The purpose of this study is to compare brolucizumab (RTH258) ophthalmic solution for
      intravitreal (IVT) injection (6 mg) to aflibercept ophthalmic solution for IVT injection (2
      mg) in subjects with untreated active choroidal neovascularization (CNV) secondary to
      age-related macular degeneration (AMD) in the study eye.

Efficacy and Safety of RTH258 Versus Aflibercept - Study 2

Neovascular Age-Related Macular Degeneration

Choroidal Neovascularization

Subjects were randomized to brolucizumab 6 mg and aflibercept 2 mg in a 1:1 ratio. Subjects
      in both treatment arms received 3 monthly loading doses (Day 0, Week 4 and Week 8), followed
      by a maintenance regimen, until the end of the study (Week 96/Exit). All subjects attended
      pre-specified visits every 4 weeks.

      Subjects in the brolucizumab 6 mg arm followed a q12w/q8w maintenance regimen. Within the
      q12w/q8w regimen, the initial treatment after the loading phase was q12w (1 injection every
      12 weeks). If disease activity was identified by the masked investigator at any of the
      disease activity assessments, dosing was adjusted to q8w (1 injection every 8 weeks)
      ("q12w/q8w regimen"). Once subjects were adjusted to the q8w interval, they stayed on that
      interval until the end of the study.

      Subjects in the aflibercept 2 mg arm followed a q8w maintenance regimen until the end of the
      study.

      Results reported up to Week 48 are based on the database locked for the primary analysis at
      Week 48. Results reported after Week 48 are based on the database locked at the end of study
      (final analysis).

Brolucizumab ophthalmic solution

Aflibercept ophthalmic solution

A Two-year, Randomized, Double-masked, Multicenter, Two-arm Study Comparing the Efficacy and Safety of RTH258 6 mg Versus Aflibercept in Subjects With Neovascular Age-related Macular Degeneration

BCVA (with spectacles or other visual corrective devices) was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) testing at 4 meters and reported in letters read correctly. Baseline was defined as the last measurement prior to first treatment. An increase (gain) in letters read from the baseline assessment indicates improvement. One eye (study eye) contributed to the analysis.

BCVA (with spectacles or other visual corrective devices) was assessed using ETDRS testing at 4 meters and reported in letters read correctly. For each subject, this endpoint was defined as the average of the changes from baseline to Weeks 36, 40, 44, and 48. Baseline was defined as the last measurement prior to first treatment. An increase (gain) in letters read from the baseline assessment indicates improvement. One eye (study eye) contributed to the analysis.

Positive q12 treatment status was defined as IVT injections per planned dosing regimen (one injection every 12 weeks "q12w", after the initial three loading injections every 4 weeks "q4w"). A disease activity assessment (DAA) was performed at pre-specified visits (Weeks 16, 20, 28, 32, 40, 44) to identify q8w (one injection every 8 weeks) need. The estimate for the proportion of subjects with a positive q12w status at Week 48 were derived from Kaplan-Meier time to event analyses for the event of first q8w need, applying event allocations (in case of lack of efficacy and/or lack of safety=efficacy/safety approach) and censoring as described in the SAP. Censored subjects were considered to be not anymore under risk for a q8 need identification at later visits. Corresponding 95% Confidence Intervals (CIs) were derived from the LOGLOG transformation. This outcome measure was pre-specified for brolucizumab 6 mg arm only. Hypothesis testing not pre-specified.

Positive q12 treatment status was defined as IVT injections per planned dosing regimen (one injection every 12 weeks "q12w", after the initial three loading injections every 4 weeks "q4w"). A disease activity assessment (DAA) was performed at pre-specified visits (Weeks 16, 20, 28, 32, 40, 44) to identify q8w need. The estimate for the proportion of subjects with a positive q12w status at Week 48 were derived from Kaplan-Meier time to event analyses for the event of first q8w need, applying event allocations (in case of lack of efficacy and/or lack of safety=efficacy/safety approach) and censoring as described in the SAP. Censored subjects were considered to be not anymore under risk for a q8 need identification at later visits. Corresponding 95% Confidence Intervals (CIs) were derived from the LOGLOG transformation. This outcome measure was pre-specified for brolucizumab 6 mg arm only. Hypothesis testing not pre-specified.

Positive q12 treatment status was defined as IVT injections per planned dosing regimen (one injection every 12 weeks "q12w", after the initial three loading injections every 4 weeks "q4w"). A disease activity assessment (DAA) was performed at pre-specified visits (Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88, 92) to identify q8w need. The estimate for the proportion of subjects with a positive q12w status at Week 48 were derived from Kaplan-Meier time to event analyses for the event of first q8w need, applying event allocations (in case of lack of efficacy and/or lack of safety=efficacy/safety approach) and censoring as described in the SAP. Censored subjects were considered to be not anymore under risk for a q8 need identification at later visits. Corresponding 95% Confidence Intervals (CIs) were derived from the LOGLOG transformation. This outcome measure was pre-specified for brolucizumab 6 mg arm only. Hypothesis testing not pre-specified.

