A Study to Evaluate the Efficacy, Durability, and Safety of KSI-301 Compared to Aflibercept in Patients With Macular Edema Due to Retinal Vein Occlusion (RVO)

Study Overview
=================
Brief Summary
-----------------
This Phase 3 study will evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept, in participants with macular edema due to treatment-naïve branch (BRVO) or central retinal vein occlusion (CRVO).

Detailed Description
-----------------
This is a Phase 3, prospective, randomized, double-masked, two-arm, multi-center non-inferiority study evaluating the efficacy and safety of repeated intravitreal dosing of KSI-301 5 mg in participants with visual impairment due to treatment-naïve macular edema secondary to RVO (either branch or central type). The primary endpoint will be assessed at Week 24; additional secondary endpoints for efficacy will be assessed at Week 24 and Week 48. This includes an optional open-label, two-arm, double-masked Extension Phase in which participants completing the primary BEACON study are eligible to participate. All participants who enroll into the Extension Phase will be treated with KSI-301 5 mg. The Extension Phase will have the final study assessment at Week 72 for efficacy endpoints and a final safety follow-up at Week 76.

Official Title
-----------------
A Prospective, Randomized, Double-masked, Active Comparator-controlled, Multi-center, Two-arm, Phase 3 Study to Evaluate the Efficacy and Safety of Intravitreal KSI-301 Compared With Intravitreal Aflibercept in Participants With Visual Impairment Due to Treatment-naïve Macular Edema Secondary to Retinal Vein Occlusion (RVO)

Conditions
-----------------
Macular Edema, Retinal Vein Occlusion

Intervention / Treatment
-----------------
* Drug: KSI-301
* Drug: Aflibercept
* Other: Sham Procedure


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent prior to participation in the study. Treatment-naïve macular edema of 6 months duration or less due to CRVO or BRVO. Participants with hemiretinal vein occlusion will be included as CRVO. BCVA ETDRS letter score between 80 and 25 (20/25 to 20/320 Snellen equivalent), inclusive in the Study Eye. CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT instruments) as determined by the Reading Center Decrease in vision determined by the Investigator to be primarily the result of ME secondary to RVO. Other protocol-specified inclusion criteria may apply. Exclusion Criteria: Macular edema in the Study Eye for reasons other than RVO Active iris or angle neovascularization, neovascular glaucoma, neovascularization of the optic disc, retinal neovascularization or vitreous hemorrhage in the Study Eye. Uncontrolled glaucoma in the Study Eye. Active retinal disease other than the condition under investigation in the Study Eye. Any history or evidence of a concurrent ocular condition present, that in the opinion of the Investigator could require either medical or surgical intervention alter visual acuity during the study Active or suspected ocular or periocular infection or inflammation Any prior use of an approved or investigational treatment for macular edema secondary to RVO in the Study Eye (e.g. anti-VEGF, intraocular or periocular steroids, macular laser photocoagulation). Women who are pregnant or lactating or intending to become pregnant during the study. Uncontrolled blood pressure defined as a systolic value ≥ 180 mmHg or diastolic value ≥100 mmHg while at rest Recent history (within the 6 months prior to screening) of myocardial infarction, stroke, transient ischemic attack, acute congestive heart failure or any acute coronary event. History of a medical condition that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product. Other protocol-specified exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized 1:1 into one of two treatment arms: KSI-301 or aflibercept. Participants in the Extension Phase will be treated with KSI-301.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KSI-301 (Arm A)<br>Intravitreal injection of KSI-301 (5 mg) at Day 1, Week 4, and once every 8 weeks through Week 20 followed by an individualized dosing regimen of Intravitreal injection of KSI-301 (5 mg) from Week 24 to Week 44. In the Extension Phase, participants randomized to KSI-301 (5 mg) in the Primary Study will continue to receive KSI-301 (5 mg) based on protocol-defined disease activity criteria. | Drug: KSI-301<br>* Intravitreal Injection<br>Other: Sham Procedure<br>* The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.<br>|
| Active Comparator: Aflibercept (Arm B)<br>Intravitreal injection of aflibercept (2 mg) once every 4 through Week 20 followed by an individualized dosing regimen of Intravitreal injection of Aflibercept (2 mg) once every 4 weeks from Week 24 to Week 44. In the Extension Phase, participants randomized to aflibercept in the Primary Study will cross over to treatment with KSI-301 (5 mg). They will receive their first dose of KSI-301 (5 mg) at Week 48 and will receive additional treatment with KSI-301 (5 mg) based on protocol-defined disease activity criteria. | Drug: Aflibercept<br>* Intravitreal Injection<br>* Other names: Eylea;Other: Sham Procedure<br>* The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority of KSI-301 to Aflibercept measured by changes in BCVA. | Demonstrate that KSI-301 5 mg administered every 8 weeks after 2 monthly doses is non-inferior to aflibercept 2 mg monthly with respect to mean change in best corrected visual acuity (BCVA). | Day 1 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of KSI-301 5 mg compared to aflibercept 2 mg based on changes in BCVA and CST. | Improvement in best corrected visual acuity (BCVA) and central subfield thickness (CST) between the two treatment arms. | Day 1 to Week 44 | 
| Durability of KSI-301 5 mg compared to aflibercept 2 mg based on number of intravitreal injections during the study. | Mean number of intravitreal injections during the course of the study between the two treatment arms. | Week 1 to Week 44 | 
| Safety and Tolerability of KSI-301 5 mg compared to aflibercept 2 mg based on the number of ocular and systemic adverse events. | Incidence of ocular and systemic adverse events up to Week 24, Week 52, and Week 76 | Day 1 to Week 76 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Eylea, RVO, Kodiak, KSI-301, Vascular endothelial growth factor, Anti-VEGF, VEGF, Antibody biopolymer conjugate, Retinal Degeneration, Retinal Diseases, Eye Diseases, Vision Disorders, Vision, low, Aflibercept