Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE)

Study Overview
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Brief Summary
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This study is a Phase I/II, multicenter, randomized, study of the efficacy and safety of ranibizumab injection monotherapy verses a duel therapy of 0.3mg ranibizumab combined with ultra wide, 200° field angiography guided pan retinal photocoagulation in patients with CSME-CI secondary to diabetes mellitus (Type 1 or 2).

Detailed Description
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Approximately 40 eyes will be randomized at 3 investigational centers in the United States. This study consists of a screening period of up to 14 days (Days -14 to -1), and a 36-month treatment period (Day 0 to Month 36). Subjects who provide consent will enter the screening period to determine eligibility. As part of the screening process, the examining investigator will evaluate the macular foveal avascular zone fluorescein images to determine subjects' eligibility. Eligible subjects will be randomized in a 1:1 ratio so that approximately 20 eyes will receive 0.3 mg ranibizumab monotherapy, and approximately 20 eyes will receive 0.3 mg ranibizumab combined with Ultra wide 200° field angiogram guided targeted pan retinal photocoagulation (PRP). Subjects must meet VA and retinal thickness eligibility requirements during the screening period. The subject can have both eyes in the study. If both eyes are eligible, one eye will be randomized, to cohort 1 while the other eye will be randomized to the cohort 2. A subject with both eyes in the trial will have each eye in a separate cohort.

Official Title
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A Phase I/II, Randomized, Study for Diabetic Macular Edema Using 0.3mg Ranibizumab Combined With Targeted PRP Monthly for 4 Months,Then PRN vs. 0.3mg Ranibizumab 4 Months Monotherapy, Then as Needed(DME-AntiVEgf) DAVE

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: 0.3 mg ranibizumab
* Procedure: Targeted Pan Retinal Photocoagulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness to provide signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization. Age ≥ 18 years Diabetes Mellitus (Type 1 or 2). The following will be considered as sufficient evidence that diabetes is present: Current regular use of insulin for the treatment of diabetes Current regular use of oral antihyperglycemic agents for the treatment of diabetes Documented diabetes according to the American Diabetes Association and/or World Health Organization criteria. BCVA score in the study eye of 20/32 to 20/320 approximate snellen equivalent using the ETDRS protocol at an initial testing distance of 4 meters, confirmed by the investigator. High Definition OCT (Spectralis) central retinal thickness measurement of ≥ 300 µm Decrease in visual acuity is determined to be primarily the result of DME and not to other cause. Ability and willingness to return for all scheduled visits and assessments. Clear ocular media and adequate pupillary dilatation to permit good quality fundus photography. Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from this study: General Exclusion Criteria Pregnancy (positive pregnancy test) or lactation Sexually active women of childbearing potential* who are unwilling to practice adequate contraception or abstinence during the study. (*Although no birth control method is 100% effective, the following are considered adequate means of contraception: surgical sterilization, use of oral contraceptives, barrier contraception using either a condom or diaphragm with spermicidal gel, intrauterine devices, or contraceptive hormone implants or patches. A subject's primary care physician, obstetrician, or gynecologist should be consulted regarding an appropriate form of birth control) Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated Participation in another simultaneous medical investigation or trial] Ocular Exclusion Criteria Prior Ocular Treatment: History of vitrectomy surgery in the study eye Any pan-retinal photocoagulation in the study eye Prior treatment with intraocular or subconjunctival steroids in the study eye 4 months prior to screen Previous treatment with antiangiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc.) within 2 months of Day 0 visit Systemic corticosteroids 4 months prior to screen Concurrent Ocular Conditions: Any concurrent ocular condition in the study eye (e.g., cataract or age-related macular degeneration) that, in the opinion of the investigator could: require medical or surgical intervention during the study period to prevent or treat visual loss that might result from that condition; or, if allowed to progress untreated, could likely contribute to a loss of at least 2 Snellen equivalent lines of BCVA over the study period Active intraocular inflammation (grade trace or above) in the study eye Current vitreous hemorrhage in the study eye History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study eye Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye Aphakia or absence of the posterior capsule in the study eye Intraocular surgery (including cataract surgery) in the study eye within 2 months preceding Day 0 Uncontrolled glaucoma in the study eye (defined as IOP ≥ 30 mmHg despite treatment with anti-glaucoma medication) History of glaucoma-filtering surgery in the study eye History of corneal transplant in the study eye High Risk PDR: New vessels within one disc diameter of the optic nerve head that are larger than one-third disc area Vitreous or preretinal hemorrhage associated with less extensive NVD or with NVE one-half disc area or more in size Extensive damage to the fovea vascular zone as determined by the principal investigator or designated site personnel Spherical equivalent of the refractive error in the study eye of more that -8.00 diopter of myopia Vitreomacular traction (vitreomacular attachment ok) Concurrent Systemic Conditions Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 mmHg while patient is seated. *If a subject's initial reading exceeds these values, a second reading may be taken 30 or more minutes later. If the subject's blood pressure needs to be controlled by antihypertensive medication, the subject can become eligible if medication is taken continuously for at least 30 days prior to Day 0 Atrial fibrillation not managed by subject's primary care physician or cardiologist within 3 months of screening visit History of stroke within the last 3 months of screening visit History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or renders the patient at high risk for treatment complications Current treatment for active systemic infection Active malignancy History of allergy to fluorescein, not amenable to treatment Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded. Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals)

