A Phase 3 interventional study of Brolucizumab and Aflibercept in Diabetic Macular Edema, sponsored by Novartis Pharmaceuticals. Completed at 92 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-08-12.
Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment
The purpose of this study was to evaluate the efficacy and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).
This study was designed as a Phase III, multi-center, randomized, double-masked, active controlled, parallel group prospective study to evaluate if brolucizumab 6 mg dosed q4w is safe and effective in the treatment of subjects with visual impairment due to diabetic macular edema (DME). Subjects who met all the inclusion and none of the exclusion criteria were randomized in a 2:1 ratio to one of two treatment arms i.e., brolucizumab 6 mg and aflibercept 2 mg. Only one eye was selected as study eye and treated with study medication.
The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 48). For all subjects, the last study assessment was performed at the Week 52/end of study (EOS) visit. All subjects had study visits q4w through Week 52. The primary analysis was performed at the EOS visit (Week 52).
To ensure masking was maintained, the investigational site had both masked and unmasked staff to perform the masked and unmasked study assessments/procedures accordingly.
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Study eye: Visual impairment due to DME with:
Exclusion Criteria:
Brolucizumab 6 mg/0.05 mL every 4 weeks.
Drug: Brolucizumab
Aflibercept 2mg/0.05 mL every 4 weeks
Drug: Aflibercept
Intravitreal injection
Also known as: RTH258, ESBA1008
Intravitreal injection
Also known as: Eylea
Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52
BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning. Last observation carried forward (LOCF) was used for the imputation of missing values.
Time frame: Baseline, Week 52
Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit
Central Subfield Thickness assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Number and Percentage of Participants With Fluid-free Macula in the Study Eye at Each Post-baseline Visit
Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with simultaneous absence of SRF and IRF in the study eye by visit. Events and censoring after 52 weeks are included in week 52 row.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Number and Percentage of Participants With Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) at Each Post-baseline Visit for the Study Eye
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Number of Subjects With Absence of SRF / IRF and Number of Subjects Censored by Visit
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Kaplan-Meier Analysis - Probability of Absence of SRF/IRF by Visit
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Number of Subjects With Probability of Absence of DME and Number Censored by Visit
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Kaplan-Meier Analysis - Probability of Absence of DME by Visit
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Best Corrected Visual Acuity (Letters Read): Change From Baseline in Best-corrected Visual Acuity (BCVA) at Each Post-baseline Visit for the Study Eye
BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
Time frame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Gain in Best-corrected Visual Acuity (BCVA) (Letters Read): Number (%) of Subjects Who Gained ≥ 5, 10, or 15 Letters in BCVA From Baseline or Reached BCVA ≥ 84 Letters in the Study Eye at Week 52
BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
Time frame: Baseline, Week 52
Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye
The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
Time frame: Baseline, Weeks 12, 24 and 52
Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye
The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
Time frame: Baseline, Weeks 12, 24 and 52
Anti-Drug Antibody (ADA): Frequency Distribution of Pre-existing ADA Status in the Brolucizumab Arm
Time frame: Baseline
Ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) by Preferred Term in the Study Eye
Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
Number of Subjects With Non-ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm)
Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
Study centers (no. of sites): Hungary (5), Israel (5), Slovakia (7), United States (78). Approximately, 495 subjects were planned to be randomized. Overall, 517 subjects were randomized either to brolucizumab 6 mg q4w arm (n=346) or aflibercept 2 mg q4w arm (n=171).
| Milestone | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Started | 346 | 171 |
| Completed | 311 | 156 |
| Not completed | 35 | 15 |
| Withdrew: Physician decision | 4 | 0 |
| Withdrew: Adverse event | 3 | 1 |
| Withdrew: Death | 7 | 5 |
| Withdrew: Withdrawal by subject | 11 | 4 |
| Withdrew: Lost to follow-up | 10 | 5 |
BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning. Last observation carried forward (LOCF) was used for the imputation of missing values.
