Study to Show a Superior Benefit in Terms of Reduction of Ranibizumab Injections in Patients Receiving Ranibizumab Plus Laser Photocoagulation Combination Therapy Without Loss of Efficacy and Safety

Study Overview
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Brief Summary
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This is a Phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study. The primary objective was assessed by the difference in the mean number of ranibizumab injections applied up to Month 11 between the 2 treatment arms. Patients were randomized in a 1:1 ratio to 1 of the 2 treatment arms; i.e. Arm 1 ranibizumab monotherapy, Arm 2 ranibizumab with Grid&Direct short pulse laser photocoagulation combination therapy. There were 3 periods in this study: Screening Period (visit 1), Treatment Period (visit 2 to Visit 13) and Follow-up Period (visit 14). In addition to screening and Baseline (visit 2), there were monthly visits from Month 1 to Month 12. This study included male and female patients (≥20 years old) diagnosed with visual impairment due to ME secondary to BRVO.

Official Title
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A 12-month, Phase IV, Open-label, Randomized, Active Controlled, 2-arm, Multicenter Study Assessing the Efficacy and Safety of Intravitreal Ranibizumab Combined With Grid&Direct Short Pulse Laser Photocoagulation Versus a PRN Ranibizumab Monotherapy in Japanese Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO)

Conditions
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Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO)

Intervention / Treatment
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* Biological: Ranibizumab
* Radiation: Grid&Direct short pulse laser photocoagulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of visual impairment exclusively due to ME secondary to BRVO Best-corrected visual acuity score at Screening and Baseline (Day 1) between 0.5 and 0.05 decimal (i.e., between 73 and 19 letters in Early Treatment Diabetic Retinopathy Study (ETDRS) testing) with Landolt C charts inclusively (i.e., approximate logarithm of the minimum angle of resolution (logMAR) units of 0.3 to 1.30). At Baseline (Day1), a maximum BCVA gain of 0.2 units logMAR conversion inclusively from screening is allowed as long as the BCVA score does not exceed the upper limit of 0.3 units logMAR. Increased central subfoveal thickness (> 300 µm at Baseline (Day 1) when measured by SD-OCT) Duration of vision deterioration ≤6 months (determined by self-report) at screening Exclusion Criteria: Pregnant or nursing (lactating) women Stroke or myocardial infarction less than 3 months before Screening Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic value of >100 mm Hg at Screening or Baseline (Day 1) Antihypertensive treatment can be initiated and must be taken for at least 30 days after which the patient can be assessed for study eligibility a second time Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline (Day 1) in either eye Uncontrolled glaucoma (intraocular pressure (IOP) ≥30 mm Hg on medication or according to investigator's judgment) at the time of Screening or Baseline (Day 1) or diagnosed within 6 months before Baseline (Day 1) in either eye Neovascularization of the iris or neovascular glaucoma in the study eye Use of any systemic anti-VEGF drugs within 6 months before Baseline (Day1) (e.g., sorafenib (Nexavar®), sunitinib (Sutent®), bevacizumab (Avastin®), ziv-aflibercept (ZALTRAP®)) Treatment (or anticipated treatment in the fellow eye for non-RVO indications during the study) with any anti-angiogenic drugs (including any anti-VEGF agents) within 3 months before Baseline (Day1) in fellow eye or before Baseline (Day 1) in the study eye (e.g., pegaptanib (Macugen®), ranibizumab (Lucentis®), bevacizumab (Avastin®), and aflibercept (EYLEA®)) Panretinal laser photocoagulation within 1 month before Baseline (Day1) or anticipated or scheduled within the next 12 months (Study periods) following Baseline (Day1) in the study eye Any giving of focal or grid laser photocoagulation before Baseline (Day1) in the study eye Use of intra- or periocular corticosteroids (including sub-Tenon) within 3 months before Screening in the study eye. Any use of intraocular corticosteroid implants (e.g., dexamethasone (Ozurdex®), fluocinolone acetonide (Iluvien®)) in the study eye

