Age-Related Macular Degeneration
Conditions
Keywords
Age-related macular degeneration, AMD, wet AMD, ranibizumab, aflibercept, geographic atrophy, inject and extend
Brief summary
The purpose of this study was to compare the development of new geographic atrophy in patients with wet Age-related Macular Degeneration (AMD) when treated with either ranibizumab or aflibercept over 24 months. Geographic atrophy is an advanced form of AMD that can result in the progressive and irreversible loss of visual function over time.
Detailed description
In each arm, patients underwent three monthly loading doses (at Baseline, Week 4, and Week 8). From Week 8, after the patient had received their third injection of study treatment, the visit intervals were determined by the patient's disease activity. If any of the protocol-specified signs of disease activity were present in the study eye, the subsequent injection visit interval was kept at 4 weeks. If none of the signs were present, the subsequent injection interval was extended by 2-week increments up until a maximum of 12-weekly intervals was reached. If there were any signs of disease activity in the study eye, the treatment interval was reduced as specified in the protocol. The planned individual duration of study participation was 24 months.
Interventions
Administered as an intravitreal injection
Administered as an intravitreal injection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Investigators were not masked. The patients, the BCVA assessors, and the Central Reading Center (who set the treatment intervals) were masked.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Written informed consent. Inclusion criteria specific to the study eye: * Diagnosis of active subfoveal Choroidal Neovascularisation (CNV) secondary to wet Age-related Macular Degeneration (AMD); * Best Corrected Visual Acuity (BCVA) score of 23 letters or more as measured by 3-metre Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts.
Exclusion criteria
* Pregnant, nursing, or at risk of becoming pregnant during the study; * Inability to comply with the study or follow-up procedures; * Recent (3 months) stroke or myocardial infarction; uncontrolled hypertension; hypersensitivity to the study treatments or to fluorescein; * In either eye: active periocular or ocular infection or inflammation; iris neovascularisation; uncontrolled or neovascular glaucoma; or one or more patch of geographic atrophy (GA) as specified in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24 | Baseline, Month 24 | Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Baseline, Month 12, Month 24 | Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center. A patient was considered to have developed new GA if they did not have any GA at the start of the study period and were subsequently diagnosed with GA during the study period (diagnosis of GA change from No to Yes). The analysis of new GA development was restricted to only those subjects without GA reported at baseline. One eye (study eye) contributed to the analysis. |
| Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Baseline, Month 12, Month 24 | The number of intravitreal injections was calculated. One eye (study eye) contributed to the analysis. |
| Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Baseline, Month 12, Month 24 | Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. BCVA change was defined as a change in letters correctly identified from the baseline assessment. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis |
| Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Baseline, Month 12, Month 24 | CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. 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 Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 2, Month 12, Month 24 | Intraretinal fluid and subretinal fluid was assessed using Optical Coherence Tomography (OCT) and recorded as Present/Absent. One eye (study eye) contributed to the analysis. |
| Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24 | Baseline, Month 12, Month 24 | Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis. |
| Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12 | Baseline, Month 12 | Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis. |
| Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months | Month 24 | The number of times the patient returned to a monthly injection interval (from an extended interval) at least once during the 24-month study was calculated. One eye (study eye) contributed to the analysis. |
| Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Baseline, Week 5, Week 9 | Blood for VEGF plasma concentration analysis was collected at Baseline and again at 7 days after the injection at Week 4 and 7 days after the injection at Week 8. |
| Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Baseline, Month 12, Month 24 | Retinal nerve fibre thickness was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change in value (i.e. thinner nerve fibre) indicates nerve damage. One eye (study eye) contributed to the analysis. |
| Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline, Week 9 | Anterior cell grade was assessed by the Investigator during slit lamp examination and graded on a 5-point scale: Grade 0=0 cells; Grade 1=1 to 10 cells; Grade 2=11 to 20 cells; Grade 3=21 to 50 cells; Grade 4=\>50 cells. The presence of blood cells (red and white) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. One eye (study eye) contributed to the analysis. |
| Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline, Week 9 | Anterior chamber flare was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe. The presence of flare (increased protein levels) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. Proportion of patients is reported as a percentage. One eye (study eye) contributed to the analysis. |
| Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24 | Baseline, Month 12, Month 24 | Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis. |
Countries
Australia
Participant flow
Recruitment details
Patients were recruited and enrolled from 24 sites located in Australia.