| Scores on a scale | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52 | 12.2 (11.2 to 13.2) | 11.0 (9.6 to 12.4) |
Central Subfield Thickness assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
| μm | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Week 4 | -146.9 (-157.9 to -136.0) | -119.5 (-135.1 to -103.9) |
| Week 8 | -174.4 (-185.3 to -163.4) | -144.1 (-159.7 to -128.5) |
| Week 12 | -191.3 (-201.8 to -180.8) | -156.7 (-171.7 to -141.8) |
| Week 16 | -200.5 (-211.0 to -189.9) | -162.4 (-177.4 to -147.4) |
| Week 20 | -209.5 (-219.6 to -199.4) | -168.7 (-183.1 to -154.2) |
| Week 24 | -217.5 (-227.3 to -207.6) | -178.8 (-192.8 to -164.7) |
| Week 28 | -222.4 (-232.5 to -212.4) | -183.6 (-197.8 to -169.3) |
| Week 32 | -227.2 (-237.2 to -217.1) | -185.9 (-200.2 to -171.6) |
| Week 36 | -229.7 (-240.1 to -219.3) | -186.7 (-201.5 to -172.0) |
| Week 40 | -233.6 (-243.7 to -223.6) | -188.4 (-202.6 to -174.1) |
| Week 44 | -237.5 (-247.4 to -227.5) | -188.1 (-202.3 to -173.9) |
| Week 48 | -237.7 (-247.7 to -227.6) | -192.0 (-206.4 to -177.7) |
| Week 52 | -237.8 (-247.9 to -227.7) | -196.5 (-210.8 to -182.1) |
Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with simultaneous absence of SRF and IRF in the study eye by visit. Events and censoring after 52 weeks are included in week 52 row.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Week 4 | 23 | 4 |
| Week 8 | 31 | 4 |
| Week 12 | 38 | 10 |
| Week 16 | 48 | 11 |
| Week 20 | 54 | 9 |
| Week 24 | 84 | 19 |
| Week 28 | 65 | 13 |
| Week 32 | 76 | 17 |
| Week 36 | 91 | 21 |
| Week 40 | 96 | 23 |
| Week 44 | 96 | 20 |
| week 48 | 92 | 23 |
| Week 52 | 144 | 38 |
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Week 4 | 61 | 9 |
| Week 8 | 93 | 24 |
| Week 12 | 124 | 33 |
| Week 16 | 147 | 42 |
| Week 20 | 167 | 47 |
| Week 24 | 177 | 52 |
| Week 28 | 186 | 57 |
| Week 32 | 195 | 62 |
| Week 36 | 206 | 63 |
| Week 40 | 211 | 65 |
| Week 44 | 216 | 69 |
| Week 48 | 222 | 68 |
| Week 52 | 229 | 71 |
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Number of subjects with absence of SRF / IRF at Week 0 (n=344,170) | 0 | 0 |
| Number of subjects with absence of SRF / IRF at Week 4 (n=344,170) | 6 | 1 |
| Number of subjects with absence of SRF / IRF at Week 8 (n=335,168) | 18 | 3 |
| Number of subjects with absence of SRF / IRF at Week 12 (n=314, 165) | 13 | 2 |
| Number of subjects with absence of SRF / IRF at Week 16 (n=297, 161) | 17 | 4 |
| Number of subjects with absence of SRF / IRF at Week 20 (n=277, 156) | 8 | 6 |
| Number of subjects with absence of SRF / IRF at Week 24 (n=265,150) | 16 | 2 |
| Number of subjects with absence of SRF / IRF at Week 28 (n=246,146) | 18 | 7 |
| Number of subjects with absence of SRF / IRF at Week 32 (n=224,139) | 3 | 1 |
| Number of subjects with absence of SRF / IRF at Week 36 (n=220,138) | 8 | 2 |
| Number of subjects with absence of SRF / IRF at Week 40 (n=211, 134) | 16 | 4 |
| Number of subjects with absence of SRF / IRF at Week 44 (194, 129) | 11 | 2 |
| Number of subjects with absence of SRF / IRF at Week 48 (n=181, 125) | 3 | 0 |
| Number of subjects with absence of SRF / IRF at Week 52 (n=177, 122) | 30 | 12 |
| Number of subjects censored at Week 0 (n=344, 170) | 0 | 0 |
| Number of subjects censored at Week 4 (n-344, 170) | 3 | 1 |
| Number of subjects censored at Week 8 (n=335,168) | 3 | 0 |
| Number of subjects censored at Week 12 (n=314, 165) | 4 | 2 |
| Number of subjects censored at Week 16 (n=297, 161) | 3 | 1 |
| Number of subjects censored at Week 20 (n=277, 156) | 4 | 0 |
