Back to resultsEfficacy and Safety of RTH258 Versus Aflibercept - Study 2 (HARRIER)
Primary Purpose
Neovascular Age-Related Macular Degeneration, Choroidal Neovascularization
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Brolucizumab ophthalmic solution
Aflibercept ophthalmic solution
Sponsored by
About this trial
This is an interventional treatment trial for Neovascular Age-Related Macular Degeneration focused on measuring AMD, CNV, IVT
Eligibility Criteria
Key Inclusion Criteria:
- Provide written informed consent;
- Active CNV lesions secondary to AMD that affected the central subfield in the study eye at Screening;
- Total area of CNV > 50% of the total lesion area in the study eye at Screening;
- Intraretinal and/or subretinal fluid affecting the central subfield of the study eye at Screening;
- Best corrected visual acuity (BCVA) between 78 and 23 letters, inclusive, in the study eye at Screening and Baseline using Early Treatment Diabetic Retinopathy Study (ETDRS) testing.
Key Exclusion Criteria:
- Any active intraocular or periocular infection or active intraocular inflammation in either eye at Baseline;
- Central subfield of the study eye affected by fibrosis or geographic atrophy or total area of fibrosis ≥ 50% of the total lesion in the study eye at Screening;
- Subretinal blood affecting the foveal center point and/or ≥ 50% of the lesion of the study eye at Screening;
- Any approved or investigational treatment for neovascular age-related macular degeneration (nAMD) in the study eye at any time;
- Retinal pigment epithelial rip/tear in the study eye at Screening or Baseline or current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Baseline;
- Pregnant or nursing women; women of child-bearing potential;
- Stroke or myocardial infarction in the 6-month period prior to Baseline.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Brolucizumab 6 mg
Aflibercept 2 mg
Arm Description
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
Outcomes
Primary Outcome Measures
Change From Baseline in Best Corrected Visual Acuity (BCVA) (Letters Read) at Week 48 - Study Eye
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.
Secondary Outcome Measures
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 36 Through Week 48 - Study Eye
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.
Proportion of Subjects With Positive q12 (Every 12 Weeks) Treatment Status at Week 48
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.
Proportion of Subjects With Positive q12 Treatment Status at Week 48 Within the Subjects With no q8 (Every 8 Weeks) Treatment Need During the Initial q12w Cycle (Week 16, Week 20)
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.
Proportion of Subjects With Positive q12 Treatment Status up to Week 96
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.
Proportion of Subjects With Positive q12 Treatment Status at Week 96 Within the Subjects With no q8 Treatment Need During the Initial q12w Cycle (Week 16, Week 20)
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.
Change From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 4 to Week 48/96 - Study Eye
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.
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 12 to Week 48/96 - Study Eye
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.
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 84 to Week 96 - Study Eye
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.
Percentage of Subjects With >=15 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With >=10 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With >=5 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With >=15 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With >=10 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With >=5 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With BCVA of 73 Letters Read or More at Each Visit - Study Eye
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.
Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit - Study Eye
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.
Average Change From Baseline in CSFT Over the Period Week 36 Through Week 48 - Study Eye
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.
Average Change From Baseline in CSFT Over the Period Week 84 Through Week 96 - Study Eye
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.
Average Change From Baseline in CSFT Over the Period Week 4 Through Week 48/96 - Study Eye
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.
Change From Baseline in Choroidal Neovascularization (CNV) Lesion Size at Week 12, Week 48, and Week 96 - Study Eye
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.
Change From Baseline in Central Subfield Neurosensory Retinal Thickness (CSFTns) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With Presence of Subretinal Fluid at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With Presence of Intraretinal Fluid at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With Presence of Sub-retinal Pigment Epithelium (RPE) Fluid at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With Presence of Subretinal and/or Intraretinal Fluid (Central Subfield) at Each Post-baseline Visit - Study Eye
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.
Percentage of Subjects With Disease Activity Present (q8 Treatment Need = "Yes") at Week 16 - Study Eye
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.
Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Score at Week 24, Week 48, Week 72, and Week 96
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.
Percentage of Subjects With Induced or Boosted Anti-drug Antibody (ADA) Status at Week 48 (Brolucizumab Only)
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.
Percentage of Subjects With Intraretinal Hemorrhage (Central Subfield) Present at the Visit While Absent at Baseline at Each Treatment - Study Eye
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.
Percentage of Subjects With Subretinal Hemorrhage (Central Subfield) Present at the Visit While Absent at Baseline at Each Treatment - Study Eye
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02434328
Brief Title
Efficacy and Safety of RTH258 Versus Aflibercept - Study 2
Acronym
HARRIER
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
July 28, 2015 (Actual)
Primary Completion Date
April 5, 2017 (Actual)
Study Completion Date
March 8, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alcon Research
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neovascular Age-Related Macular Degeneration, Choroidal Neovascularization
Keywords
AMD, CNV, IVT
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
1048 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Brolucizumab 6 mg
Arm Type
Experimental
Arm Description
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
Arm Title
Aflibercept 2 mg
Arm Type
Active Comparator
Arm Description
Single IVT injection of aflibercept ophthalmic solution at Day 0, Week 4, and Week 8, followed by q8w maintenance regimen until study exit
Intervention Type
Drug
Intervention Name(s)
Brolucizumab ophthalmic solution
Other Intervention Name(s)
RTH258
Intervention Description
Ophthalmic solution for IVT injection administered as a 6 mg/50 µL dose
Intervention Type
Drug
Intervention Name(s)
Aflibercept ophthalmic solution
Other Intervention Name(s)
EYLEA®
Intervention Description
Ophthalmic solution for IVT injection administered as a 2 mg/50 µL dose
Primary Outcome Measure Information:
Title
Change From Baseline in Best Corrected Visual Acuity (BCVA) (Letters Read) at Week 48 - Study Eye
Description
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.
Time Frame
Baseline, Week 48
Secondary Outcome Measure Information:
Title
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 36 Through Week 48 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 36, 40, 44, 48
Title
Proportion of Subjects With Positive q12 (Every 12 Weeks) Treatment Status at Week 48
Description
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.
Time Frame
Weeks 16, 20, 28, 32, 40, 44, 48
Title
Proportion of Subjects With Positive q12 Treatment Status at Week 48 Within the Subjects With no q8 (Every 8 Weeks) Treatment Need During the Initial q12w Cycle (Week 16, Week 20)
Description
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.
Time Frame
Weeks 16, 20, 28, 32, 40, 44, 48
Title
Proportion of Subjects With Positive q12 Treatment Status up to Week 96
Description
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.
Time Frame
Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88, 92, 96
Title
Proportion of Subjects With Positive q12 Treatment Status at Week 96 Within the Subjects With no q8 Treatment Need During the Initial q12w Cycle (Week 16, Week 20)
Description
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.
Time Frame
Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88, 92, 96
Title
Change From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 4 to Week 48/96 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 12 to Week 48/96 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Average Change From Baseline in BCVA (Letters Read) Over the Period Week 84 to Week 96 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 84, 88, 92, 96
Title
Percentage of Subjects With >=15 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With >=10 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With >=5 Letter Gain From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With >=15 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With >=10 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With >=5 Letter Loss From Baseline in BCVA (Letters Read) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With BCVA of 73 Letters Read or More at Each Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Average Change From Baseline in CSFT Over the Period Week 36 Through Week 48 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 36, 40, 44, 48
Title
Average Change From Baseline in CSFT Over the Period Week 84 Through Week 96 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 84, 88, 92, 96
Title
Average Change From Baseline in CSFT Over the Period Week 4 Through Week 48/96 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Change From Baseline in Choroidal Neovascularization (CNV) Lesion Size at Week 12, Week 48, and Week 96 - Study Eye
Description
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.
