A Study of Faricimab (RO6867461) in Participants With Center-Involving Diabetic Macular Edema

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The primary analysis used a Linear Mixed Effects Model for Repeated Measurements. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Baseline, Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Free Ang-2 concentrations were determined in plasma samples using an appropriate assay method. The lower limit of quantification (LLOQ) of the assay was 0.9 nanograms per millilitre (ng/mL). Plasma free Ang-2 concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Baseline and Weeks 1, 4, 12, 16, 24, 26, 28, 32, and 36

Population: Pharmacodynamics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

Free Ang-2 concentrations were determined in plasma samples using an appropriate assay method. The lower limit of quantification (LLOQ) of the assay was 0.9 nanograms per millilitre (ng/mL). Plasma free Ang-2 concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Baseline and Weeks 1, 4, 12, 16, 24, 26, 28, 32, and 36

Population: Pharmacodynamics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

The concentration of free VEGF was determined in plasma samples using an enzyme-linked immunosorbent assay (ELISA) method. The lower limit of quantification (LLOQ) of the assay was 15.6 picograms per millilitre (pg/mL). Plasma free VEGF concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Baseline and Weeks 1, 4, 12, 16, 24, 26, 28, 32, and 36

Population: Pharmacodynamics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

The concentration of free VEGF was determined in plasma samples using an enzyme-linked immunosorbent assay (ELISA) method. The lower limit of quantification (LLOQ) of the assay was 15.6 picograms per millilitre (pg/mL). Plasma free VEGF concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Baseline and Weeks 1, 4, 12, 16, 24, 26, 28, 32, and 36

Population: Pharmacodynamics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

Total Ang-2 concentrations were determined in plasma samples using an appropriate assay method. The lower limit of quantification (LLOQ) of the assay was 0.09 nanograms per millilitre (ng/mL). Plasma total Ang-2 concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Baseline and Weeks 1, 4, 12, 16, 24, 26, 28, 32, and 36

Population: Pharmacodynamics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

Total Ang-2 concentrations were determined in plasma samples using an appropriate assay method. The lower limit of quantification (LLOQ) of the assay was 0.09 nanograms per millilitre (ng/mL). Plasma total Ang-2 concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Baseline and Weeks 1, 4, 12, 16, 24, 26, 28, 32, and 36

Population: Pharmacodynamics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The primary analysis used a Linear Mixed Effects Model for Repeated Measurements. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Baseline, Week 24

Population: Efficacy Population: all participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The primary analysis used a Linear Mixed Effects Model for Repeated Measurements. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Baseline, Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Central subfield thickness (CST) is defined as the mean thickness from the inner limiting membrane to the retinal pigment epithelial over the 1 millimetre (mm) central subfield. Central subfield thickness was measured using SD-OCT.

Time frame: Baseline, Week 24

Population: Efficacy Population: all participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Central subfield thickness (CST) is defined as the mean thickness from the inner limiting membrane to the retinal pigment epithelial over the 1 millimetre (mm) central subfield. Central subfield thickness was measured using SD-OCT.

Time frame: Baseline, Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Central subfield thickness (CST) is defined as the mean thickness from the inner limiting membrane to the retinal pigment epithelial over the 1 millimetre (mm) central subfield. Central subfield thickness was measured using SD-OCT.

Time frame: Baseline, Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Foveal center point thickness (FCPT) is defined as the thickness from the inner limiting membrane to the retinal pigment epithelial at the horizontal slice closest to the center of the fovea. Foveal center point thickness was measured using spectral domain optical coherence tomography (SD-OCT).

Time frame: Baseline, Week 24

Population: Efficacy Population: all participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Foveal center point thickness (FCPT) is defined as the thickness from the inner limiting membrane to the retinal pigment epithelial at the horizontal slice closest to the center of the fovea. Foveal center point thickness was measured using spectral domain optical coherence tomography (SD-OCT).

Time frame: Baseline, Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Foveal center point thickness (FCPT) is defined as the thickness from the inner limiting membrane to the retinal pigment epithelial at the horizontal slice closest to the center of the fovea. Foveal center point thickness was measured using spectral domain optical coherence tomography (SD-OCT).

Time frame: Baseline, Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

The size of the foveal avascular zone was to be measured by fundus fluorescein angiography (FFA).

Time frame: Baseline, Week 24

Population: Due to the poor image quality available, size of the foveal avascular zone could not be assessed in any of the participant populations.

Triplicate 12-lead electrocardiogram (ECG), i.e., three useful ECGs without artifacts, were performed on all evaluable participants. To minimize variability, it was important that participants be in a resting position for at least 10 minutes prior to the ECG evaluation. Body position was to be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation, mobile phones) were to be minimized before and during ECG recording. Triplicate ECGs were to be obtained within a 5-minute interval. The predefined standard reference range for heart rate measured by ECG was 40 (low) to 100 (high) beats per minute.

