Proliferative Diabetic Retinopathy
Conditions
Keywords
proliferative diabetic retinophathy, retinal neovascularization, anti-VEGF, brolucizumab, intravitreal injection, panretinal photocoagulation
Brief summary
The purpose of this study was to evaluate the efficacy and safety of brolucizumab compared to panretinal photocoagulation laser (PRP) in patients with proliferative diabetic retinopathy (PDR). This evaluation will provide information that brolucizumab is non-inferior to PRP with respect to the change in best corrected visual acuity at Week 54.
Detailed description
Phase III, 96-week, two-arm, randomized (1:1 ratio), single-masked, multi-center, active-controlled study to evaluate the efficacy and safety of brolucizumab compared to Panretinal photocoagulation (PRP) in subjects with Proliferative diabetic retinopathy (PDR). Subjects who consented underwent screening assessments to evaluate their eligibility based on the inclusion and exclusion criteria. Subjects who met all the inclusion and none of the exclusion criteria were randomized in a 1:1 ratio to one of the following treatments: Brolucizumab 6 mg: 3 x q6w loading then q12w maintenance through Week 90, with the option from Week 48 onwards to extend the treatment interval by 6 weeks at a time up to 24 weeks, and revert to q12w if disease worsens. More frequent injection with q6w interval in the maintenance phase could be administered at the discretion of the Investigator if the disease worsens. PRP: initial treatment in 1-4 sessions up to Week 12, followed with additional PRP treatment (may split into 2-4 sessions) as needed up to Week 90. Visits occurred every 6 weeks throughout the study, regardless of treatment or not.
Interventions
BIOLOGICALBrolucizumab 6 mg
3 x q6w loading injections, followed by q12w maintenance through Week 90
PROCEDUREPanretinal photocoagulation laser
initial treatment in 1-4 sessions up to Week 12, followed with additional PRP treatment as needed
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent must be obtained prior to participation * Able to complete adequate fundus photographs and retinal images * Diagnosis of type 1 or 2 Diabetes Mellitus (DM) and HbA1c less than or equal to 12% at screening * DM treatment stable for at least 3 months * PDR diagnosis with no previous PRP treatment in the study eye
Exclusion criteria
* Concomitant conditions or ocular disorders in the study eye at Screening or Baseline that could compromise a response to study treatment. * Presence of diabetic macular edema in the study eye * Active infection or inflammation in the study eye * Uncontrolled glaucoma (IOP greater than 25 mmHg) * Intravitreal anti-VEGF treatment within 6 months * Treatment with intraocular corticosteroids * End stage renal disease requiring dialysis or kidney transplant * Uncontrolled blood pressure * Systemic anti-VEGF therapy at any time Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 54 for the Study Eye | Baseline, Week 54 | BCVA was 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 \>= 34 ETDRS letters (Snellen equivalent 20/200) at Screening / Baseline 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 96 for the Study Eye | Week 96 | Proliferative diabetic retinopathy (PDR) is derived from the diabetic retinopathy severity scale (DRSS) as assessed by the central reading center (CRC) using 7-field color fundus photography image. The DRSS on the original score with scores varying from 10 (DR absent) to 85 (very advanced PDR) were then converted into a 12-level scale (Range is from 1 - diabetic retinopathy (DR) absent, to 12- very advanced PDR). (A lower score represents a better outcome.) The event of No PDR is then defined as DRSS (12-level scale) \< 7. |
| Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 54 for the Study Eye | Up to Week 54 | Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. PRP = Panretinal photocoagulation laser |
| Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 96 for the Study Eye | Up to Week 96 | Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. PRP = Panretinal photocoagulation laser |
| Area Under the Curve in Change From Baseline in BCVA up to Week 54 and up to Week 96 - for the Study Eye | Baseline, up to Week 54 and up to Week 96 | BCVA was 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 \>= 34 ETDRS letters (Snellen equivalent 20/200) at Screening / Baseline 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. The AUC in change from Baseline in BCVA up to Week 54 (or Week 96) is referred to as the averaged change from Baseline in BCVA at each visit up to 54 (or Week 96), which was calculated as (BCVA at Week 6 + BCVA at Week 12 + ... + BCVA at Week 54 (or Week 96)) / number of visits with valid BCVA data from Week 6 to Week 54 (or Week 96) - BCVA at Baseline. |
| Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Baseline, Week 54 and Week 96 | 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. |
| Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 54 for the Study Eye | Week 54 | Proliferative diabetic retinopathy (PDR) is derived from the diabetic retinopathy severity scale (DRSS) as assessed by the central reading center (CRC) using 7-field color fundus photography image. The DRSS on the original score with scores varying from 10 (DR absent) to 85 (very advanced PDR) were then converted into a 12-level scale (Range is from 1 - diabetic retinopathy (DR) absent, to 12- very advanced PDR). (A lower score represents a better outcome.) The event of No PDR is then defined as DRSS (12-level scale) \< 7. |
| Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Baseline, Week 54 and Week 96 | 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. |
| Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Baseline, Week 54 and Week 96 | 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. |
| Number and Percentage of Subjects Developing Vision-threatening Complications Associated With Diabetic Retinopathy up to Week 54 and up to Week 96 | up to Week 54 and up to Week 96 | The vision-threatening complications associated with Diabetic retinopathy (DR) are defined as any event of the following list occurring in the study eye at any time point after Baseline: * Center-involved Diabetic macular edema (CI-DME) as defined as Central sub-field thickness (CSFT) ≥280 µm according to Central reading center (CRC) evaluation of Optical coherent tomography (OCT) image * Retinal detachment * Vitreous hemorrhage * Neovascular glaucoma, iris/ anterior chamber angle neovascularization * Vitrectomy for DR complications |
| Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | Adverse events are reported from first dose of study treatment up to Week 90, plus approximately 6 weeks post-treatment, up to a maximum timeframe of approximately 96 weeks. | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. AEs that started after alternative diabetic retinopathy treatment/relevant diabetic macular edema treatment in the study eye are censored. |
| Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Adverse events are reported from first dose of study treatment up to Week 90, plus approximately 6 weeks post-treatment, up to a maximum timeframe of approximately 96 weeks. | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. AEs that started after alternative diabetic retinopathy treatment/relevant diabetic macular edema treatment in the study eye are censored. |
| Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Baseline, Week 54 and Week 96 | 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. |
Countries
Argentina, Australia, Brazil, Canada, Chile, China, India, Japan, Mexico, Philippines, Puerto Rico, Russia, South Korea, Taiwan, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Brolucizumab 6 mg Brolucizumab 6 mg: 3 x q6w loading then q12w maintenance through Week 90, with the option from Week 48 onwards to extend the treatment interval by 6 weeks at a time up to 24 weeks and revert to q12w if disease worsens. More frequent injection with q6w interval in the maintenance phase could be administered at the discretion of the Investigator if the disease worsens. | 347 |
| Panretinal Photocoagulation Laser Arm Initial treatment in 1-4 sessions up to Week 12, followed by additional PRP treatment as needed. | 342 |
| Total | 689 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 5 |
| Overall Study | Death | 8 | 9 |
| Overall Study | Lost to Follow-up | 11 | 13 |
| Overall Study | Physician Decision | 4 | 6 |
| Overall Study | Progressive disease | 0 | 2 |
| Overall Study | Withdrawal by Subject | 20 | 20 |
Baseline characteristics
| Characteristic | Panretinal Photocoagulation Laser Arm | Total | Brolucizumab 6 mg |
|---|---|---|---|
| Age, Continuous | 54.7 Years STANDARD_DEVIATION 10.83 | 53.9 Years STANDARD_DEVIATION 11.39 | 53.2 Years STANDARD_DEVIATION 11.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 148 Participants | 305 Participants | 157 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 38 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 169 Participants | 335 Participants | 166 Participants |
| Sex: Female, Male Female | 132 Participants | 276 Participants | 144 Participants |
| Sex: Female, Male Male | 210 Participants | 413 Participants | 203 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 347 | 9 / 342 | 17 / 689 |
| other Total, other adverse events | 241 / 347 | 254 / 342 | 495 / 689 |
| serious Total, serious adverse events | 96 / 347 | 105 / 342 | 201 / 689 |
Outcome results
Primary
Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 54 for the Study Eye
BCVA was 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 \>= 34 ETDRS letters (Snellen equivalent 20/200) at Screening / Baseline 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 54