| Number of subjects censored at Week 24 (n=265, 150) | 3 | 2 |
| Number of subjects censored at Week 28 (n=246, 146) | 4 | 0 |
| Number of subjects censored at Week 32 (n=224,139) | 1 | 0 |
| Number of subjects censored at Week 36 (220, 138) | 1 | 2 |
| Number of subjects censored at Week 40 (n=211,134) | 1 | 1 |
| Number of subjects censored at Week 44 (n=194,129) | 2 | 2 |
| Number of subjects censored at Week 48 (n=181, 125) | 1 | 3 |
| Number of subjects censored at Week 52 (n=177, 122) | 147 | 110 |
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
| Probability of absence of SRF/IRF | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Probability of absence of SRF/IRF at Week 0 (n=344,170) | 0.000 (NA to NA) | 0.000 (NA to NA) |
| Probability of absence of SRF/IRF at Week 4 (n=344,170) | 0.018 (0.007 to 0.036) | 0.006 (0.001 to 0.030) |
| Probability of absence of SRF/IRF at Week 8 (n=335,168) | 0.071 (0.047 to 0.101) | 0.024 (0.008 to 0.056) |
| Probability of absence of SRF/IRF at Week 12 (n=314, 165) | 0.109 (0.079 to 0.145) | 0.036 (0.015 to 0.072) |
| Probability of absence of SRF/IRF at Week 16 (n=297, 161) | 0.161 (0.124 to 0.202) | 0.060 (0.030 to 0.103) |
| Probability of absence of SRF/IRF at Week 20 (n=277, 156) | 0.185 (0.145 to 0.228) | 0.096 (0.057 to 0.146) |
| Probability of absence of SRF/IRF at Week 24 (n=265,150) | 0.234 (0.190 to 0.281) | 0.108 (0.067 to 0.161) |
| Probability of absence of SRF/IRF at Week 28 (n=246,146) | 0.291 (0.243 to 0.341) | 0.151 (0.101 to 0.210) |
| Probability of absence of SRF/IRF at Week 32 (n=224,139) | 0.300 (0.252 to 0.351) | 0.157 (0.106 to 0.217) |
| Probability of absence of SRF/IRF at Week 36 (n=220,138) | 0.326 (0.275 to 0.377) | 0.169 (0.116 to 0.230) |
| Probability of absence of SRF/IRF at Week 40 (n=211, 134) | 0.377 (0.324 to 0.430) | 0.194 (0.137 to 0.258) |
| Probability of absence of SRF/IRF at Week 44 (194, 129) | 0.412 (0.358 to 0.466) | 0.206 (0.148 to 0.271) |
| Probability of absence of SRF/IRF at Week 48 (n=181, 125) | 0.422 (0.368 to 0.476) | 0.206 (0.148 to 0.271) |
| Probability of absence of SRF/IRF at Week 52 (n=177, 122) | 0.653 (0.540 to 0.745) | 0.328 (0.234 to 0.426) |
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Number of subjects with Probability of absence of DME at Week 0 (n=346,171) | 0 | 0 |
| Number of subjects with Probability of absence of DME at Week 4 (n=346,171) | 14 | 1 |
| Number of subjects with Probability of absence of DME at Week 8 (n=329,169) | 54 | 12 |
| Number of subjects with Probability of absence of DME at Week 12 (n=272, 157) | 32 | 13 |
| Number of subjects with Probability of absence of DME at Week 16 (n=239, 142) | 33 | 11 |
| Number of subjects with Probability of absence of DME at Week 20 (n=204, 130) | 26 | 10 |
| Number of subjects with Probability of absence of DME at Week 24 (n=174,120) | 12 | 4 |
| Number of subjects with Probability of absence of DME at Week 28 (n=161,115) | 13 | 7 |
| Number of subjects with Probability of absence of DME at Week 32 (n=146,107) | 9 | 5 |
| Number of subjects with Probability of absence of DME at Week 36 (n=135,102) | 10 | 2 |
| Number of subjects with Probability of absence of DME at Week 40 (n=125, 98) | 7 | 1 |
| Number of subjects with Probability of absence of DME at Week 44 (117, 96) | 11 | 2 |
| Number of subjects with Probability of absence of DME at Week 48 (n=106, 92) | 6 | 3 |
| Number of subjects with Probability of absence of DME at Week 52 (n=99, 88) | 13 | 4 |
| Number censored at Week 0 (n=346,171) | 0 | 0 |
| Number censored at Week 4 (n=346,171) | 3 | 1 |