Pre-assignment details
This reporting group includes all patients randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab 0.5 mg 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity \[treat and extend\] | 142 |
| Aflibercept 2.0 mg 3 monthly loading doses (Baseline, Week 4, and Week 8), followed by an individualised treatment and evaluation regimen according to disease activity \[treat and extend\] | 139 |
| Total | 281 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 11 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Protocol Deviation | 4 | 0 |
| Overall Study | Site Administration Problems | 1 | 0 |
| Overall Study | Subject Withdrew Consent | 6 | 14 |
Baseline characteristics
| Characteristic | Aflibercept 2.0 mg | Ranibizumab 0.5 mg | Total |
|---|---|---|---|
| Age, Continuous | 78.7 years STANDARD_DEVIATION 7.45 | 76.6 years STANDARD_DEVIATION 8.5 | 77.7 years STANDARD_DEVIATION 8.06 |
| Race/Ethnicity, Customized Asian | 7 participants | 8 participants | 15 participants |
| Race/Ethnicity, Customized Black African | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 130 participants | 132 participants | 262 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Sex: Female, Male Female | 76 Participants | 72 Participants | 148 Participants |
| Sex: Female, Male Male | 63 Participants | 70 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 141 | 6 / 139 |
| other Total, other adverse events | 122 / 141 | 123 / 139 |
| serious Total, serious adverse events | 50 / 141 | 58 / 139 |
Outcome results
Primary
Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24
Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 24
Population: All randomized patients with at least one post-baseline efficacy value for the primary endpoint (FAS). Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24 | Baseline | 0.024 mm | Standard Deviation 0.0988 |
| Ranibizumab 0.5 mg | Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24 | Change from Baseline at Month 24 | 0.363 mm | Standard Deviation 0.7105 |
| Aflibercept 2.0 mg | Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24 | Baseline | 0.050 mm | Standard Deviation 0.2345 |
| Aflibercept 2.0 mg | Mean Change in Square-root Area of Geographic Atrophy (GA) From Baseline to Month 24 | Change from Baseline at Month 24 | 0.285 mm | Standard Deviation 0.5392 |
p-value: 0.23695% CI: [-0.05, 0.21]Mixed Models Analysis
Secondary
Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24
Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. BCVA change was defined as a change in letters correctly identified from the baseline assessment. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis
Time frame: Baseline, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Baseline | 65.3 letters | Standard Deviation 15.1 |
| Ranibizumab 0.5 mg | Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | 6.9 letters | Standard Deviation 12.25 |
| Ranibizumab 0.5 mg | Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | 6.5 letters | Standard Deviation 14.38 |
| Aflibercept 2.0 mg | Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Baseline | 65.1 letters | Standard Deviation 12.53 |
| Aflibercept 2.0 mg | Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | 5.2 letters | Standard Deviation 12.83 |
| Aflibercept 2.0 mg | Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | 5.3 letters | Standard Deviation 13.33 |
Comparison: Baseline to Month 12 Analysisp-value: 0.07995% CI: [-0.27, 4.92]Mixed Models Analysis
Comparison: Baseline to Month 24 Analysisp-value: 0.15195% CI: [-0.71, 4.61]Mixed Models Analysis
Secondary
Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24
CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. 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, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Baseline | 468.2 micrometers | Standard Deviation 150.82 |
| Ranibizumab 0.5 mg | Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | -147.2 micrometers | Standard Deviation 128.38 |
| Ranibizumab 0.5 mg | Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | -151.3 micrometers | Standard Deviation 133.37 |
| Aflibercept 2.0 mg | Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | -181.7 micrometers | Standard Deviation 155.48 |
| Aflibercept 2.0 mg | Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Baseline | 483.5 micrometers | Standard Deviation 168.05 |
| Aflibercept 2.0 mg | Mean Change in Central Subfield Foveal Thickness (CSFT) From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | -171.6 micrometers | Standard Deviation 150.12 |
Comparison: Baseline to Month 12 Analysisp-value: 0.29495% CI: [-8.82, 29.06]Mixed Models Analysis
Comparison: Baseline to Month 24 Analysisp-value: 0.22595% CI: [-7.35, 31.07]Mixed Models Analysis
Secondary
Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12
Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center, where the area of GA was measured. Area was treated as zero if GA was reported as absent (Overall determination of GA presence). Mean change from baseline in GA area was reported in square root-transformed data (mm). One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 12
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12 | Baseline | 0.024 mm | Standard Deviation 0.0988 |
| Ranibizumab 0.5 mg | Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12 | Change from Baseline at Month 12 | 0.155 mm | Standard Deviation 0.4272 |
| Aflibercept 2.0 mg | Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12 | Baseline | 0.050 mm | Standard Deviation 0.2345 |
| Aflibercept 2.0 mg | Mean Change in Square-root Area of Geographic Atrophy From Baseline to Month 12 | Change from Baseline at Month 12 | 0.145 mm | Standard Deviation 0.3179 |
p-value: 0.76995% CI: [-0.11, 0.15]Mixed Models Analysis
Secondary
Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment
Blood for VEGF plasma concentration analysis was collected at Baseline and again at 7 days after the injection at Week 4 and 7 days after the injection at Week 8.
