Diabetic Macular Edema
Conditions
Keywords
DME, Diabetic, macula, edema, ranibizumab, RESTORE
Brief summary
CRFB002D2301: The core study was designed to confirm the efficacy and safety of ranibizumab (0.5 mg) as adjunctive therapy when added to laser photocoagulation and/or mono-therapy in patients with visual impairment due to diabetic macular edema. CRFB002D2301E1: A 24 month open-label extension study for participants who completed the 12 month core study evaluated the long-term safety and efficacy of ranibizumab (0.5 mg) as symptomatic treatment for visual impairment due to diabetic macular edema.
Interventions
DRUGRanibizumab
0.5 mg ranibizumab administered by intravitreal injection.
PROCEDURELaser
Laser photocoagulation treatment
PROCEDURESham laser
Sham to laser procedure.
DRUGSham to ranibizumab
Sham to ranibizumab administered as an intravitreal injection.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Visual acuity impairment * Diabetic macular edema in at least one eye * Type 1 or type 2 diabetes mellitus * Medication for the diabetes treatment must be stable for the last 3 months
Exclusion criteria
* Patients with uncontrolled systemic or ocular diseases * Laser photocoagulation in the study eye for the last 3 months * Any history of any intraocular surgery in the study eye within the past 3 months * Blood pressure \> 160/100 mmHg Extension Inclusion Criteria: -Completion of the Core Study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Baseline through the end of study (Month 12) | Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. |
| Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months] | Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section. |
| Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months] | Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Baseline to Month 12 | The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure a patient's subjective assessment of vision-related quality of life. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function. |
| Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 months] | Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section. |
| Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Baseline to Month 12 | Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. |
| Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | Extension baseline (Month12 -end of core study), Month 36 (end of extension study) | Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement. |
| Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | Core baseline (Day 1 of the core study), Month 36 (end of extension study) | Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement. |
| Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 Months] | Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about Adverse Events can be found in the Adverse Event section. |
| Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Baseline to Month 12 | Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. |
| Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Baseline to Month 12 | Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation. |
Countries
Australia, Belgium, Canada, France, Germany, Greece, Hungary, Italy, Netherlands, Spain, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
Participants who completed the 12 month randomized core study CRFB002D2301 were eligible to participate in the 24 month open-label extension study CRFB002D2301E1. The reporting groups for the participants in the extension study are according to their assigned treatment groups in the core study.
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab 0.5 mg Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met:
Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA \> 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits.
Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician.
Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. | 116 |
| Ranibizumab 0.5 mg + Laser Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met:
Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA \> 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits.
Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician.
Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. | 118 |
| Laser Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met:
Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA \> 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits.
Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. | 111 |
| Total | 345 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Study | Abnormal laboratory value(s) | 1 | 0 | 0 |
| Core Study | Adverse Event | 5 | 3 | 3 |
| Core Study | Death | 2 | 2 | 2 |
| Core Study | Lack of Efficacy | 1 | 1 | 1 |
| Core Study | Lost to Follow-up | 0 | 1 | 0 |
| Core Study | Protocol Violation | 1 | 1 | 0 |
| Core Study | Withdrawal by Subject | 4 | 7 | 7 |
| Open-Label Extension Study | Administrative problems | 1 | 1 | 0 |
| Open-Label Extension Study | Adverse Event | 2 | 2 | 2 |
| Open-Label Extension Study | Death | 2 | 3 | 3 |
| Open-Label Extension Study | Lost to Follow-up | 2 | 1 | 2 |
| Open-Label Extension Study | Subject withdrew consent | 3 | 4 | 4 |
Baseline characteristics
| Characteristic | Laser | Total | Ranibizumab 0.5 mg | Ranibizumab 0.5 mg + Laser |
|---|---|---|---|---|
| Age Continuous | 63.5 years STANDARD_DEVIATION 8.81 | 63.5 years STANDARD_DEVIATION 8.75 | 62.9 years STANDARD_DEVIATION 9.29 | 64.0 years STANDARD_DEVIATION 8.15 |
| Age, Customized 55 - <65 years | 53 Participants | 136 Participants | 41 Participants | 42 Participants |
| Age, Customized < 55 years | 13 Participants | 51 Participants | 24 Participants | 14 Participants |
| Age, Customized 65 - <75 years | 31 Participants | 124 Participants | 40 Participants | 53 Participants |
| Age, Customized >=75 years | 14 Participants | 34 Participants | 11 Participants | 9 Participants |
| Sex: Female, Male Female | 53 Participants | 144 Participants | 43 Participants | 48 Participants |
| Sex: Female, Male Male | 58 Participants | 201 Participants | 73 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 79 / 115 | 83 / 120 | 50 / 59 | 31 / 51 |
| serious Total, serious adverse events | 41 / 115 | 43 / 120 | 28 / 59 | 7 / 51 |
Outcome results
Primary
Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12
Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
Time frame: Baseline through the end of study (Month 12)
