Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Patients With Visual Impairment Due to Macular Edema Secondary to Central Retinal Vein Occlusion

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of brolucizumab in treatment of patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO).

Detailed Description
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The study included Screening Period (Day -28 to Day -1), double-masked treatment period (Day 1 to Week 72), and post-treatment follow-up period (Week 72 to Week 76). Treatment visits were scheduled in 4-week intervals. After 6 initial monthly injections of brolucizumab or aflibercept (loading phase), subjects entered a one-year individualized flexible treatment (IFT) phase. During the IFT phase, an assessment of disease stability was performed at each monthly visit and subjects received either an active or a sham injection. Treatment with active was interrupted when disease stability was reached.

Official Title
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An Eighteen-Month, Two-Arm, Randomized, Double Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Adult Patients With Visual Impairment Due to Macular Edema Secondary to Central Retinal Vein Occlusion

Conditions
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Central Retinal Vein Occlusion

Intervention / Treatment
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* Drug: Brolucizumab 6 mg
* Drug: Aflibercept 2 mg
* Other: Sham injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Patients with visual impairment due to ME secondary to CRVO diagnosed < 6 months prior to screening. BCVA score between 78 and 23 letters, inclusive, using ETDRS visual acuity testing charts (approximate Snellen equivalent of 20/32 to 20/320) at both screening and baseline visits. Exclusion criteria Concomitant conditions or ocular disorders in the study eye at screening or baseline which could, in the opinion of the investigator, prevent response to study treatment or may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the first 12-month study period (e.g. structural damage of the fovea, vitreous hemorrhage, retinal vascular occlusion other than CRVO, retinal detachment, macular hole, or choroidal neovascularization of any cause, diabetic retinopathy (except mild non-proliferative) and diabetic macular edema). Any active intraocular or periocular infection or active intraocular inflammation (e.g. infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in study eye at screening or baseline Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg on medication, or according to investigator's judgment, at screening or baseline Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA < 20/200 at screening (except when due to conditions whose surgery may improve VA, e.g. cataract) Previous treatment with any anti-VEGF therapy or investigational drugs in the study eye at any time prior to baseline Previous use of intraocular or periocular steroids in study eye at any time prior to baseline Macular laser photocoagulation (focal/grid) in the study eye at any time prior to baseline and peripheral laser photocoagulation in the study eye within 3 months prior to the baseline Intraocular surgery in the study eye during the 3-month period prior to baseline Vitreoretinal surgery in the study eye at any time prior to baseline Aphakia with the absence of posterior capsule in the study eye

