Study of Efficacy and Safety of Brolucizumab vs. Aflibercept in Chinese Patients With Neovascular Age-Related Macular Degeneration

Study Overview
=================
Brief Summary
-----------------
To compare brolucizumab to aflibercept in Chinese patients with untreated active choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD)

Official Title
-----------------
A Twelve-Month, Randomized, Double-Masked, Multicenter, Phase III, Two-Arm Study Comparing the Efficacy and Safety of Brolucizumab 6 mg Versus Aflibercept in Chinese Patients With Neovascular Age-Related Macular Degeneration

Conditions
-----------------
Neovascular Age-Related Macular Degeneration

Intervention / Treatment
-----------------
* Drug: Brolucizumab 6mg
* Drug: Aflibercept 2 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Active choroidal neovascularization (CNV) lesions secondary to AMD that affect the central subfield in the study eye Total area of CNV>50% of the total lesion area in the study eye at screening Exclusion Criteria: Any active intraocular or periocular infection or active intraocular inflammation (e.g. infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in study eye at Baseline. Central subfield of the study eye affected by fibrosis or geographic atrophy Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) >25 mmHg Previous treatment with any anti-VEGF drugs in the study eye. Previous treatment with any approved or investigational drugs for neovascular AMD in the study eye. Other protocol-specified inclusion or exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 50 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brolucizumab 6 mg<br> | Drug: Brolucizumab 6mg<br>* Subjects will receive Brolucizumab 3 x q4w up to Week 8 followed by q12w / q8w up to Week 40 or Week 44, depending on disease activity status.<br>|
| Active Comparator: Aflibercept 2 mg<br> | Drug: Aflibercept 2 mg<br>* Subjects will receive Aflibercept 3 x q4w up to Week 8 followed by q8w up to Week 40.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Best-Corrected Visual Acuity | To demonstrate that brolucizumab 6 mg is not inferior to aflibercept 2 mg with respect to the change in BCVA | Baseline to Week 48 | 
| Average change in Best-Corrected Visual Acuity | To demonstrate that brolucizumab 6 mg is not inferior to aflibercept 2 mg with respect to the change in BCVA | Baseline, over the period Week 36 to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with treatment regimen of every 12 weeks in brolucizumab arm | To estimate the proportion of q12w subjects (1 injection every 12 weeks) up to Week 48 in the brolucizumab 6 mg treatment arm | Baseline up to Week 48 | 
| Proportion of patients with treatment regimen of every 12 weeks (q12w) interval at Week 48 of those who do not need every 8 weeks treatment interval in brolucizumab arm | To estimate the predictive value of the first regimen of every 12 weeks (q12w) cycle (at Week 16 and Week 20) for maintenance of q12w treatment regimen | Week 16, Week 20 and Week 48 | 
| Change in Best Corrected Visual Acuity (BCVA) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period | Baseline up to Week 48 | 
| Average change in Best-Corrected Visual Acuity | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period | Baseline, over the period of Week 4 to Week 48 | 
| Average change in Best-Corrected Visual Acuity | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period | Baseline, over the period of Week 12 to Week 48 | 
| Proportion of patients who gain in best-correct visual acuity of 15/10/5 letters or more | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period | Baseline up to Week 48 | 
| Percentage of subjects with Best-Corrected Visual Acuity of 73 letters or more at each visit | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period | Baseline up to Week 48 | 
| Proportion of subjects who loss in best-corrected visual acuity of 15/10/5 letters or more | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period | Baseline up to Week 48 | 
| Change in Central Subfield Thickness Total | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline up to Week 48 | 
| Average change in Central Subfield Thickness Total | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline, over the period of Week 36 to Week 48 | 
| Average Change in Central Subfield Thickness Total | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline, over the period of Week 4 to Week 48 | 
| Change in Central Subfield Thickness-neurosensory retina | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | From Baseline up to Week 48 | 