Time frame: Baseline, Week 5, Week 9
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Baseline | 44.29 picogram/milliliter (pg/mL) | Standard Deviation 43.369 |
| Ranibizumab 0.5 mg | Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Change from Baseline at Week 5 | -0.48 picogram/milliliter (pg/mL) | Standard Deviation 30.299 |
| Ranibizumab 0.5 mg | Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Change from Baseline at Week 9 | 0.48 picogram/milliliter (pg/mL) | Standard Deviation 35.125 |
| Aflibercept 2.0 mg | Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Baseline | 41.88 picogram/milliliter (pg/mL) | Standard Deviation 35.236 |
| Aflibercept 2.0 mg | Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Change from Baseline at Week 5 | -26.37 picogram/milliliter (pg/mL) | Standard Deviation 36.22 |
| Aflibercept 2.0 mg | Mean Change in Vascular Endothelial Growth Factor (VEGF) Plasma Concentration From Baseline to 7 Days After the Second and 7 Days After the Third Mandated Intravitreal Injection of Treatment | Change from Baseline at Week 9 | -25.14 picogram/milliliter (pg/mL) | Standard Deviation 32.525 |
Comparison: Baseline to Week 5 Analysisp-value: <0.00195% CI: [21.44, 32.95]Mixed Models Analysis
Comparison: Baseline to Week 9 Analysisp-value: <0.00195% CI: [23.08, 34.68]Mixed Models Analysis
Secondary
Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24
The number of intravitreal injections was calculated. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Baseline to Month 12 | 9.7 injections | Standard Deviation 2.78 |
| Ranibizumab 0.5 mg | Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Month 12 to Month 24 | 8.9 injections | Standard Deviation 3.24 |
| Ranibizumab 0.5 mg | Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Baseline to Month 24 | 17.7 injections | Standard Deviation 6.44 |
| Aflibercept 2.0 mg | Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Baseline to Month 24 | 17.0 injections | Standard Deviation 6.3 |
| Aflibercept 2.0 mg | Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Baseline to Month 12 | 9.7 injections | Standard Deviation 2.54 |
| Aflibercept 2.0 mg | Mean Number of Intravitreal Injections From Baseline to Month 12 and to Month 24 | Month 12 to Month 24 | 8.3 injections | Standard Deviation 3.56 |
Comparison: Baseline to \<Month 12 Analysisp-value: 0.73395% CI: [0.95, 1.04]Negative Binomial Regression Model
Comparison: Baseline to Month 24 Analysisp-value: 0.74595% CI: [0.95, 1.08]Negative Binomial Regression Model
Secondary
Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months
The number of times the patient returned to a monthly injection interval (from an extended interval) at least once during the 24-month study was calculated. One eye (study eye) contributed to the analysis.
Time frame: Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data. Descriptive statistics only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.5 mg | Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months | 2.3 occurrences | Standard Deviation 1.28 |
| Aflibercept 2.0 mg | Mean Number of Times a Patient Needed to Return to Monthly Intravitreal Injections Over 24 Months | 2.3 occurrences | Standard Deviation 1.15 |
Secondary
Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24
Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | 22.0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | 24.8 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | 20.7 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing Greater Than and Equal to 15 Letters Gain for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | 18.5 percentage of patients |
Comparison: Baseline to Month 12 Analysisp-value: 0.89195% CI: [0.53, 2.08]Regression, Logistic
Comparison: Baseline to Month 24 Analysisp-value: 0.20695% CI: [0.77, 3.35]Regression, Logistic
Secondary
Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24
Visual acuity was assessed with spectacles or other visual corrective devices in place using logMAR charts and recorded in number of letters correctly identified. A gain in letters correctly identified indicates an improvement in visual acuity, while a loss indicates a worsening. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | 96.9 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | 94.0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 12 | 95.0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing Less Than and Equal to 15 Letters Loss for BCVA From Baseline to Month 12 and to Month 24 | Change from Baseline at Month 24 | 94.4 percentage of patients |
Comparison: Baseline to Month 12 Analysisp-value: 0.4695% CI: [0.45, 5.93]Regression, Logistic
Comparison: Baseline to Month 24 Analysisp-value: 0.91395% CI: [0.3, 2.9]Regression, Logistic
Secondary
Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF)
Intraretinal fluid and subretinal fluid was assessed using Optical Coherence Tomography (OCT) and recorded as Present/Absent. One eye (study eye) contributed to the analysis.