BCVA (with spectacles or other visual corrective devices) was assessed using ETDRS testing at 4 meters and reported in letters read correctly. Baseline was defined as the last measurement prior to first treatment. An increase (gain) in letters read from the baseline assessment indicates improvement. One eye (study eye) contributed to the analysis.

BCVA (with spectacles or other visual corrective devices) was assessed using ETDRS testing at 4 meters and reported in letters read correctly. Baseline was defined as the last measurement prior to first treatment. An increase (gain) in letters read from the baseline assessment indicates improvement. 95% confidence interval (CI) for binomial proportions was based on Clopper-Pearson exact method. One eye (study eye) contributed to the analysis.

BCVA (with spectacles or other visual corrective devices) was assessed using ETDRS testing at 4 meters and reported in letters read correctly (0-100 letters). A score of 65 to 70 letters represents a low to moderate visual acuity. Baseline was defined as the last measurement prior to first treatment. 95% confidence interval (CI) for binomial proportions was based on Clopper-Pearson exact method. One eye (study eye) contributed to the analysis.

CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Spectral-Domain Optical Coherence Tomography (SD-OCT), a non-invasive measurement which produces cross-sectional and 3-dimensional images of the eye. A negative change value indicates an improvement, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis.

CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using SD-OCT, a non-invasive measurement which produces cross-sectional and 3-dimensional images of the eye. A negative change value indicates an improvement, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis.

CNV lesion size (the area of new blood vessels in the choroid layer of the retina) size was measured using fluorescein angiography (FA). A negative change value indicates a reduction in lesion size, whereas a positive change value indicates an increase. An increase in CNV lesion size may indicate progression of the underlying disease. Only one eye (study eye) contributed to the analysis.

CSFTns was assessed using SD-OCT. A negative change value indicates an improvement, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis.

Subretinal fluid was assessed using SD-OCT and recorded as Present/Absent. The presence of subretinal fluid is an indicator of underlying disease. One eye (study eye) contributed to the analysis.

Intraretinal fluid was assessed using SD-OCT and recorded as Present/Absent. The presence of intraretinal fluid is an indicator of underlying disease. One eye (study eye) contributed to the analysis.

Sub-retinal pigment epithelium (RPE) fluid was assessed using SD-OCT and recorded as Present/Absent. The presence of sub-RPE fluid is an indicator of underlying disease. One eye (study eye) contributed to the analysis.

Subretinal fluid and intraretinal fluid were assessed using SD-OCT and recorded as Present/Absent. The presence of subretinal and/or intraretinal fluid is an indicator of underlying disease. 95% confidence interval (CI) for binomial proportions was based on Clopper-Pearson exact method. One eye (study eye) contributed to the analysis.

A disease activity assessment (DAA) was performed to identify q8 treatment need. 95% confidence interval (CI) for binomial proportions is based on Clopper-Pearson exact method. One eye (study eye) contributed to the analysis. Hypothesis testing not pre-specified.

The National Eye Institute Visual Function Questionnaire-25 (VFQ-25) is a validated questionnaire that collects 25 vision-targeted responses from AMD subjects. The 25 questions pertain to global vision rating (1), difficulty with near vision activities (3), difficulty with distance vision activities (3), limitations in social functioning due to vision (2), role limitations due to vision (2), dependency on others due to vision (3), mental health symptoms due to vision (4), driving difficulties (3), limitations with peripheral (1) and color vision (1), and ocular pain (2). Each response is converted to a 0 to 100 sub-scale, with the lowest and highest possible scores set at 0 and 100 points, respectively. The overall composite score (0 to 100) is obtained by averaging the 25 sub-scale scores. A high score represents better functioning.

Serum samples were collected and assessed for anti-drug antibody status. Subjects were categorized as ADA negative when one of the following was met: ADA negative at all time points (predose and postdose); ADA negative at predose and no titer values above 10 at all other time points; or ADA titer of 10 at predose but negative at all other time points. ADA induced was defined as ADA negative at predose with postdose titer value greater than or equal to a titer of 30 at any timepoint. ADA boosted was defined as ADA positive at predose with postdose titer values that increased by at least two dilutions (9-fold) from their respective predose value at any time point.

Intraretinal hemorrhage was assessed using SD-OCT and recorded as Present/Absent. The presence of intraretinal hemorrhage is an indicator of underlying disease. 95% confidence interval (CI) for binomial proportions was based on Clopper-Pearson exact method. One eye (study eye) contributed to the analysis.

Subretinal hemorrhage was assessed using SD-OCT and recorded as Present/Absent. The presence of subretinal hemorrhage is an indicator of underlying disease. 95% confidence interval (CI) for binomial proportions was based on Clopper-Pearson exact method. One eye (study eye) contributed to the analysis.

Single intravitreal (IVT) injection of brolucizumab at Day 0, Week 4, and Week 8, followed by 1 injection every 8 weeks/1 injection every 12 weeks (q8w/q12w) maintenance regimen until study exit

Single IVT injection of aflibercept ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit

Efficacy and Safety of RTH258 Versus Aflibercept - Study 2

About this trial

Study ID

Status

Type

Phase

Placebo

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Trial Timing

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