Effect of the Vitreous in Response to Intravitreal Injections of Ranibizumab for the Treatment of Diabetic Macular Edema

Study Overview
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Brief Summary
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PURPOSE: To evaluate the effect of the vitreous in response to intravitreal (IV) injections of ranibizumab 0.5 mg/0.05ml (Lucentis; Genentech, South San Francisco, CA) for the treatment of diabetic macular edema (DME). METHODS: Prospective, observational, multicenter study, conducted at Centro Hospitalar e Universitário do Porto, Portugal. Best-corrected visual acuity and central foveal thickness will be evaluated at baseline and every month until the end of follow-up. OCT biomarkers such as retinal layers thickness will also be analyzed. A p value of 0.05 or less will be considered to be statistically significant. HYPOTHESIS: Vitrectomized patients will improve less than non-vitrectomized patients.

Detailed Description
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Patients will be included in two different groups according to the vitreous status: group 1 - non vitrectomized eyes; group 2 - vitrectomized eyes. Patients will be followed-up according to the standard of care and a final analysis of the results will be performed at 12+/-1 months of follow-up, which is the minimum follow-up period required for each patient. In group 1 the effect of VMA existence and PVD status will also be analyzed. The recruitment period will be of 6 months. Treatment All patients will be treated with IV ranibizumab injections (0.5 mg/0.05ml) following a PRN regimen. The injections will be performed in the operating room following the standard intravitreal injections protocol. When required, adjunct treatment, with macular and/or peripheral LASER (rescue LASER), will be also admitted at or after 24 weeks if persistent DME not improving after at least 2 injections. Treatment Schedule Repeat injections at every 4-week visit if eye improves or worsens (defined as ≥5 letter change from last injection or ≥10% CST change on OCT from last injection or CSF>300 μm at any timepoint). Defer injections if either BCVA of 85 letters and OCT CSF normal (CSF≤300 μm and non-existent intra- or sub-retinal fluid); or OCT CSF normal (CSF≤300 μm) and stable BCVA (defined as < 5 letters change from last injection) after two consecutive injections during the first 24 weeks, or after one injection if the initial stability period has already been achieved (OCT CSF normal and stable BCVA). Resume injections if BCVA or OCT worsens.

Official Title
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Effect of the Vitreous in Response to Intravitreal (IV) Injections of Ranibizumab (0.5mg/0.05ml) for the Treatment of Diabetic Macular Edema