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 0.3 mg Ranibizumab<br>Cohort 1: Subjects will receive 4 IVT of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will be seen monthly (+/- 7 days) & will receive IVT of 0.3 mg ranibizumab on a pro re nata (PRN) schedule per retreatment criteria. | Drug: 0.3 mg ranibizumab<br>* Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.<br>* Other names: Lucentis;|
| Experimental: Targeted PRP with 0.3 mg Ranibizumab<br>Cohort 2: Subjects will receive 4 it of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will then be seen monthly (+/- 7 days) & receive IVT of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at Day 7 they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide field angiography. Ultra wide field angiography will be performed every 3 months to indicate areas of peripheral ischemia, which will be selectively be treated with PRP at Month 6, Month 18, and Month 25, preserving areas of more perfused retina. | Drug: 0.3 mg ranibizumab<br>* Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.<br>* Other names: Lucentis;Procedure: Targeted Pan Retinal Photocoagulation<br>* Cohort 2: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan retinal photocoagulation (PRP) based on ultra wide 200º field angiography. After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.<br>* Other names: Pan Retinal Photocoagulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period | Assess the number of ranibizumab injections in the ranibizumab and targeted panretinal photocoagulation (PRP) with ranibizumab cohorts through Month 36. | 36 Months | 
| Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36 | Evaluate the mean change over time in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts through Month 36. | 36 Months | 
| Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36. | Incidence and severity of ocular and non-ocular adverse events (AE's) in the monotherapy and combination cohorts through Month 36. | 36 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | Percentage of patients in the ranibizumab and targeted PRP with ranibizumab cohorts who experience a loss of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA. | Month 12, 24, and 36 | 
| Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Determine percentage of patients who experience a gain of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts. | Month 12, 24, and 36 | 
| Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Evaluate mean change in central retinal thickness in the ranibizumab and targeted PRP with ranibizumab cohorts over time through Month 12, 24, and 36 as assessed by high resolution OCT's. | Month 12, 24, and 36 | 
| Patients With Persistent Macular Edema Post-intravitreal Injection. | Percentage of patients with persistent macular edema post-intravitreal injection in the ranibizumab and targeted PRP with ranibizumab cohorts. | Month 36 | 
| Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36. | Mean change in peripheral visual field as measured by Goldmann visual field at screen and Month 36 in the ranibizumab and targeted PRP with ranibizumab cohorts. | 36 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Proliferative Diabetic Retinopathy, Diabetic Retinopathy, Macular Edema, Background Diabetic Retinopathy, Pre Proliferative Diabetic Retinopathy