| Change in in area of choroidal neovascularization lesion | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline, Weeks 12 and Week 48 | 
| Proportion of subjects who have presence of subretinal and/or intraretinal fluid (central subfield) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline up to Week 48, specifically at Week 16 and Week 48 | 
| Number of visits with simultaneous absence of subretinal and intraretinal fluid (central subfield) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Over the period of Week 36 to Week 48 | 
| Proportion of subjects who have presence of subretinal fluid (central subfield) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline up to Week 48 | 
| Proportion of subjects who have presence of intraretinal fluid (central subfield) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline up to Week 48 | 
| Proportion of subjects who presence of sub retinal pigment epithelium fluid (central subfield) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters | Baseline up to Week 48 | 
| Change in Central Subfield Thickness Total | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg at the end of the matched treatment phase | Baseline up to week 16 | 
| Proportion of subjects who presence of subretinal and /or intraretinal fluid (central subfield) | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg at the end of the matched treatment phase | At Week 16 | 
| Proportion of subjects who need every 8 weeks injection | To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg over the time period by assessing changes in anatomical parameters To evaluate the efficacy of brolucizumab 6 mg relative to aflibercept 2 mg at the end of the matched treatment phase | At Week 16 | 
| Change in subject reported outcomes (Visual Function Questionnaire-25) total and subscale scores | To assess visual function-related subject reported outcomes following treatment with brolucizumab 6 mg relative to aflibercept 2 mg. The VFQ-25 includes a series of 25 questions pertaining to vision or feelings about a vision condition. Answers are selected among a numbered list of possible responses, the values of which are ultimately recoded and converted to a 0 to 100 scale. Items within each subscale are averaged together to create 12 subscale scores. An overall composite score will be calculated by averaging vision-targeted subscale scores, excluding the general health rating question. | Baseline up to Weeks 24 and Week 48 | 
| Proportion of subjects who have positive anti-drug antibodies status | To assess immunogenicity of brolucizumab 6 mg | At Baseline (enrollment), Weeks 4, 12, 24, 36, and 48 (End of Study) | 
| Pharmacokinetic parameters: Cmax after first brolucizumab 6 mg dose in a subset of subjects | PK draw 6 hours post-injection on Day 1, after first brolucizumab 6 mg dose in a subset of subjects to assess Cmax (maximum concentration) of brolucizumab at 6 mg following a single intravitreal injection | Day 1, Day 2, Day 8, Day 15, Day 22, and Day 29 | 
| Pharmacokinetic parameters: Tmax after first brolucizumab 6 mg dose in a subset of subjects | PK draw 6 hours post-injection on Day 1, after first brolucizumab 6 mg dose in a subset of subjects to assess Tmax (time to maximum concenration) of brolucizumab at 6 mg following a single intravitreal injection | Day 1, Day 2, Day 8, Day 15, Day 22, and Day 29 | 
| Pharmacokinetic parameters: AUClast after first brolucizumab 6 mg dose in a subset of subjects | PK draw 6 hours post-injection on Day 1, after first brolucizumab 6 mg dose in a subset of subjects to assess AUClast (Area under the curve up to the last validated measurable plasma concentration) of brolucizumab at 6 mg following a single intravitreal injection | Day 1, Day 2, Day 8, Day 15, Day 22, and Day 29 | 
| Pharmacokinetic parameters: AUCinf after first brolucizumab 6 mg dose in a subset of subjects | PK draw 6 hours post-injection on Day 1, after first brolucizumab 6 mg dose in a subset of subjects to assess AUCinf (area under the curve total exposure) of brolucizumab at 6 mg following a single intravitreal injection | Day 1, Day 2, Day 8, Day 15, Day 22, and Day 29 | 
| Pharmacokinetic parameters: Thalf after first brolucizumab 6 mg dose in a subset of subjects | PK draw 6 hours post-injection on Day 1, after first brolucizumab 6 mg dose in a subset of subjects to assess Thalf (time to elimination of half-life) of brolucizumab at 6 mg following a single intravitreal injection | Day 1, Day 2, Day 8, Day 15, Day 22, and Day 29 |