Time Frame
Baseline, Weeks 12, 48, 96
Title
Change From Baseline in Central Subfield Neurosensory Retinal Thickness (CSFTns) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With Presence of Subretinal Fluid at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With Presence of Intraretinal Fluid at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With Presence of Sub-retinal Pigment Epithelium (RPE) Fluid at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With Presence of Subretinal and/or Intraretinal Fluid (Central Subfield) at Each Post-baseline Visit - Study Eye
Description
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.
Time Frame
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96
Title
Percentage of Subjects With Disease Activity Present (q8 Treatment Need = "Yes") at Week 16 - Study Eye
Description
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.
Time Frame
Week 16
Title
Change From Baseline in Visual Function Questionnaire (VFQ-25) Composite Score at Week 24, Week 48, Week 72, and Week 96
Description
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.
Time Frame
Baseline, Weeks 24, 48, 72, 96
Title
Percentage of Subjects With Induced or Boosted Anti-drug Antibody (ADA) Status at Week 48 (Brolucizumab Only)
Description
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.
Time Frame
Week 48
Title
Percentage of Subjects With Intraretinal Hemorrhage (Central Subfield) Present at the Visit While Absent at Baseline at Each Treatment - Study Eye
Description
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.
Time Frame
Baseline, Weeks 12, 48, 96
Title
Percentage of Subjects With Subretinal Hemorrhage (Central Subfield) Present at the Visit While Absent at Baseline at Each Treatment - Study Eye
Description
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.
Time Frame
Baseline, Weeks 12, 48, 96
10. Eligibility
Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Provide written informed consent;
Active CNV lesions secondary to AMD that affected the central subfield in the study eye at Screening;
Total area of CNV > 50% of the total lesion area in the study eye at Screening;
Intraretinal and/or subretinal fluid affecting the central subfield of the study eye at Screening;
Best corrected visual acuity (BCVA) between 78 and 23 letters, inclusive, in the study eye at Screening and Baseline using Early Treatment Diabetic Retinopathy Study (ETDRS) testing.
Key Exclusion Criteria:
Any active intraocular or periocular infection or active intraocular inflammation in either eye at Baseline;
Central subfield of the study eye affected by fibrosis or geographic atrophy or total area of fibrosis ≥ 50% of the total lesion in the study eye at Screening;
Subretinal blood affecting the foveal center point and/or ≥ 50% of the lesion of the study eye at Screening;
Any approved or investigational treatment for neovascular age-related macular degeneration (nAMD) in the study eye at any time;
Retinal pigment epithelial rip/tear in the study eye at Screening or Baseline or current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Baseline;
Pregnant or nursing women; women of child-bearing potential;
Stroke or myocardial infarction in the 6-month period prior to Baseline.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Group Trial Lead
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
Citations:
PubMed Identifier
34968756
Citation
Singh RP, Jhaveri C, Wykoff CC, Gale RP, Staurenghi G, Iida T, Koh A, B G, Gedif K, Singer M. Efficacy Outcomes of Brolucizumab Versus Aflibercept in Neovascular Age-Related Macular Degeneration Patients with Early Residual Fluid. Ophthalmol Retina. 2022 May;6(5):377-386. doi: 10.1016/j.oret.2021.12.014. Epub 2021 Dec 27.
Results Reference
derived
PubMed Identifier
33207259
Citation
Mones J, Srivastava SK, Jaffe GJ, Tadayoni R, Albini TA, Kaiser PK, Holz FG, Korobelnik JF, Kim IK, Pruente C, Murray TG, Heier JS. Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER. Ophthalmology. 2021 Jul;128(7):1050-1059. doi: 10.1016/j.ophtha.2020.11.011. Epub 2020 Nov 15.
Results Reference
derived
PubMed Identifier
30986442
Citation
Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 Jan;127(1):72-84. doi: 10.1016/j.ophtha.2019.04.017. Epub 2019 Apr 12.
Results Reference
derived
Learn more about this trial
Efficacy and Safety of RTH258 Versus Aflibercept - Study 2
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