Macular Edema, Retinal Vein Occlusion
Conditions
Keywords
Lucentis, RVO, BRVO, Edema
Brief summary
This was a Phase III, multicenter, randomized, double-masked, sham injection-controlled study of the efficacy and safety of intravitreal ranibizumab compared with sham injections in patients with macular edema secondary to branch retinal vein occlusion (BRVO); 397 patients with BRVO were enrolled at 93 investigational sites in the United States. The study included a treatment period (6 months) and an observation period (6 months).
Interventions
Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
DRUGSham injection
Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willingness to provide signed Informed Consent Form * Age ≥ 18 years * For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study * Ability and willingness to return for all scheduled visits and assessments Ocular Inclusion Criterion (Study Eye): * Foveal center-involved macular edema secondary to BRVO * BCVA using ETDRS charts of 20/40 to 20/400 (Snellen equivalent) * Mean central subfield thickness ≥ 250 μm on two optical coherence tomography (OCT) measurements (at screening \[confirmed by the central reading center\] and Day 0 \[confirmed by the evaluating physician\]) * Media clarity, pupillary dilation, and participant cooperation sufficient to obtain adequate fundus photographs
Exclusion criteria
* History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0 * History of any anti-vascular endothelial growth factor (VEGF) treatment in fellow eye within 3 months prior to Day 0 * History of any systemic anti-VEGF or pro-VEGF treatment within 6 months prior to Day 0 * History of allergy to fluorescein * History of allergy to ranibizumab injection or related molecule * Relevant systemic disease that may be associated with increased systemic VEGF levels (namely, all active malignancies); history of successfully treated malignancies is not an exclusion criterion * Uncontrolled blood pressure * Pregnancy or lactation * Any condition that, in the opinion of the investigator, would preclude participation in the study (e.g., chronic alcoholism or drug abuse, personality disorder or use of major tranquilizers, indicated difficulty in long-term follow-up, and likelihood of survival of less than 1 year) * Participation in an investigational trial within 30 days prior to Day 0 that involved treatment with any drug (excluding vitamins and minerals) or device that has not received regulatory approval at time of study entry Ocular
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Baseline and 6 months | BCVA score in the study eye was based on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline | Baseline and 6 months | BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters. The percentage of subjects who lost \<15 letters will be greater than the percentage of subjects who gained \>=15 letters as losing \<15 letters includes both those who gained \>=15 letters and those who were stable (i.e. lost between 1 and 14 letters, had no change, or gained between 1 and 14 letters). |
| Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6 | 6 months | A central reading center assessed all optical coherence tomography (OCT) images. Central foveal thickness was defined as the center point thickness. |
| Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline | Baseline and 6 months | BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters. |
| Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Baseline and 6 months | The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A3, A4, and A5 pertained to the Near Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning. |
| Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Baseline and 6 months | The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A6, A7, and A8 pertained to the Distance Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning. |
| Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Baseline and 6 months | A central reading center assessed all OCT images. Central foveal thickness was defined as the center point thickness. |
Participant flow
Recruitment details
Please note that although the table below is titled Overall Study, the completion rates are for the 6-month Treatment Period only (i.e., does not include the 6-month Observation Period data).
Participants by arm
| Arm | Count |
|---|---|
| Sham Injection Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections. | 132 |
| Ranibizumab Injection 0.3 mg Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections. | 134 |
| Ranibizumab Injection 0.5 mg Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections. | 131 |
| Total | 397 |
Baseline characteristics
| Characteristic | Ranibizumab Injection 0.3 mg | Ranibizumab Injection 0.5 mg | Sham Injection | Total |
|---|---|---|---|---|
| Age, Continuous | 66.6 years STANDARD_DEVIATION 11.2 | 67.5 years STANDARD_DEVIATION 11.8 | 65.2 years STANDARD_DEVIATION 12.7 | 66.4 years STANDARD_DEVIATION 11.9 |
| Age, Customized 45 to < 65 years | 51 participants | 51 participants | 59 participants | 161 participants |
| Age, Customized < 45 years | 5 participants | 4 participants | 8 participants | 17 participants |
| Age, Customized 65 to < 85 years | 74 participants | 69 participants | 60 participants | 203 participants |
| Age, Customized ≥ 85 years | 4 participants | 7 participants | 5 participants | 16 participants |
| Sex: Female, Male Female | 67 Participants | 60 Participants | 58 Participants | 185 Participants |
| Sex: Female, Male Male | 67 Participants | 71 Participants | 74 Participants | 212 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 115 / 131 | 125 / 134 | 115 / 130 |
| serious Total, serious adverse events | 6 / 131 | 14 / 134 | 14 / 130 |
Outcome results
Primary
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months
BCVA score in the study eye was based on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.
Time frame: Baseline and 6 months
Population: Intent to treat (randomized) population. Missing values were imputed using the last-observation-carried-forward (LOCF) method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Baseline | 54.7 Units on a scale | Standard Deviation 12.2 |
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Change from Baseline at Month 6 | 7.3 Units on a scale | Standard Deviation 13 |
| Ranibizumab Injection 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Baseline | 56.0 Units on a scale | Standard Deviation 12.1 |
| Ranibizumab Injection 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Change from Baseline at Month 6 | 16.6 Units on a scale | Standard Deviation 11 |
| Ranibizumab Injection 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Baseline | 53.0 Units on a scale | Standard Deviation 12.5 |
| Ranibizumab Injection 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months | Change from Baseline at Month 6 | 18.3 Units on a scale | Standard Deviation 13.2 |
p-value: <0.000195% CI: [6.6, 12.2]ANOVA
p-value: <0.000195% CI: [7.6, 13.6]ANOVA
Secondary
Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6
A central reading center assessed all OCT images. Central foveal thickness was defined as the center point thickness.