| Number censored at Week 8 (n=329,169) | 3 | 0 |
| Number censored at Week 12 (n=272, 157) | 1 | 2 |
| Number censored at Week 16 (n=239, 142) | 2 | 1 |
| Number censored at Week 20 (n=204, 130) | 4 | 0 |
| Number censored at Week 24 (n=174,120) | 1 | 1 |
| Number censored at Week 28 (n=161,115) | 2 | 1 |
| Number censored at Week 32 (n=146,107) | 2 | 0 |
| Number censored at Week 36 (n=135,102) | 0 | 2 |
| Number censored at Week 40 (n=125, 98) | 1 | 1 |
| Number censored at Week 44 (117, 96) | 0 | 2 |
| Number censored at Week 48 (n=106, 92) | 1 | 1 |
| Number censored at Week 52 (n=99, 88) | 86 | 84 |
Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
| Probability of absence of DME | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Probability of absence of DME at Week 0 (n=346,171) | 0.000 (NA to NA) | 0.000 (NA to NA) |
| Probability of absence of DME at Week 4 (n=346,171) | 0.041 (0.023 to 0.066) | 0.006 (0.001 to 0.030) |
| Probability of absence of DME at Week 8 (n=329,169) | 0.199 (0.158 to 0.243) | 0.076 (0.043 to 0.123) |
| Probability of absence of DME at Week 12 (n=272, 157) | 0.293 (0.246 to 0.342) | 0.153 (0.104 to 0.212) |
| Probability of absence of DME at Week 16 (n=239, 142) | 0.391 (0.339 to 0.443) | 0.219 (0.160 to 0.284) |
| Probability of absence of DME at Week 20 (n=204, 130) | 0.470 (0.416 to 0.522) | 0.279 (0.213 to 0.348) |
| Probability of absence of DME at Week 24 (n=174,120) | 0.506 (0.452 to 0.559) | 0.303 (0.235 to 0.374) |
| Probability of absence of DME at Week 28 (n=161,115) | 0.547 (0.491 to 0.598) | 0.346 (0.274 to 0.418) |
| Probability of absence of DME at Week 32 (n=146,107) | 0.575 (0.520 to 0.626) | 0.376 (0.303 to 0.450) |
| Probability of absence of DMEE at Week 36 (n=135,102) | 0.606 (0.551 to 0.657) | 0.389 (0.314 to 0.462) |
| Probability of absence of DME at Week 40 (n=125, 98) | 0.628 (0.574 to 0.678) | 0.395 (0.320 to 0.468) |
| Probability of absence of DME at Week 44 (117, 96) | 0.663 (0.609 to 0.712) | 0.408 (0.332 to 0.482) |
| Probability of absence of DME at Week 48 (n=106, 92) | 0.682 (0.629 to 0.730) | 0.427 (0.351 to 0.501) |
| Probability of absence of DME at Week 52 (n=99, 88) | 0.866 (0.302 to 0.983) | 0.516 (0.357 to 0.654) |
BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
| scores on a scale | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Week 4 | 5.7 (5.1 to 6.4) | 5.4 (4.5 to 6.4) |
| Week 8 | 7.7 (6.9 to 8.5) | 7.4 (6.4 to 8.5) |
| Week 12 | 9.1 (8.3 to 9.9) | 8.0 (6.9 to 9.1) |
| Week 16 | 9.6 (8.8 to 10.4) | 8.5 (7.3 to 9.7) |
| Week 20 | 10.2 (9.3 to 11.1) | 9.2 (7.9 to 10.5) |
| Week 24 | 10.7 (9.8 to 11.6) | 9.6 (8.3 to 10.9) |
| Week 28 | 10.9 (10.0 to 11.8) | 10.7 (9.3 to 12.0) |
| Week 32 | 11.5 (10.6 to 12.5) | 10.5 (9.2 to 11.9) |
| Week 36 | 11.6 (10.6 to 12.6) | 10.8 (9.4 to 12.2) |
| Week 40 | 11.7 (10.7 to 12.6) | 10.7 (9.4 to 12.1) |
| Week 44 | 12.0 (11.0 to 13.0) | 10.6 (9.2 to 12.0) |
| Week 48 | 12.2 (11.2 to 13.2) | 10.7 (9.3 to 12.1) |
| Week 52 | 12.2 (11.2 to 13.2) | 11.0 (9.6 to 12.4) |
BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| ≥ 5 letters gain from baseline or BCVA ≥ 84 letters at Week 52 | 286 (78.2 to 86.5) | 127 (67.0 to 80.6) |
| ≥ 10 letters gain from baseline or BCVA ≥ 84 letters at Week 52 | 211 (55.6 to 66.2) | 95 (47.8 to 63.1) |
| ≥ 15 letters gain from baseline or BCVA ≥ 84 letters at Week 52 | 151 (38.3 to 49.0) | 69 (32.9 to 48.1) |
The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Week 12 | 56 | 21 |
| Week 24 | 82 | 38 |
| Week 52 | 95 | 45 |