Population: Full analysis set consists of all patients who received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent to treat principle, patients were analyzed according to the treatment assigned. Last Observation Carried Forward (LOCF) imputation was utilized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Average Month 1 to month 12 | 70.8 Letters | Standard Deviation 10.53 |
| Ranibizumab 0.5 mg | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Baseline | 64.7 Letters | Standard Deviation 10.07 |
| Ranibizumab 0.5 mg | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Change from Baseline | 6.1 Letters | Standard Deviation 6.43 |
| Ranibizumab 0.5 mg + Laser | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Average Month 1 to month 12 | 69.2 Letters | Standard Deviation 11.44 |
| Ranibizumab 0.5 mg + Laser | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Baseline | 63.4 Letters | Standard Deviation 9.99 |
| Ranibizumab 0.5 mg + Laser | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Change from Baseline | 5.9 Letters | Standard Deviation 7.92 |
| Laser | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Baseline | 62.6 Letters | Standard Deviation 11.01 |
| Laser | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Change from Baseline | 0.8 Letters | Standard Deviation 8.56 |
| Laser | Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 | Average Month 1 to month 12 | 63.4 Letters | Standard Deviation 12.26 |
Primary
Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study
Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Time frame: Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]
Population: Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Adverse Events | 73.5 Percentage of participants |
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Serious Adverse Events | 27.7 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Serious Adverse Events | 30.1 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Adverse Events | 73.5 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Adverse Events | 71.2 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Serious Adverse Events | 37.3 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Adverse Events | 73.3 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study | Serious Adverse Events | 13.3 Percentage of participants |
Primary
Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study
Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Time frame: Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]
Population: Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Adverse Events | 56.6 Percentage of participants |
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Serious Adverse Events | 2.4 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Serious Adverse Events | 1.2 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Adverse Events | 56.6 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Adverse Events | 52.5 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Serious Adverse Events | 1.7 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Adverse Events | 40.0 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study | Serious Adverse Events | 0.0 Percentage of participants |
Secondary
Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12
Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
Time frame: Baseline to Month 12
Population: Full analysis set consists of all patients who received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent to treat principle, patients were analyzed according to the treatment assigned. Last Observation Carried Forward (LOCF) imputation was utilized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Gain of ≥ 10 letters | 43 Participants |
| Ranibizumab 0.5 mg | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Loss of ≥ 10 letters | 4 Participants |
| Ranibizumab 0.5 mg | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Gain of ≥ 15 letters | 26 Participants |
| Ranibizumab 0.5 mg | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Loss of ≥ 15 letters | 1 Participants |
| Ranibizumab 0.5 mg + Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Loss of ≥ 15 letters | 4 Participants |
| Ranibizumab 0.5 mg + Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Gain of ≥ 10 letters | 51 Participants |
| Ranibizumab 0.5 mg + Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Gain of ≥ 15 letters | 27 Participants |
| Ranibizumab 0.5 mg + Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Loss of ≥ 10 letters | 5 Participants |
| Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Loss of ≥ 15 letters | 9 Participants |
| Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Loss of ≥ 10 letters | 14 Participants |
| Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Gain of ≥ 15 letters | 9 Participants |
| Laser | Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 | Gain of ≥ 10 letters | 17 Participants |
Secondary
Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye
Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation.
Time frame: Baseline to Month 12
Population: The number analyzed is the Full Analysis Set, including patients with a value at both baseline and the Month 12 visit. Last Observation Carried Forward imputation was utilized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Value at Month 12 | 308.4 Micrometers | Standard Deviation 112.26 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Baseline | 427.1 Micrometers | Standard Deviation 118.42 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Change from Baseline | -118.7 Micrometers | Standard Deviation 115.07 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Value at Month 12 | 288.2 Micrometers | Standard Deviation 90.11 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Baseline | 416.4 Micrometers | Standard Deviation 119.91 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Change from Baseline | -128.3 Micrometers | Standard Deviation 114.34 |
| Laser | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Baseline | 412.4 Micrometers | Standard Deviation 124.53 |
| Laser | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Change from Baseline | -61.3 Micrometers | Standard Deviation 132.29 |
| Laser | Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye | Value at Month 12 | 351.1 Micrometers | Standard Deviation 139.91 |
Secondary
Core Study: Mean Change From Baseline in Patient-reported Visual Functioning
The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure a patient's subjective assessment of vision-related quality of life. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function.