Ages Eligible for Study
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Minimum Age: 20 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
Interventional Model Description: Phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: mono therapy<br>ranibizumab alone | Biological: Ranibizumab<br>* Ranibizumab is a biologic and known anti-VEGF (vascular endothelial growth factor) medication approved for treatment of ME (Macular Edema) due to RVO (Retinal Vein occlusion) 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL, with or without laser treatment<br>* Other names: RFB002E;|
| Experimental: combination therapy<br>ranibizumab with Grid&Direct short pulse laser photocoagulation | Biological: Ranibizumab<br>* Ranibizumab is a biologic and known anti-VEGF (vascular endothelial growth factor) medication approved for treatment of ME (Macular Edema) due to RVO (Retinal Vein occlusion) 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL, with or without laser treatment<br>* Other names: RFB002E;Radiation: Grid&Direct short pulse laser photocoagulation<br>* Grid&Direct short pulse laser photocoagulation is a kind of laser treatment to retina within vascular arcades and used to suppress macular edema<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Mean Number of Ranibizumab Injections | Number of ranibizumab treatments from Day 1 to Month 11 using full analysis set (observed) based on a stratified Cochran-Mantel-Haenszel (CMH) test. Stratification was done based on categories of baseline decimal VA (<0.3, or =>0.3). Difference of mean number of injections, 95% confidence interval (CI) of difference and one-sided p-value of the CMH test was reported. Analysis was conducted within the FAS with observed data. Stratification was based on baseline visual acuity on logMAR scale (<0.52, >=0.52). Test was one-sided. | Month 1 through Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Mean Change in Best Corrected Visual Acuity (BCVA) Using Decimal Chart and Early Treatment Diabetic Retinopathy Study (ETDRS) Compared to Baseline | Summary of BCVA (letters) absolute value and change from Baseline at Month 12 in the study eye - full analysis set (LOCF) was based on an analysis of variance (ANOVA) model with treatment group, and stratification factors. Stratification was done based on categories of baseline decimal VA (<0.3, or =>0.3). The analyses was conducted within the FAS using the LOCF approach Stratification was based on baseline visual acuity on logMAR scale (<0.52, >=0.52). Test was one-sided. | Month 1 through Month 12 (for ETDRS: Month 6 and Month 12) | 
| The Mean Change in BCVA From Month 1 Through Month 12 Compared to Baseline (Day 1) by the Treatment Arms | Summary of BCVA (logMAR) absolute value and change from Baseline at Month 12 in the study eye - full analysis set (LOCF) was based on an analysis of variance (ANOVA) model with treatment group, and stratification factors. Stratification was based on baseline visual acuity (< 0.52, >= 0.52). The analyses was conducted within the FAS using the LOCF approach | Month 1 through Month 12 | 
| BCVA (Letters) Number and Proportion of Patients With a BCVA Improvement vs. Baseline, Loss Less Than 15 Letters, or Attainment of Greater Than or Equal to 85 Letters at Month 6 and at Month 12 in the Study Eye | Endpoints related to the number and proportion of patients with BCVA letter gain or loss from Baseline (Day1) was analyzed via stratified CMH test with stratification factors as described in primary model. The mean (SD) average (per patient) BCVA (logMAR) change from Baseline through Month 12 Summary of BCVA (logMAR) mean average change from Baseline from Month 1 through Month 12 in the study eye | Month 6 and Month 12 | 
| The Mean Change in Change in Central Subfield Foveal Thickness (CSFT) From Month 1 Through Month 12 Compared to Baseline (Day1) by the Treatment Arms | The mean change in investigator-assessed CSFT from Month 1 through Month 12 was compared to Baseline (Day1) by the treatment arms. The analyses at each visit was based on an analysis of variance (ANOVA) model as analogous to BCVA. The analyses was conducted within the FAS using the Last-Observation-Carried-Forward (LOCF) approach | Month 1 through Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ranibizumab, Grid&Direct short pulse laser photocoagulation, Macular edema, Branch retinal vein occlusion, BRVO, BCVA, CSFT, pro re nata