Population: Full Analysis Set- Last Observation Carried Forward (FAS - LOCF), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 6 mg | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 54 for the Study Eye | 0.2 Letters Read | Standard Error 0.72 |
| Panretinal Photocoagulation Laser Arm | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 54 for the Study Eye | -4.2 Letters Read | Standard Error 0.73 |
Comparison: 1p-value: <0.00195% CI: [2.4, 6.4]ANCOVA
Comparison: 2p-value: <0.001ANCOVA
Secondary
Area Under the Curve in Change From Baseline in BCVA up to Week 54 and up to Week 96 - for the Study Eye
BCVA was 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 \>= 34 ETDRS letters (Snellen equivalent 20/200) at Screening / Baseline 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. The AUC in change from Baseline in BCVA up to Week 54 (or Week 96) is referred to as the averaged change from Baseline in BCVA at each visit up to 54 (or Week 96), which was calculated as (BCVA at Week 6 + BCVA at Week 12 + ... + BCVA at Week 54 (or Week 96)) / number of visits with valid BCVA data from Week 6 to Week 54 (or Week 96) - BCVA at Baseline.
Time frame: Baseline, up to Week 54 and up to Week 96
Population: Full Analysis Set- Last Observation Carried Forward (FAS - LOCF), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Brolucizumab 6 mg | Area Under the Curve in Change From Baseline in BCVA up to Week 54 and up to Week 96 - for the Study Eye | up to Week 54 | 0.5 Letters read |
| Brolucizumab 6 mg | Area Under the Curve in Change From Baseline in BCVA up to Week 54 and up to Week 96 - for the Study Eye | up to Week 96 | -0.1 Letters read |
| Panretinal Photocoagulation Laser Arm | Area Under the Curve in Change From Baseline in BCVA up to Week 54 and up to Week 96 - for the Study Eye | up to Week 54 | -3.2 Letters read |
| Panretinal Photocoagulation Laser Arm | Area Under the Curve in Change From Baseline in BCVA up to Week 54 and up to Week 96 - for the Study Eye | up to Week 96 | -4.3 Letters read |
Secondary
Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96
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.
Time frame: Baseline, Week 54 and Week 96
Population: Full Analysis Set- Last Observation Carried Forward (FAS - LOCF), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=282, 279) | 128 Participants |
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=295, 289) | 123 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=282, 279) | 57 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=295, 289) | 65 Participants |
Comparison: Week 54p-value: <0.00195% CI: [19.5, 33.3]Cochran-Mantel-Haenszel
Secondary
Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96
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.
Time frame: Baseline, Week 54 and Week 96
Population: Full Analysis Set- Observed, for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=225,220) | 6 Participants |
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=236, 201) | 18 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=225,220) | 31 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥2 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=236, 201) | 27 Participants |
Secondary
Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96
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.
Time frame: Baseline, Week 54 and Week 96
Population: Full Analysis Set- Last Observation Carried Forward (FAS - LOCF), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=282, 279) | 58 Participants |
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=295, 289) | 49 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=282, 279) | 30 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Improvement From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=295, 289) | 33 Participants |
Secondary
Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96
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.
Time frame: Baseline, Week 54 and Week 96
Population: Full Analysis Set-Observed, for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=225, 220) | 4 Participants |
| Brolucizumab 6 mg | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=236, 201) | 11 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 54 (n=225, 220) | 16 Participants |
| Panretinal Photocoagulation Laser Arm | Diabetic Retinopathy Severity Scale (DRSS): Number and Percentage of Subjects With ≥3 Steps Worsening From Baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) DRSS Score at Week 54 and Week 96 | Week 96 (n=236, 201) | 16 Participants |
Secondary
Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. AEs that started after alternative diabetic retinopathy treatment/relevant diabetic macular edema treatment in the study eye are censored.
Time frame: Adverse events are reported from first dose of study treatment up to Week 90, plus approximately 6 weeks post-treatment, up to a maximum timeframe of approximately 96 weeks.