Time frame: Baseline and 6 months
Population: Intent to treat (randomized) population. Missing values were imputed using the LOCF method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Injection | Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Baseline | 488.0 μm | Standard Deviation 192.2 |
| Sham Injection | Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Mean Absolute Change from Baseline at Month 6 | -157.7 μm | Standard Deviation 224.2 |
| Ranibizumab Injection 0.3 mg | Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Baseline | 522.1 μm | Standard Deviation 201.9 |
| Ranibizumab Injection 0.3 mg | Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Mean Absolute Change from Baseline at Month 6 | -337.3 μm | Standard Deviation 224.4 |
| Ranibizumab Injection 0.5 mg | Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Baseline | 551.7 μm | Standard Deviation 223.5 |
| Ranibizumab Injection 0.5 mg | Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 | Mean Absolute Change from Baseline at Month 6 | -345.2 μm | Standard Deviation 238.2 |
p-value: <0.000195% CI: [-183.6, -113.8]ANCOVA
p-value: <0.000195% CI: [-172.7, -96.8]ANCOVA
Secondary
Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6
The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A3, A4, and A5 pertained to the Near Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning.
Time frame: Baseline and 6 months
Population: Intent to treat (randomized) population; however, patients without a baseline score were excluded from analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Injection | Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Baseline | 69.6 Points on the NEI VFQ-25 subscale | Standard Deviation 20.2 |
| Sham Injection | Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Change from baseline at Month 6 | 7.3 Points on the NEI VFQ-25 subscale | Standard Deviation 15.3 |
| Ranibizumab Injection 0.3 mg | Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Baseline | 67.9 Points on the NEI VFQ-25 subscale | Standard Deviation 22.1 |
| Ranibizumab Injection 0.3 mg | Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Change from baseline at Month 6 | 12.1 Points on the NEI VFQ-25 subscale | Standard Deviation 17.3 |
| Ranibizumab Injection 0.5 mg | Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Baseline | 69.4 Points on the NEI VFQ-25 subscale | Standard Deviation 20.5 |
| Ranibizumab Injection 0.5 mg | Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 | Change from baseline at Month 6 | 13.7 Points on the NEI VFQ-25 subscale | Standard Deviation 18 |
p-value: 0.021495% CI: [0.6, 7.6]ANCOVA
p-value: 0.000295% CI: [3, 9.8]ANCOVA
Secondary
Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6
The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A6, A7, and A8 pertained to the Distance Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning.
Time frame: Baseline and 6 months
Population: Intent to treat (randomized) population; however, patients without a baseline score were excluded from analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Injection | Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Baseline | 76.4 Points on the NEI-VFQ-25 subscale | Standard Deviation 20.6 |
| Sham Injection | Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Mean Change from Baseline at Month 6 | 6.3 Points on the NEI-VFQ-25 subscale | Standard Deviation 15 |
| Ranibizumab Injection 0.3 mg | Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Baseline | 76.0 Points on the NEI-VFQ-25 subscale | Standard Deviation 20.5 |
| Ranibizumab Injection 0.3 mg | Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Mean Change from Baseline at Month 6 | 10.3 Points on the NEI-VFQ-25 subscale | Standard Deviation 17.2 |
| Ranibizumab Injection 0.5 mg | Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Baseline | 76.7 Points on the NEI-VFQ-25 subscale | Standard Deviation 18.1 |
| Ranibizumab Injection 0.5 mg | Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 | Mean Change from Baseline at Month 6 | 11.3 Points on the NEI-VFQ-25 subscale | Standard Deviation 16.6 |
p-value: 0.024895% CI: [0.5, 7]ANCOVA
p-value: 0.001495% CI: [2, 8.3]ANCOVA
Secondary
Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline
BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.
Time frame: Baseline and 6 months
Population: Intent to treat (randomized) population. Missing values were imputed using the LOCF method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Injection | Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline | 28.8 Percentage of participants |
| Ranibizumab Injection 0.3 mg | Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline | 55.2 Percentage of participants |
| Ranibizumab Injection 0.5 mg | Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline | 61.1 Percentage of participants |
p-value: <0.000195% CI: [15.6, 38]Cochran-Mantel-Haenszel χ²
p-value: <0.000195% CI: [20.1, 42.6]Cochran-Mantel-Haenszel χ²
Secondary
Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline
BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters. The percentage of subjects who lost \<15 letters will be greater than the percentage of subjects who gained \>=15 letters as losing \<15 letters includes both those who gained \>=15 letters and those who were stable (i.e. lost between 1 and 14 letters, had no change, or gained between 1 and 14 letters).
Time frame: Baseline and 6 months
Population: Intent to treat (randomized) population. Missing values were imputed using the LOCF method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Injection | Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline | 95.5 Percentage of participants |
| Ranibizumab Injection 0.3 mg | Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline | 100 Percentage of participants |
| Ranibizumab Injection 0.5 mg | Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline | 98.5 Percentage of participants |
p-value: 0.014195% CI: [1.6, 9.9]Fisher Exact
p-value: 0.281595% CI: [-1.5, 8.3]Fisher Exact
Secondary
Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6
A central reading center assessed all optical coherence tomography (OCT) images. Central foveal thickness was defined as the center point thickness.
Time frame: 6 months
Population: Intent to treat (randomized) population. Missing values were imputed using the LOCF method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Injection | Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6 | 45.5 Percentage of participants |
| Ranibizumab Injection 0.3 mg | Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6 | 91.0 Percentage of participants |
| Ranibizumab Injection 0.5 mg | Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6 | 84.7 Percentage of participants |
p-value: <0.000195% CI: [36, 55]Cochran-Mantel-Haenszel χ²
p-value: <0.000195% CI: [29.9, 50.2]Cochran-Mantel-Haenszel χ²