The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Week 12 | 18 | 8 |
| Week 24 | 33 | 16 |
| Week 52 | 40 | 18 |
| Participants | Brolucizumab 6mg q4w |
|---|---|
| Negative | 112 |
| Positive | 230 |
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Number of subjects with at least one AE | 105 | 59 |
| Vitreous detachment | 10 | 7 |
| Cataract | 9 | 6 |
| Conjunctival haemorrhage | 9 | 7 |
| Punctate keratitis | 9 | 2 |
| Uveitis | 8 | 1 |
| Vitreous floaters | 8 | 5 |
| Dry eye | 7 | 4 |
| Eye pain | 6 | 5 |
| Corneal abrasion | 0 | 5 |
| Diabetic retinal oedema | 0 | 4 |
| Participants | Brolucizumab 6mg q4w | Aflibercept 2mg q4w |
|---|---|---|
| Number of Subjects With Non-ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) | 209 | 96 |
Collected over Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.. Non-serious events are listed at a 2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Brolucizumab 6mg | 7/346 (2%) | 74/346 (21.4%) | 144/346 (41.6%) |
| Aflibercept 2mg | 5/171 (2.9%) | 36/171 (21.1%) | 92/171 (53.8%) |
| Overall | 12/517 (2.3%) | 110/517 (21.3%) | 236/517 (45.6%) |
| Event | Brolucizumab 6mg | Aflibercept 2mg | Overall |
|---|---|---|---|
| Cerebrovascular accidentNervous system disorders | 6/346 | 6/171 | 12/517 |
| COVID-19Infections and infestations | 8/346 | 1/171 | 9/517 |
| Diabetic foot infectionInfections and infestations | 1/346 | 2/171 | 3/517 |
| OsteomyelitisInfections and infestations | 3/346 | 2/171 | 5/517 |
| PneumoniaInfections and infestations | 3/346 | 2/171 | 5/517 |
| HypertensionVascular disorders | 1/346 | 2/171 | 3/517 |
| Cardiac failure congestiveCardiac disorders | 4/346 | 0/171 | 4/517 |
| COVID-19 pneumoniaInfections and infestations | 4/346 | 0/171 | 4/517 |
| Acute kidney injuryRenal and urinary disorders | 4/346 | 1/171 | 5/517 |
| Cardiac failureCardiac disorders | 3/346 | 1/171 | 4/517 |
| Event | Brolucizumab 6mg | Aflibercept 2mg | Overall |
|---|---|---|---|
| HypertensionVascular disorders | 18/346 | 13/171 | 31/517 |
| COVID-19Infections and infestations | 11/346 | 11/171 | 22/517 |
| CoughRespiratory, thoracic and mediastinal disorders | 3/346 | 9/171 | 12/517 |
| Conjunctival haemorrhage - Study eyeEye disorders | 9/346 | 7/171 | 16/517 |
| Diabetic retinal oedema - Fellow eyeEye disorders | 10/346 | 7/171 | 17/517 |
| Vitreous detachment - Study eyeEye disorders | 10/346 | 7/171 | 17/517 |
| Blood creatinine increasedInvestigations | 4/346 | 7/171 | 11/517 |
| HeadacheNervous system disorders | 3/346 | 7/171 | 10/517 |
| Cataract - Study eyeEye disorders | 9/346 | 6/171 | 15/517 |
| Dry eye - Fellow eyeEye disorders | 6/346 | 6/171 | 12/517 |
| Age, Categorical(Participants) | Brolucizumab 6mg q4w | Aflibercept 2mg q4w | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 208 | 115 | 323 |
| >=65 years | 138 | 56 | 194 |
| Age, Continuous(years) | Brolucizumab 6mg q4w | Aflibercept 2mg q4w | Total |
|---|---|---|---|
| Mean | 60.9 ± 10.59 | 60.2 ± 9.31 | 60.7 ± 10.18 |
| Sex: Female, Male(Participants) | Brolucizumab 6mg q4w | Aflibercept 2mg q4w | Total |
|---|---|---|---|
| Female | 152 | 66 | 218 |
| Male | 194 | 105 | 299 |
| Race (NIH/OMB)(Participants) | Brolucizumab 6mg q4w | Aflibercept 2mg q4w | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 1 | 1 |
| Asian | 14 | 7 | 21 |
| Native Hawaiian or Other Pacific Islander | 1 | 0 | 1 |
| Black or African American | 40 | 15 | 55 |
| White | 288 | 145 | 433 |
| More than one race | 2 | 0 | 2 |
| Unknown or Not Reported | 1 | 3 | 4 |
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