Time frame: Baseline to Month 12
Population: The number analyzed is the Full Analysis Set, including the number of patients with a value at both baseline and the Month 12 visit. Last Observation Carried Forward imputation was utilized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Month 12 | 77.8 Units on a scale | Standard Deviation 19.19 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Baseline | 72.8 Units on a scale | Standard Deviation 16.91 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Change from Baseline | 5.0 Units on a scale | Standard Deviation 12.97 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Month 12 | 79.5 Units on a scale | Standard Deviation 17.29 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Baseline | 74.1 Units on a scale | Standard Deviation 18.06 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Change from Baseline | 5.4 Units on a scale | Standard Deviation 11.14 |
| Laser | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Baseline | 73.5 Units on a scale | Standard Deviation 18.18 |
| Laser | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Change from Baseline | 0.6 Units on a scale | Standard Deviation 12.56 |
| Laser | Core Study: Mean Change From Baseline in Patient-reported Visual Functioning | Month 12 | 74.1 Units on a scale | Standard Deviation 18.8 |
Secondary
Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time
Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
Time frame: Baseline to Month 12
Population: Full analysis set, utilizing last observation carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 1 | 2.9 Letters | Standard Error 0.49 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 2 | 4.4 Letters | Standard Error 0.64 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 3 | 5.9 Letters | Standard Error 0.65 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 4 | 5.3 Letters | Standard Error 0.68 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 5 | 5.9 Letters | Standard Error 0.68 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 6 | 6.7 Letters | Standard Error 0.68 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 7 | 7.0 Letters | Standard Error 0.72 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 8 | 7.1 Letters | Standard Error 0.75 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 9 | 6.8 Letters | Standard Error 0.76 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 10 | 7.3 Letters | Standard Error 0.77 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 11 | 6.9 Letters | Standard Error 0.79 |
| Ranibizumab 0.5 mg | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 12 | 6.8 Letters | Standard Error 0.77 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 12 | 6.4 Letters | Standard Error 1.08 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 1 | 3.1 Letters | Standard Error 0.56 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 7 | 6.5 Letters | Standard Error 0.84 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 9 | 6.8 Letters | Standard Error 1.05 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 2 | 4.9 Letters | Standard Error 0.56 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 6 | 6.2 Letters | Standard Error 0.78 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 11 | 6.8 Letters | Standard Error 1.1 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 3 | 5.8 Letters | Standard Error 0.65 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 8 | 6.4 Letters | Standard Error 1.06 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 5 | 5.7 Letters | Standard Error 0.76 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 4 | 5.4 Letters | Standard Error 0.69 |
| Ranibizumab 0.5 mg + Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 10 | 6.4 Letters | Standard Error 1.04 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 4 | 0.5 Letters | Standard Error 0.92 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 5 | 0.9 Letters | Standard Error 0.88 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 10 | 0.8 Letters | Standard Error 1 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 6 | 0.9 Letters | Standard Error 0.94 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 7 | 1.1 Letters | Standard Error 0.98 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 8 | 1.3 Letters | Standard Error 0.96 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 11 | 1.4 Letters | Standard Error 0.95 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 1 | 0.5 Letters | Standard Error 0.64 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 2 | 0.4 Letters | Standard Error 0.84 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 9 | 1.4 Letters | Standard Error 0.9 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 3 | -0.5 Letters | Standard Error 0.92 |
| Laser | Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time | Month 12 | 0.9 Letters | Standard Error 1.09 |
Secondary
Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36
Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.
Time frame: Core baseline (Day 1 of the core study), Month 36 (end of extension study)
Population: Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.5 mg | Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | 8.0 Letters | Standard Deviation 10.09 |
| Ranibizumab 0.5 mg + Laser | Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | 6.7 Letters | Standard Deviation 9.59 |
| Laser | Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | 6.0 Letters | Standard Deviation 9.35 |
Secondary
Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36
Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.
Time frame: Extension baseline (Month12 -end of core study), Month 36 (end of extension study)
Population: Participants from the Safety Population that included all participants who entered the extension and who had at least one safety assessment in the extension study with data available for analyses. Participants were grouped according to the treatment assigned in the Core study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.5 mg | Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | 0.1 Letters | Standard Deviation 9.1 |
| Ranibizumab 0.5 mg + Laser | Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | -0.5 Letters | Standard Deviation 9.19 |
| Laser | Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 | 3.7 Letters | Standard Deviation 6.88 |
Secondary
Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies
Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about Adverse Events can be found in the Adverse Event section.
Time frame: Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 Months]
Population: Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Adverse Events | 83.1 Percentage of participants |
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 36.1 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 37.3 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Adverse Events | 81.9 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Adverse Events | 84.7 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 42.4 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Adverse Events | 73.3 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 13.3 Percentage of participants |
Secondary
Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies
Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Time frame: Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 months]
Population: Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Adverse Events | 66.3 Percentage of participants |
| Ranibizumab 0.5 mg | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 2.4 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 3.6 Percentage of participants |
| Ranibizumab 0.5 mg + Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Adverse Events | 67.5 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Adverse Events | 64.4 Percentage of participants |
| Laser | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 5.1 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Adverse Events | 46.7 Percentage of participants |
| Laser Without Ranibizumab in Extension | Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies | Serious Adverse Events | 0.0 Percentage of participants |