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brolucizumab 6 mg<br>1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individual flexible treatment (IFT) | Drug: Brolucizumab 6 mg<br>* Solution for injection (intravitreal use)<br>* Other names: ESBA1008;Other: Sham injection<br>* Empty sterile syringe without a needle administered as a sham injection for masking. From Week 24 to Week 72 inclusive, a sham treatment was performed to maintain subject masking in case treatment with brolucizumab or aflibercept was not deemed necessary by the investigator.<br>|
| Active Comparator: Aflibercept 2 mg<br>1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individual flexible treatment (IFT) | Drug: Aflibercept 2 mg<br>* Solution for injection (Intravitreal use)<br>* Other names: EYLEA®;Other: Sham injection<br>* Empty sterile syringe without a needle administered as a sham injection for masking. From Week 24 to Week 72 inclusive, a sham treatment was performed to maintain subject masking in case treatment with brolucizumab or aflibercept was not deemed necessary by the investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 24 | BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Missing and censored BCVA values were imputed by Last observation carried forward (LOCF) as the primary approach. Observed values from both scheduled and unscheduled post-baseline visits were used for the LOCF imputation. For subjects with no post-baseline BCVA value, the baseline value was carried forward. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in BCVA Averaged Over Week 40 to Week 52 | An average BCVA over week 40 to week 52 was calculated. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. | Baseline, Week 40 to Week 52 | 
| Change From Baseline in BCVA Averaged Over Week 64 to Week 76 | An average BCVA over week 64 to week 76 was calculated. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. | Baseline, Week 64 to Week 76 | 
| Change From Baseline in BCVA by Visit up to Week 76 | BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. | Baseline and every 4 weeks from baseline up to Week 76 | 
| Proportion of Participants With a Gain ≥ 5, 10 and 15 Letters in BCVA by Visit Compared to Baseline | The summary by visit was conducted based on the BCVA observed from each of the corresponding visits. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Every 5 letters represents 1 line of vision on the reading chart. | Baseline and every 4 weeks from baseline up to Week 76 | 
| Proportion of Participants With a Loss ≥ 5, 10 and 15 Letters in BCVA by Visit Compared to Baseline | The summary by visit was conducted based on the BCVA observed from each of the corresponding visit. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Every 5 letters represents 1 line of vision on the reading chart. | Baseline and every 4 weeks from baseline up to Week 76 | 
| Change From Baseline in CSFT Averaged Over Week 40 to Week 52 | Change from baseline in central subfield thickness (CSFT) averaged over Week 40 to Week 52, measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT) | Baseline, Week 40 to Week 52 | 
| Change From Baseline in CSFT Averaged Over Week 64 to Week 76 | Change from baseline in central subfield thickness (CSFT) averaged over Week 64 to Week 76, measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT) | Baseline, Week 64 to Week 76 | 
| Change From Baseline in CSFT by Visit up to Week 76 | Change from baseline in central subfield thickness (CSFT) measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT) | Baseline, and every 4 weeks from baseline up to Week 76 | 
| Proportion of Subjects With Presence of Retinal Fluid (Intra- and/or Subretinal Fluid) in the Study Eye by Visit up to Week 76 | Presence of retinal fluid (intra- and/or subretinal fluid) assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) | Every 4 weeks from week 4 up to Week 76 | 
| Proportion of Subjects With a CSFT < 300 μm for the Study Eye by Visit up to Week 76 | Central subfield thickness (CSFT) is measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT) | Every 4 weeks from week 4 up to Week 76 | 
| Number of Injections Between Week 24 and Week 52 and Between Week 24 and Week 72 | Number of administered injections during the individualized flexible treatment (IFT) period, between Week 24 and Week 52 and between Week 24 and Week 72 are presented | Week 24 to Week 52 and Week 24 to Week 72 | 
| Time to Recurrence After Week 20 and up to Week 76 | Recurrence is defined as the need for injection while showing a lack of disease stability for the first time after Week 20 and up to Week 76. For subjects with recurrence after the Week 20 visit, time-to-event is calculated as (first time with the lack of disease stability - the injection date on Week 20 visit + 1). For subjects without recurrence after Week 20, the censoring time will be calculated as (last visit with disease stability assessment - the injection date on Week 20 visit + 1). | Week 20 to Week 76 | 
| Number of Subjects With Ocular and Non-ocular AEs up to Week 52 and Week 76 | Number of subjects with at least one ocular or non-ocular Adverse Events (AEs). | Baseline to Week 76 | 
| Change From Baseline in Patient Reported Outcomes (NEI VFQ-25) at Week 24, Week 52 and Week 76 | The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures a patient's subjective assessment of vision-related Quality of Life (QoL). The 11 subscales in the VFQ-25 are general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated better vision-related quality of life. | Baseline, Week 24, Week 52 and Week 76 | 
| Number of Subjects According to Their Anti-drug Antibody (ADA) Titer at Screening and Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76 | Anti-drug antibodies (ADA) levels were assessed from subjects assigned to brolucizumab treatment only. | Baseline, Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Visual impairment, Macular edema, Central retinal vein occlusion, CRVO, Brolucizumab, Aflibercept, Vascular endothelial growth factor, VEGF, anti-VEGF