to the study eye, according to a pre-defined treat and extend regimen.<br>* Other names: Eylea;|
| Experimental: Targeted laser therapy with Aflibercept<br>Targeted laser photocoagulation therapy to areas of peripheral retinal ischaemia and intravitreal aflibercept injections using a treat and extend regimen. | Drug: Aflibercept<br>* Aflibercept is a soluble decoy receptor and is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which are then fused to the Fc region of human IgG-1. By binding to VEGF-A, aflibercept prevents activation of the native VEGF receptors, VEGFR-1 and VEGFR-2. The study sites will be supplied by Bayer with aflibercept. Intravitreal injection of 2mg in 0.05 ml aflibercept will be administered to the study eye, according to a pre-defined treat and extend regimen.<br>* Other names: Eylea;Procedure: Targeted laser therapy<br>* In the experimental group, targeted laser photocoagulation will be applied to areas of peripheral retinal ischaemia 1 month after the initial intravitreal aflibercept. The trial design allows another session of targeted laser photocoagulation 1 month later to complete the treatment if required. Wide-field photography is planned at 3 months to determine if further targeted laser photocoagulation is required, and if so a third session can be applied. The laser settings are based on those used in current clinical practice and have been prospectively defined in the protocol.<br>* Other names: Laser;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of intravitreal aflibercept injections over 24 months | Number of intravitreal aflibercept injections in each of the 2 groups required over 24 months | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of intravitreal aflibercept injections over 12 months | Number of intravitreal aflibercept injections in each of the 2 groups required over 12 months | 12 months | 
| Proportion of eyes that have central macular thickness <300 microns at 12 months |  | 12 months | 
| Mean change in central macular thickness (CMT) as measured by OCT at 12 months |  | 12 months | 
| Mean change in best corrected visual acuity | Mean change in best corrected visual acuity at 12 months | 12 months | 
| Any change in best corrected visual acuity at 12 months | Any change in best corrected visual acuity at 12 months | 12 months | 
| Effect of peripheral retinal ischaemia on number of aflibercept injections | Correlation between area of peripheral retinal ischaemia and number of intravitreal injections required at 12 months | 12 months | 
| Disc vessel measurement | Change in disc vessel diameter at 12 months | 12 months | 
| Number of intravitreal aflibercept injections in each of the 2 groups required over 24 months |  | 24 months | 
| Proportion of eyes that have central macular thickness <300 microns at 24 months |  | 24 months | 
| Mean change in central macular thickness (CMT) as measured by OCT at 24 months |  | 24 months | 
| Mean change in best corrected visual acuity | Mean change in best corrected visual acuity at 24 months | 24 months | 
| Any change in best corrected visual acuity at 24 months | Any change in best corrected visual acuity at 24 months | 24 months | 
| Effect of peripheral retinal ischaemia on number of aflibercept injections | Correlation between area of peripheral retinal ischaemia and number of intravitreal injections required at 24 months | 24 months | 
| Disc vessel measurement | Change in disc vessel diameter at 24 months | 24 months | 
| Time until vision stabilisation | Length of time from baseline to vision stabilisation | 24 months | 
| Quality of life assessment | Quality of life assessment using IVI and NEI VFQ-25 forms at 24 months | 24 months | 
| Change in area of macular hard exudates | Change in area of macular hard exudates from baseline to 24 months | 24 months | 
| Change in distance of closest hard exudate from the foveal centre | Change in distance of closest hard exudate from the foveal centre between baseline and 24 months | 24 months | 
| Mean change in treatment interval over time | Mean change in treatment interval between intravitreal aflibercept injections over time | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic, Macular Oedema, Retinopathy