24 Week Study to Compare Systemic VEGF-levels of Ranibizumab and Aflibercept in DME.

Study Overview
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Brief Summary
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The purpose of the study is to compare the effect of intravitreal injections of ranibizumab and aflibercept on systemic VEGF levels in DME patients in a detailed time course.

Detailed Description
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The purpose of the study is to compare the effect of monthly intravitreal injections of 0.5 mg ranibizumab and 2.0 mg aflibercept on systemic VEGF levels in patients with visual impairment due to DME over a 24 week period. In addition, the study will also assess the effect on systemic VEGF-A levels when patients are switched from aflibercept to ranibizumab.

Official Title
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A 24-week, Randomized, Single-masked, Multicenter, Phase IV Study to Compare sysTemic VEGF Levels Following Monthly Intravitreal Injections of 0.5 mg Ranibizumab Versus 2 mg Aflibercept Until Week 24 in Patients With Visual Impairment DuE to Diabetic Macular Edema (TIDE DME).

Conditions
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Visual Impairment Due to Diabetic Macular Edema

Intervention / Treatment
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* Drug: Ranibizumab
* Drug: Aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 or Type 2 diabetes mellitus Visual impairment due to DME BCVA of 78 to 24 (20/32-20/320) ETDRS letters Exclusion Criteria: Stroke or myocardial infarction less than 3 months prior to screening. Presence of uncontrolled systolic blood pressure or diastolic blood pressure Renal failure requiring dialysis or renal transplant or renal insufficiency Untreated diabetes mellitus Use of any systemic anti-VEGF drugs within 6 months prior to screening. Use of systemic or inhaled corticosteroids for at least 30 consecutive days within 3 months prior to screening. Women who are pregnant or breast feeding or who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception For either eye: Any active periocular or ocular infection or inflammation Uncontrolled glaucoma Neovascularization of the iris or neovascular glaucoma History of treatment with any anti-angiogenic drugs For study eye: Atrophy or fibrosis involving the center of the fovea at the time of screening or baseline. Cataract (if causing significant visual impairment), planned cataract surgery during the study period, vitrectomy, aphakia, glaucoma surgery, severe vitreous hemorrhage, rhegm Irreversible structural damage within 0.5 disc diameter of the center of the macula Panretinal laser photocoagulation within 6 months prior to randomization. Focal/grid laser photocoagulation within 3 months prior to randomization. Any intraocular procedure (including cataract surgery, Yttrium-Aluminum-Garnet capsulotomy) within 3 months prior to baseline or anticipated within the next 6 months following Topical ocular corticosteroids administered for at least 30 consecutive days within 3 months prior to screening. Application of intravitreal corticosteroids in vitreous within 6 months prior to screening. Prior application of fluocinolonacetonid releasing implant in vitreous within 36 months prior to screening. For fellow eye - Retinal or choroidal neovascularization or macula edema of any cause Other protocol-defined inclusion/exclusion criteria may apply.

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Monthly intravitreal injections of 0.5 mg ranibizumab for six months | Drug: Ranibizumab<br>* 0.5 mg intravitreal injections<br>* Other names: Lucentis;|
| Experimental: Group 2<br>Monthly intravitreal injections of 2 mg aflibercept for the initial three months followed by monthly intravitreal injections of 0.5 mg ranibizumab for the next three months. | Drug: Ranibizumab<br>* 0.5 mg intravitreal injections<br>* Other names: Lucentis;Drug: Aflibercept<br>* 2 mg intravitreal injections<br>* Other names: Eylea;|
| Experimental: Group 3<br>Monthly injections of 2 mg aflibercept for six months | Drug: Aflibercept<br>* 2 mg intravitreal injections<br>* Other names: Eylea;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of VEGF-A levels from baseline to week 24 | Systemic VEGF-A levels following monthly intravitreal injections of 0.5 mg ranibizumab versus 2 mg aflibercept (Area under the curve) expressed in pg/ml*days. The AUC will be standardized (=divided) by the individual follow-up time and will be calculated by the trapezoidal rule.. | baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Systemic VEGF-A levels in serum for patients in treatment group 1 and treatment group 2 within specific time points | To compare systemic VEGF-A levels (pg/ml) in patients switching from monthly 2 mg aflibercept injections for first three months to monthly 0.5 mg ranibizumab (treatment group 2) for the next three months compared to patients treated with monthly 0.5 mg ranibizumab (treatment group 1) for six months at specific time points from week 12 to week 24. The comparison will be performed at specific time points between week 12 and week 24, based on the blood samples collected for visits 10 to 16. | Day 7, Day 15, Week 4, week 8, week 12, week 14, week 16, week 18, week 20, week 24 | 
| Mean Systemic VEGF-A levels in serum for patients in treatment group 1 and treatment group 3 within specific time points | To compare systemic VEGF-A levels (pg/ml) in patients switching from monthly 2 mg aflibercept injections for first three months to monthly 0.5 mg ranibizumab (treatment group 2) for the next three months compared to patients treated with monthly 2 mg aflibercept (treatment group 3) for six months at specific time points from week 12 to week 24. The comparison will be performed at specific time points between week 12 and week 24, based on the blood samples collected for visits 10 to 16. | Day 7, Day 15, Week 4, week 8, week 12, week 14, week 16, week 18, week 20, week 24 | 
| Proportion of patients reporting ocular and/or systemic adverse events in all the three treatment groups. | To evaluate ocular and systemic safety in all the three treatment groups. Only treatment-emergent AEs will be summarized. AEs will be summarized by presenting for each treatment group the number and percentage of patients having any AE, having an eye-related AEs, having an AE in each primary system organ class and having each individual AEs based on the preferred term. All other information collected (e.g., severity or relationship to study treatment) will be tabulated and listed as appropriate. Summary tables will also be presented for the subset of AEs suspected to be treatment related. | From Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Macular Edema.