Time frame: Baseline, Week 24

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received. This analysis included participants with non-missing assessments at Baseline and Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Baseline up to Week 24

Population: Efficacy Population: all participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Baseline up to Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Baseline, Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Week 24

Population: Efficacy Population: all participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Week 24

Population: Efficacy Population: all participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time frame: Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Plasma concentrations of ranibizumab were measured by an appropriate assay only from samples of participants randomized to Arm A: 0.3 mg Ranibizumab. Plasma concentrations of faricimab were measured by a specific validated enzyme-linked immunoabsorbent assay (ELISA) only from samples of participants randomized to Arm B: 1.5 mg Faricimab and Arm C: 6 mg Faricimab. Baseline was defined as the last non-missing predose assessment. The lower limit of quantification (LLOQ) for the ranibizumab and faricimab assays were 0.015 nanograms per millilitre (ng/mL) and 0.800 ng/mL, respectively. Values below the limit of quantification were imputed as LLOQ divided by 2.

Time frame: Predose at Baseline and Weeks 1, 4, 12, 20, 24, 26, 28, 32, and 36

Population: Pharmacokinetics Population: The analysis included participants who received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study) and had plasma samples available at a given study visit timepoint.

Triplicate 12-lead electrocardiogram (ECG), i.e., three useful ECGs without artifacts, were performed on all evaluable participants. To minimize variability, it was important that participants be in a resting position for at least 10 minutes prior to the ECG evaluation. Body position was to be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation, mobile phones) were to be minimized before and during ECG recording. Triplicate ECGs were to be obtained within a 5-minute interval. Baseline was defined as the last non-missing predose assessment. The predefined standard reference ranges for the intervals measured by ECG were defined as follows (ranges are from low to high, in milliseconds \[msec\]): PR: 120-200 msec; RR: 600-1500 msec; QT: 200-500 msec; QRS: 40-120 msec.

Time frame: Baseline, Week 24

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received. This analysis included participants with non-missing assessments at Baseline and Week 24.

The number and percentage of participants who tested negative or positive for plasma anti-drug antibodies (ADA) to faricimab at baseline and at the study visits was tabulated, except for those who were randomized to treatment with ranibizumab in Arm A.

Time frame: Baseline and Weeks 1, 4, 12, 16, 20, 24, 26, 28, 32, and 36

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received. Analysis only included participants who were randomized to treatment with faricimab in Arms B and C.

Abnormal body temperature (supine) was defined as any value outside of the standard reference range, from \<36.5 (low) to \>37.5 (high) degrees Celsius. Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Time frame: Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 26, 28, 32, and 36

Population: Safety Population; the number of participants with an abnormal vital sign (numerator) is reported among the number analyzed (denominator), which represents the number of participants without the abnormal vital sign at baseline and who were evaluable at a given assessment timepoint.

Abnormal diastolic blood pressure (supine) was defined as any value outside of the standard reference range, from \<40 (low) to \>110 (high) millimetres of mercury (mmHg) or a change from baseline of greater than 20 mmHg (decrease or increase). Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Time frame: Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 26, 28, 32, and 36

Population: Safety Population; the number of participants with an abnormal vital sign (numerator) is reported among the number analyzed (denominator), which represents the number of participants without the abnormal vital sign at baseline and who were evaluable at a given assessment timepoint.

Abnormal systolic blood pressure (supine) was defined as any value outside of the standard reference range, from \<70 (low) to \>180 (high) millimetres of mercury (mmHg) or a change from baseline of greater than 30 mmHg (decrease or increase). Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Time frame: Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 26, 28, 32, and 36

Population: Safety Population; the number of participants with an abnormal vital sign (numerator) is reported among the number analyzed (denominator), which represents the number of participants without the abnormal vital sign at baseline and who were evaluable at a given assessment timepoint.

Abnormal heart rate (supine) was defined as any value outside of the standard reference range, from \<40 (low) to \>100 (high) beats per minute. Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Time frame: Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 26, 28, 32, and 36

Population: Safety Population; the number of participants with an abnormal vital sign (numerator) is reported among the number analyzed (denominator), which represents the number of participants without the abnormal vital sign at baseline and who were evaluable at a given assessment timepoint.

The investigator assessed adverse event severity according to the following grading scale: Mild = Discomfort noticed, but no disruption of normal daily activity; Moderate = Discomfort sufficient to reduce or affect normal daily activity; Severe = Incapacitating with inability to work or to perform normal daily activity. Only the most severe intensity was counted for multiple occurrences of the same adverse event per participant at the preferred term level. Severity and seriousness are not synonymous; regardless of severity, some adverse events may have also met seriousness criteria.

Time frame: From Baseline up to Week 24

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received.