Time frame: Month 2, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 2 | 56.9 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 12 | 55.9 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 24 | 57.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 2 | 61.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 12 | 63.6 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients Showing no Intraretinal Fluid (IRF)/Subretinal Fluid (SRF) | Month 24 | 60.6 percentage of patients |
Comparison: Month 2 Analysisp-value: 0.46195% CI: [0.51, 1.35]Regression, Logistic
Comparison: Month 12 Analysisp-value: 0.21595% CI: [0.44, 1.21]Regression, Logistic
Comparison: Month 24 Analysisp-value: 0.61695% CI: [0.51, 1.48]Regression, Logistic
Secondary
Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24
Retinal nerve fibre thickness was assessed using Optical Coherence Tomography (OCT) and measured in micrometers. A negative change in value (i.e. thinner nerve fibre) indicates nerve damage. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 12, Month 24
Population: Safety Set. All patients who received at least one application of study treatment and had at least one post-baseline safety assessment, as treated. Descriptive statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 12: No Change from Baseline | 96.7 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 12: Decrease from Baseline | 2.5 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 12: Increase from Baseline | 0.8 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 24: Decrease from Baseline | 3.6 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 24: No Change from Baseline | 96.4 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 24: Increase from Baseline | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 24: No Change from Baseline | 97.9 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 24: Decrease from Baseline | 1.0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 12: Decrease from Baseline | 2.7 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 12: No Change from Baseline | 97.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 24: Increase from Baseline | 1.0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Change in Retinal Nerve Fibre Thickness From Baseline to Month 12 and Month 24 | Month 12: Increase from Baseline | 0 percentage of patients |
Secondary
Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study
Multimodal images of the eye were obtained by trained study site personnel and forwarded to an independent Central Reading Center. A patient was considered to have developed new GA if they did not have any GA at the start of the study period and were subsequently diagnosed with GA during the study period (diagnosis of GA change from No to Yes). The analysis of new GA development was restricted to only those subjects without GA reported at baseline. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Month 12, Month 24
Population: FAS. Following the intent-to-treat principle, patients were analyzed according to the treatment regimen they were assigned to at randomization, with no imputation for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Baseline to Month 12 | 17.6 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Month 12 to Month 24 | 15.1 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Baseline to Month 24 | 28.8 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Baseline to Month 12 | 20.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Month 12 to Month 24 | 7.2 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Newly Developed Geographic Atrophy During the Overall 24 Months of the Study | Baseline to Month 24 | 25.4 percentage of patients |
Comparison: Baseline to Month 12 Analysisp-value: 0.58695% CI: [0.44, 1.59]Regression, Logistic
Comparison: Month 12 to Month 24 Analysisp-value: 0.1195% CI: [0.83, 6.22]Regression, Logistic
Comparison: Baseline to Month 24 Analysisp-value: 0.55495% CI: [0.67, 2.09]Regression, Logistic
Secondary
Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells
Anterior cell grade was assessed by the Investigator during slit lamp examination and graded on a 5-point scale: Grade 0=0 cells; Grade 1=1 to 10 cells; Grade 2=11 to 20 cells; Grade 3=21 to 50 cells; Grade 4=\>50 cells. The presence of blood cells (red and white) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Week 9
Population: Safety Set. All patients who received at least one application of study treatment and had at least one post-baseline safety assessment, as treated. Descriptive statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 3+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 4+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 0 | 99.3 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 1+ | 0.7 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 2+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 3+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 4+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 0 | 95.1 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 1+ | 4.9 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 2+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 0 | 92.7 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 3+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 3+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 4+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 2+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 0 | 98.5 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 4+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 1+ | 1.5 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Week 9: Grade 1+ | 7.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Cells | Baseline: Grade 2+ | 0 percentage of patients |
Secondary
Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare
Anterior chamber flare was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe. The presence of flare (increased protein levels) in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the cornea's innermost surface) is a sign of intraocular inflammation. A score of 0 indicates an absence of inflammation. Proportion of patients is reported as a percentage. One eye (study eye) contributed to the analysis.
Time frame: Baseline, Week 9
Population: Safety Set. All patients who received at least one application of study treatment and had at least one post-baseline safety assessment, as treated. Descriptive statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 0 | 97.8 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 3+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 4+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 1+ | 2.2 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 2+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 3+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 0 | 94.3 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 1+ | 5.7 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 4+ | 0 percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 2+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 1+ | 7.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 0 | 99.3 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 3+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 3+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 4+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 2+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 1+ | 0.7 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 4+ | 0 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Week 9: Grade 0 | 92.7 percentage of patients |
| Aflibercept 2.0 mg | Percentage of Patients With Ocular Inflammation at Baseline and 7 Days Post-injection Following 3rd Mandated Intravitreal Injection - Anterior Chamber Flare | Baseline: Grade 2+ | 0 percentage of patients |