Population: Safety Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Pyrexia | 15 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperlipidaemia | 9 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Nasopharyngitis | 22 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperuricaemia | 9 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperglycaemia | 13 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Chronic kidney disease | 8 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | COVID-19 | 44 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Depression | 8 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperkalaemia | 12 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Blood glucose increased | 7 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Anaemia | 15 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hypercholesterolaemia | 7 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Urinary tract infection | 12 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Nausea | 7 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Upper respiratory tract infection | 28 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Type 2 diabetes mellitus | 7 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Diabetes mellitus | 10 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Arthralgia | 5 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Cough | 15 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Influenza | 5 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Pneumonia | 10 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | -Vomiting | 5 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hypertension | 35 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Diabetic neuropathy | 2 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Coronary artery disease | 9 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Diabetic foot | 1 Participants |
| Brolucizumab 6 mg | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Number of subjects with at least one AE | 226 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Diabetic foot | 7 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Number of subjects with at least one AE | 217 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | COVID-19 | 47 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hypertension | 24 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Upper respiratory tract infection | 16 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Nasopharyngitis | 16 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Anaemia | 15 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Cough | 10 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Pyrexia | 7 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperglycaemia | 10 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperkalaemia | 2 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Urinary tract infection | 13 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Diabetes mellitus | 5 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Pneumonia | 4 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Coronary artery disease | 5 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperlipidaemia | 8 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hyperuricaemia | 4 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Chronic kidney disease | 5 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Depression | 3 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Blood glucose increased | 5 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Hypercholesterolaemia | 5 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Nausea | 6 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Type 2 diabetes mellitus | 6 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Arthralgia | 7 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Influenza | 8 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | -Vomiting | 9 Participants |
| Panretinal Photocoagulation Laser Arm | Non-ocular AEs (≥ 2% in Any Treatment Arm) by Preferred Term | Diabetic neuropathy | 10 Participants |
Secondary
Number and Percentage of Subjects Developing Vision-threatening Complications Associated With Diabetic Retinopathy up to Week 54 and up to Week 96
The vision-threatening complications associated with Diabetic retinopathy (DR) are defined as any event of the following list occurring in the study eye at any time point after Baseline: * Center-involved Diabetic macular edema (CI-DME) as defined as Central sub-field thickness (CSFT) ≥280 µm according to Central reading center (CRC) evaluation of Optical coherent tomography (OCT) image * Retinal detachment * Vitreous hemorrhage * Neovascular glaucoma, iris/ anterior chamber angle neovascularization * Vitrectomy for DR complications
Time frame: up to Week 54 and up to Week 96
Population: Full Analysis Set - Observed, for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Number and Percentage of Subjects Developing Vision-threatening Complications Associated With Diabetic Retinopathy up to Week 54 and up to Week 96 | up to Week 54 | 117 Participants |
| Brolucizumab 6 mg | Number and Percentage of Subjects Developing Vision-threatening Complications Associated With Diabetic Retinopathy up to Week 54 and up to Week 96 | up to Week 96 | 144 Participants |
| Panretinal Photocoagulation Laser Arm | Number and Percentage of Subjects Developing Vision-threatening Complications Associated With Diabetic Retinopathy up to Week 54 and up to Week 96 | up to Week 54 | 258 Participants |
| Panretinal Photocoagulation Laser Arm | Number and Percentage of Subjects Developing Vision-threatening Complications Associated With Diabetic Retinopathy up to Week 54 and up to Week 96 | up to Week 96 | 270 Participants |
Secondary
Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 54 for the Study Eye
Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. PRP = Panretinal photocoagulation laser
Time frame: Up to Week 54
Population: Full Analysis Set (FAS), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brolucizumab 6 mg | Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 54 for the Study Eye | 108 Participants |
| Panretinal Photocoagulation Laser Arm | Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 54 for the Study Eye | 248 Participants |
p-value: <0.00195% CI: [-48, -34.2]Cochran-Mantel-Haenszel
Secondary
Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 96 for the Study Eye
Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. PRP = Panretinal photocoagulation laser
Time frame: Up to Week 96
Population: Full Analysis Set (FAS), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brolucizumab 6 mg | Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 96 for the Study Eye | 126 Participants |
| Panretinal Photocoagulation Laser Arm | Number and Percentage of Subjects With Center-involved Diabetic Macular Edema (CI- DME) up to Week 96 for the Study Eye | 262 Participants |
Secondary
Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 54 for the Study Eye
Proliferative diabetic retinopathy (PDR) is derived from the diabetic retinopathy severity scale (DRSS) as assessed by the central reading center (CRC) using 7-field color fundus photography image. The DRSS on the original score with scores varying from 10 (DR absent) to 85 (very advanced PDR) were then converted into a 12-level scale (Range is from 1 - diabetic retinopathy (DR) absent, to 12- very advanced PDR). (A lower score represents a better outcome.) The event of No PDR is then defined as DRSS (12-level scale) \< 7.