The investigator assessed adverse event severity according to the following grading scale: Mild = Discomfort noticed, but no disruption of normal daily activity; Moderate = Discomfort sufficient to reduce or affect normal daily activity; Severe = Incapacitating with inability to work or to perform normal daily activity. Only the most severe intensity was counted for multiple occurrences of the same adverse event per participant at the preferred term level. Severity and seriousness are not synonymous; regardless of severity, some adverse events may have also met seriousness criteria.

Time frame: From Baseline up to Week 24

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received.

Clinical laboratory tests for blood chemistry parameters were performed and any marked abnormal values (High or Low) were based on Roche's predefined standard reference ranges. Marked laboratory abnormalities are presented according to COG3007 abnormality criteria: Single, Not Last = abnormality detected at a single assessment, but not at the last assessment; Last or Replicated = abnormality detected at the last assessment or replicated at one or more assessments. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. SGOT/AST = serum glutamic oxaloacetic transaminase / aspartate aminotransferase

Time frame: Predose at Baseline, Weeks 12 and 24, and at Early Termination and Unscheduled Visits (up to 36 weeks)

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received. This analysis included participants with non-missing assessments.

Clinical laboratory tests for coagulation parameters were performed and any marked abnormal values (High or Low) were based on Roche's predefined standard reference ranges. Marked laboratory abnormalities are presented according to COG3007 abnormality criteria: Single, Not Last = abnormality detected at a single assessment, but not at the last assessment; Last or Replicated = abnormality detected at the last assessment or replicated at one or more assessments. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. aPTT = activated partial thromboplastin time; INR = International Normalized Ratio (prothrombin time)

Time frame: Predose at Baseline, Weeks 12 and 24, and at Early Termination and Unscheduled Visits (up to 36 weeks)

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received. This analysis included participants with non-missing assessments.

Clinical laboratory tests for hematology parameters were performed and any marked abnormal values (High or Low) were based on Roche's predefined standard reference ranges. Marked laboratory abnormalities are presented according to COG3007 abnormality criteria: Single, Not Last = abnormality detected at a single assessment, but not at the last assessment; Last or Replicated = abnormality detected at the last assessment or replicated at one or more assessments. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Abs. = absolute count; Ery. = erythrocyte; Hemo. = hemoglobin

Time frame: Predose at Baseline, Weeks 12 and 24, and at Early Termination and Unscheduled Visits (up to 36 weeks)

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received. This analysis included participants with non-missing assessments.

Leakage at the macula describes the leakage of fluorescein at the macula region as measured by fundus fluorescein angiography (FFA).

Time frame: Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Leakage at the macula describes the leakage of fluorescein at the macula region as measured by fundus fluorescein angiography (FFA).

Time frame: Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Week 24.

Intraretinal fluid is described as the presence of fluid within the retina. Resolution of intraretinal fluid was measured by SD-OCT.

Time frame: Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Intraretinal fluid is described as the presence of fluid within the retina. Resolution of intraretinal fluid was measured by SD-OCT.

Time frame: Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Subretinal fluid is defined as the presence of fluid between the retina and the retinal pigment epithelium. Resolution of subretinal fluid was measured using SD-OCT.

Time frame: Week 24

Population: Efficacy Population: all previously treated participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

Subretinal fluid is defined as the presence of fluid between the retina and the retinal pigment epithelium. Resolution of subretinal fluid was measured using SD-OCT.

Time frame: Week 24

Population: Efficacy Population: all treatment-naive participants who had received at least one dose of study drug grouped by treatment assigned at randomization (did not differ from actual treatment during the study). This analysis only included participants with non-missing assessments at Baseline and Week 24.

This safety summary reports the number and percentage of participants who experienced at least one adverse event (AE) during the post-treatment observation period (i.e., from Week 24 up to Week 36). AEs are categorized as any AEs, ocular AEs occurring in the study eye or fellow eye, systemic AEs, serious AEs, AEs related to treatment with study drug, AEs leading to discontinuation of treatment with study drug, and AEs with fatal outcome. Multiple occurrences of the same AE in one individual were counted only once.

Time frame: From Week 24 up to Week 36

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received.

This safety summary reports the number and percentage of participants who experienced at least one adverse event (AE) within 28 days of the end of the treatment period (i.e., up to Week 24). AEs are categorized as any AEs, ocular AEs occurring in the study eye or fellow eye, systemic AEs, serious AEs, AEs related to treatment with study drug, AEs leading to discontinuation of treatment with study drug, and AEs with fatal outcome. Multiple occurrences of the same AE in one individual were counted only once.

Time frame: From Baseline up to Week 24

Population: Safety Population: all participants who had received at least one dose of the study drug, whether prematurely withdrawn from the study or not, grouped according to the actual treatment received.