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Ranibizumab 0.5 MG/0.05 ML Intraocular Solution [LUCENTIS]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: at least 18 years of age with either type 1 or type 2 diabetes mellitus; maximal central subfield foveal thickness (CSF) of at least 300μm (according to SD-OCT images - Spectral Domain Optical Coherence Tomography); BCVA of 20 to 80 letters, using ETDRS letters chart; ability to provide written informed consent. Exclusion Criteria: Pregnant or lactating; Epiretinal membrane (ERM) existence in the study eye; persistent posterior hyaloid adherence after vitrectomy for group 2; previous vitrectomy for group 1; history of other retinal vascular diseases in the study eye; LASER photocoagulation or intravitreal injections (IV) of anti-VEGF or systemic anti-VEGF or pro-anti-VEGF treatment and cataract surgery in the 6 months previously to the study eye inclusion; IV or peribulbar corticosteroid injections in the 6 months previously to study eye inclusion; history of IV of implant of fluocinolone acetonide in the study eye; vitreous hemorrhage or opacification in the study eye; active proliferative diabetic retinopathy in the study eye; active ocular inflammation or infection in either eye; aphakia in the study eye; other causes for macular edema, for example, after cataract surgery in the study eye; other causes of visual loss in the study eye; other diseases that may affect the course of macular edema in the study eye; uncontrolled glaucoma in either eye (intraocular pressure > 24 mmHg with treatment); history of arterial thrombotic event in the previous 6 months; uncontrolled arterial hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure > 100 mmHg); ward of the state.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| non vitrectomized eyes<br>ranibizumab injections (0.5 mg/0.05ml) following a PRN regimen | Drug: Ranibizumab 0.5 MG/0.05 ML Intraocular Solution [LUCENTIS]<br>* PRN regimen. Treatment Schedule Repeat injections at every 4-week visit if eye improves or worsens (defined as ≥5 letter change from last injection or ≥10% CST change on OCT from last injection or CSF>300 μm at any timepoint). Defer injections if either BCVA of 85 letters and OCT CSF normal (CSF≤300 μm and non-existent intra- or sub-retinal fluid); or OCT CSF normal (CSF≤300 μm) and stable BCVA (defined as < 5 letters change from last injection) after two consecutive injections during the first 24 weeks, or after one injection if the initial stability period has already been achieved (OCT CSF normal and stable BCVA). Resume injections if BCVA or OCT worsens.<br>|
| vitrectomized eyes<br>ranibizumab injections (0.5 mg/0.05ml) following a PRN regimen | Drug: Ranibizumab 0.5 MG/0.05 ML Intraocular Solution [LUCENTIS]<br>* PRN regimen. Treatment Schedule Repeat injections at every 4-week visit if eye improves or worsens (defined as ≥5 letter change from last injection or ≥10% CST change on OCT from last injection or CSF>300 μm at any timepoint). Defer injections if either BCVA of 85 letters and OCT CSF normal (CSF≤300 μm and non-existent intra- or sub-retinal fluid); or OCT CSF normal (CSF≤300 μm) and stable BCVA (defined as < 5 letters change from last injection) after two consecutive injections during the first 24 weeks, or after one injection if the initial stability period has already been achieved (OCT CSF normal and stable BCVA). Resume injections if BCVA or OCT worsens.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| assess the number of IV injections needed to control DME between groups | DME control is defined as 1) BCVA of 85 letters and OCT CFT normal (CFT≤300 μm and non-existent intra- or sub-retinal fluid); or 2) OCT CFT normal (CFT≤300 μm) and stable BCVA (defined as <5 letters change from last injection) after two consecutive injections during the first 24 weeks, or after one injection if the initial stability period has already been achieved (OCT CFT normal and stable BCVA). | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| compare the functional changes at the end of follow-up between groups | Functional change will be measured by the Early Treatment Diabetic Retinopathy Scale (ETDRS) which measures the best-corrected visual acuity with an ETDRS-like chart at 4 meters in number letters or at 1 meter when patients are unable to read any letters on the ETDRS chart at 4 meters. The ETDRS scale varies from 1 to 85 letters (85 letters correspond to a 20/20 in the Snellen scale). The higher the value the better the outcome. A clinical significant functional improvement will be considered for a gain of ≥5 EDTRS letters. | 18 months | 
| compare the anatomical changes at the end of follow-up between groups | Anatomical change will be measured by central foveal thickness (CFT), measured by Optical Coherence Tomography, automatically measured by the software in the central 1 mm. A CFT <240µm or >300 µm is considered pathological. A CFT between 240 and 300 µm is considered physiological. CFT has no defined minimum or maximum values. Since patients with diabetic macular edema usually have CFT >300 µm the goal of treatment is to lower the CFT to values between 240 and 300 µm. A clinical significant anatomical improvement will be considered for a change in CFT≥10%. | 18 months | 
| compare the percentage of type of responder during the follow-up period between groups | Type of responder is defined as follows: good responder: when beyond the 24th week of follow-up (maximum 7 injections) there was a complete anatomical response (CFT≤300μm) with an increase in BCVA ≥5 letters; non-responder: 13 injections and final CFT >400 um or ≤10% of CFT reduction and BCVA decrease (or BCVA gain <5 letters) incomplete responder: between good and non-responder criteria. | 18 months | 
| access the percentage, in group 2, of focal VMA and PVD status and type of response | to access the percentage, in group 2, of focal VMA and PVD status, and if those changed during the follow-up period influenced the type of response | 18 months | 
| assess retinal layers thickness as prognostic and pathophysiological biomarkers of DME treatment response | to assess baseline retinal layers thickness correlation with final BCVA to assess the influence of the variation of retinal layers thickness (baseline versus final) on final BCVA to assess differences between groups according to the above points; to associate the type of responder and baseline and final retinal layers thickness. | 18 months |