A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE)

Study Overview
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Brief Summary
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This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection in patients with clinically significant macular edema with center involvement (CSME-CI) secondary to diabetes mellitus (Type 1 or 2). This study is identical in design to study NCT00473382 (Protocol ID FVF4168g). The open-label extension phase of the study was stopped after receiving FDA approval of the study drug (ranibizumab) for diabetic macular edema.

Detailed Description
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This study is composed of 3 phases: (1) A 24-month controlled treatment period (monthly treatment with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injection) followed by (2) a 12-month treatment period in which patients randomized to the sham group who had not discontinued from treatment (still masked) could choose to receive monthly ranibizumab 0.5 mg while the 2 ranibizumab treatment groups continued on the same treatment they received in the first 2 years. Patients who had not discontinued treatment by Month 36 were eligible to continue treatment with ranibizumab 0.5 mg as needed (pro re nata, PRN) in (3) an extension phase of the study for up to 2 more years, resulting in up to 5 years possible total treatment time for some patients.

Official Title
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A Phase III, Double-masked, Multicenter, Randomized, Sham Injection-controlled Study of the Efficacy and Safety of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus

Conditions
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Diabetes Mellitus, Macular Edema

Intervention / Treatment
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* Drug: Ranibizumab
* Drug: Sham injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness to provide written informed consent and, at U.S. sites, Health Insurance Portability and Accountability Act (HIPAA) authorization, and in other countries, as applicable according to national laws. Age ≥ 18 years. Diabetes mellitus (Type 1 or 2) . Retinal thickening secondary to diabetes mellitus (DME) involving the center of the fovea with central macular thickness ≥ 275 µm in the center subfield as assessed on optical coherence tomography (OCT). Best corrected visual acuity (BCVA) score in the study eye of 20/40 to 20/320 approximate Snellen equivalent using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at an initial testing distance of 4 meters. Decrease in vision determined to be primarily the result of DME and not to other causes. For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study. Ability (in the opinion of the investigator) and willingness to return for all scheduled visits and assessments. Exclusion Criteria: History of vitreoretinal surgery in the study eye. Panretinal photocoagulation (PRP) or macular laser photocoagulation in the study eye within 3 months of screening. Previous use of intraocular corticosteroids in the study eye (eg, triamcinolone acetonide [TA]) within 3 months of screening. Previous treatment with anti-angiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc) within 3 months of the Day 0 (first day of treatment) visit. Proliferative diabetic retinopathy (PDR) in the study eye, with the exception of inactive, regressed PDR. Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in the study eye. Concurrent Ocular Conditions Vitreomacular traction or epiretinal membrane in the study eye. Ocular inflammation (including trace or above) in the study eye. History of idiopathic or autoimmune uveitis in either eye. Structural damage to the center of the macula in the study eye that is likely to preclude improvement in VA following the resolution of macular edema, including atrophy of the retinal pigment epithelium (RPE), subretinal fibrosis, or organized hard-exudate plaque. Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization (CNV) of any cause (eg, age-related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia). Concurrent disease in the study eye that would compromise visual acuity or require medical or surgical intervention during the study period. Cataract surgery in the study eye within 3 months, yttrium-aluminum-garnet (YAG) laser capsulotomy within the past 2 months, or any other intraocular surgery within the 90 days preceding Day 0. Aphakia or absence of the posterior capsule in the study eye. Uncontrolled glaucoma or previous filtration surgery in the study eye. Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia. Evidence at examination of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye or current treatment for serious systemic infection. Uncontrolled blood pressure. History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0. Uncontrolled diabetes mellitus. Renal failure requiring dialysis or renal transplant. Participation in an investigational trial within 30 days prior to screening that involved treatment with any drug (excluding vitamins and minerals) or device. 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 an investigational drug, might affect interpretation of the results of the study, or renders the subject at high risk from treatment complications. Pregnancy or lactation. History of allergy to fluorescein. History of allergy to ranibizumab injection or related molecule.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranibizumab 0.3 mg<br>Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. | Drug: Ranibizumab<br>* Sterile solution for intravitreal injection.<br>* Other names: Lucentis;|
| Experimental: Ranibizumab 0.5 mg<br>Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. | Drug: Ranibizumab<br>* Sterile solution for intravitreal injection.<br>* Other names: Lucentis;|
| Sham Comparator: Sham injection/ranibizumab 0.5 mg<br>Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. | Drug: Sham injection<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. | Baseline to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. | Baseline to Month 48 | 
| Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | VA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart. | Months 24, 36, and 48 | 
| Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. | Baseline to Month 48 | 
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. | Baseline to Month 36 | 
| Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement. | Baseline to Month 48 | 
| Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative [NP]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative [P]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy. | Baseline to Month 36 | 
| Percentage of Patients With Resolution of Leakage at Month 24 | Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center. | Baseline to Month 24 | 
| Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3. | Baseline to Month 36 | 
| Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. | Baseline to Month 48 | 
| Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. | Month 36 to Month 48 | 
| Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. | Month 36 to Month 48 | 
| Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48 | Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement. | Month 36 to Month 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lucentis, DME, Diabetes, Vision loss