Study of Safety and Efficacy of Brolucizumab 6 mg Drug Product Intended for Commercialization in Patients With nAMD

Study Overview
=================
Brief Summary
-----------------
The purpose of this extension study was to assess the safety and efficacy of the new formulation of brolucizumab 6 mg ophthalmic solution when given to the same patients who received brolucizumab in the core trial CRTH258A2301 (also known as CRTH258-C002). The medical condition treated in the core and extension trials was neo-vascular age-related macular degeneration (nAMD).

Detailed Description
-----------------
Subjects in the United States who had completed the 96 week core trial, CRTH258A2301 (also referred as CRTH258-C002), were eligible to participate in the extension trial provided the core trial Visit 26 at week 96, was less than or equal to 12 weeks from the Baseline Visit in the extension trial, CRTH258A2301E1. Subjects who were treated with aflibercept during the core trial and met the eligibility requirements of this extension trial continued to receive aflibercept in this extension trial in order to maintain the masking during the extension trial. No hypothesis testing or descriptive analyses were planned. Subjects who were treated in the core trial with brolucizumab 3mg or brolucizumab 6 mg, and met the eligibility requirements of this extension trial, received the new formulation of brolucizumab 6 mg solution in the extension trial. Enrolled subjects were to receive three intravitreal (IVT) ophthalmic injections. The study eye was the same eye that received the treatment in the core study. The extension trial consisted of 7 study visits at 4 week intervals over a period of 24 weeks. Assessment of the efficacy and safety of brolucizumab 6 mg was based on a within-patient comparison with the last 6 months of corresponding core-study efficacy and safety data serving as the reference. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned.

Official Title
-----------------
A 24-week, Double-masked, Multicenter, Two-arm Extension Study to Collect Safety and Efficacy Data on Brolucizumab 6 mg Drug Product Intended for Commercialization in Patients With Neovascular Age-related Macular Degeneration Who Have Completed the CRTH258A2301 Study

Conditions
-----------------
Neovascular Age-related Macular Degeneration

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sign written informed consent Completed the core study, CRTH258A2301, also known as CRTH258-C002 as defined by assessments at Visit 26/Week 96 within ≤12 weeks of the baseline. Exclusion Criteria: Patient discontinued the treatment or the core study prematurely at any time Patient received standard of care treatment for nAMD after completion of the core study Pregnant or nursing women and women of child-bearing potential Stroke or MI (myocardial infarction) within 3 months of the baseline extension visit

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brolucizumab<br>Brolucizumab 6 mg solution for IVT injection, single injection at Day 1 (baseline), Week 8, and Week 16 or Week 20 | Drug: Brolucizumab 6 mg<br>* Administered as opthalmic solution for an intravitreal injection to the study eye<br>* Other names: RTH258;|
| Other: Aflibercept<br>Aflibercept 2 mg solution for IVT injection, single injection at Day 1 (baseline), Week 8 and Week 16 to maintain the masking of the extension trial only. | Drug: Aflibercept 2 mg<br>* Administered as an opthalmic solution for intravitreal injection to the study eye<br>* Other names: EYELEA;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Ocular and Non-Ocular Treatment Emergent Adverse Events | Number of participants with ocular and non-ocular treatment emergent events with the new formulation brolucizumab 6 mg in this extension trial up to week 24 vs. the corresponding last 6 months of brolucizumab treatment in the Core trial >= 2%. Safety assessment of the new formulation brolucizumab 6 mg was based on a within-patient comparison with the last 6 months of corresponding Core safety data. Missing brolucizumab data were imputed using last observation carried forward (LOCF). | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Loss in BCVA of 15 Letters or More From Extension Baseline at Each Post-baseline Visit | Best-corrected visual acuity for the study eye was tested at all study visits in a sitting position using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. Outcome measure was prespecified for brolucizumab arm only. Neither patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data presented descriptively for only brolucizumab in line with study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF). | Extension Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Change in BCVA From Extension Baseline at Each Post-baseline Visit | Best-corrected visual acuity for the study eye was tested at all study visits in a sitting position using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF). | Extension baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Patients With Positive q12w Treatment Status at Week 20 | The estimate for the proportion of patients with a positive q12w treatment status at Week 24 was derived from Kaplan Meier time-to-event analyses for the event 'first q8w-need'. The outcome of the Kaplan-Meier analysis was estimated probability for maintaining on q12w up to the Disease Activity Assessment (DAA) at exWeek 20. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF). | Week 20 | 
| Change in Central Sub-Field Thickness (CSFT) From Extension Baseline at Each Post-baseline Visit | Measurement of the central subfield thickness of the retina was assessed using Optical Coherence Tomography (OCT) at each visit for the study eye. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF). | Extension Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 | 
| Percentage of Subjects With Positive Anti-drug Antibody (ADA) Status for Brolucuzumab 6 mg in Extension | Positive integrated anti-drug antibodies (ADA) status is defined as induced ADA status with ADA negative at pre-dose and a post-dose titer value of greater than or equal to 30 at any time point or boosted ADA status with ADA positive at pre-dose and a post-dose titer value increase by more than 3-fold (1 dilution) at any time point. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF). | Extension Baseline, Week 8, Week 16, Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
double-masked, extension study, neovascular age-related macular degeneration, intravitreal injection, brolucizumab, aflibercept