Time frame: Week 54
Population: Full Analysis Set- Last Observation Carried Forward (FAS - LOCF), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brolucizumab 6 mg | Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 54 for the Study Eye | 187 Participants |
| Panretinal Photocoagulation Laser Arm | Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 54 for the Study Eye | 65 Participants |
p-value: <0.00195% CI: [32, 46.8]Cochran-Mantel-Haenszel
Secondary
Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 96 for the Study Eye
Proliferative diabetic retinopathy (PDR) is derived from the diabetic retinopathy severity scale (DRSS) as assessed by the central reading center (CRC) using 7-field color fundus photography image. The DRSS on the original score with scores varying from 10 (DR absent) to 85 (very advanced PDR) were then converted into a 12-level scale (Range is from 1 - diabetic retinopathy (DR) absent, to 12- very advanced PDR). (A lower score represents a better outcome.) The event of No PDR is then defined as DRSS (12-level scale) \< 7.
Time frame: Week 96
Population: Full Analysis Set- Last Observation Carried Forward (FAS - LOCF), for patients with a valid measurement with no protocol deviations with impact.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Brolucizumab 6 mg | Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 96 for the Study Eye | 188 Participants |
| Panretinal Photocoagulation Laser Arm | Number and Percentage of Subjects With no Proliferative Diabetic Retinopathy (PDR) at Week 96 for the Study Eye | 86 Participants |
Secondary
Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. AEs that started after alternative diabetic retinopathy treatment/relevant diabetic macular edema treatment in the study eye are censored.
Time frame: Adverse events are reported from first dose of study treatment up to Week 90, plus approximately 6 weeks post-treatment, up to a maximum timeframe of approximately 96 weeks.
Population: Safety Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Macular oedema | 9 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Dry eye | 15 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Vitreous floaters | 9 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | Number of subjects with at least one AE | 152 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Conjunctivitis | 7 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Intraocular pressure increased | 12 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Diabetic retinal oedema | 7 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Cataract | 26 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Retinal hemorrhage | 5 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Diabetic retinopathy | 4 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Conjunctival hemorrhage | 10 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Eye pain | 3 Participants |
| Brolucizumab 6 mg | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Vitreous hemorrhage | 38 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Eye pain | 7 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | Number of subjects with at least one AE | 199 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Vitreous hemorrhage | 83 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Cataract | 27 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Dry eye | 8 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Intraocular pressure increased | 3 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Conjunctival hemorrhage | 5 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Macular oedema | 34 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Vitreous floaters | 9 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Conjunctivitis | 4 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Diabetic retinal oedema | 36 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Diabetic retinopathy | 13 Participants |
| Panretinal Photocoagulation Laser Arm | Ocular AEs (>= 2% in Any Treatment Arm) by Preferred Term for the Study Eye | -Retinal hemorrhage | 12 Participants |
Post Hoc
All Collected Deaths
On-treatment deaths are reported from first dose of study treatment until end of study treatment at the time of the interim analysis, plus 4 weeks post treatment, up to a maximum timeframe of approximately 96 weeks. Post-treatment deaths are reported for the timeframe of greater than 30 days after last treatment, also up to Week 96. All deaths refer to the sum of on-treatment and post-treatment deaths.
Time frame: On-treatment - within 30 days after last treatment, up to Week 96; Post-treatment - greater than 30 days after last treatment, also up to Week 96.