Diabetes Mellitus, Macular Edema
Conditions
Keywords
Lucentis, DME, Diabetes, Vision loss
Brief summary
This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection in patients with clinically significant macular edema with center involvement (CSME-CI) secondary to diabetes mellitus (Type 1 or 2). This study is identical in design to study NCT00473330 (Protocol ID FVF4170g). The open-label extension phase of the study was stopped after receiving FDA approval of the study drug (ranibizumab) for diabetic macular edema.
Detailed description
This study is composed of 3 phases: (1) A 24-month controlled treatment period (monthly treatment with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injection) followed by (2) a 12-month treatment period in which patients randomized to the sham group who had not discontinued from treatment (still masked) could choose to receive monthly ranibizumab 0.5 mg while the 2 ranibizumab treatment groups continued on the same treatment they received in the first 2 years. Patients who had not discontinued treatment by Month 36 were eligible to continue treatment with ranibizumab 0.5 mg as needed (pro re nata, PRN) in (3) an extension phase of the study for up to 2 more years, resulting in up to 5 years possible total treatment time for some patients. As per the protocol, Genentech terminated the study approximately 30 days after approval of ranibizumab for diabetic macular edema in the United States.
Interventions
DRUGRanibizumab
Sterile solution for intravitreal injection.
DRUGSham injection
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 written informed consent and, at U.S. sites, Health Insurance Portability and Accountability Act (HIPAA) authorization, and in other countries, as applicable according to national laws. * Age ≥ 18 years. * Diabetes mellitus (Type 1 or 2) . * Retinal thickening secondary to diabetes mellitus (DME) involving the center of the fovea with central macular thickness ≥ 275 µm in the center subfield as assessed on optical coherence tomography (OCT). * Best corrected visual acuity (BCVA) score in the study eye of 20/40 to 20/320 approximate Snellen equivalent using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at an initial testing distance of 4 meters. * Decrease in vision determined to be primarily the result of DME and not to other causes. * For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study. * Ability (in the opinion of the investigator) and willingness to return for all scheduled visits and assessments.
Exclusion criteria
* History of vitreoretinal surgery in the study eye. * Panretinal photocoagulation (PRP) or macular laser photocoagulation in the study eye within 3 months of screening. * Previous use of intraocular corticosteroids in the study eye (eg, triamcinolone acetonide \[TA\]) within 3 months of screening. * Previous treatment with anti-angiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc) within 3 months of the Day 0 (first day of treatment) visit. * Proliferative diabetic retinopathy (PDR) in the study eye, with the exception of inactive, regressed PDR. * Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in the study eye. Concurrent Ocular Conditions * Vitreomacular traction or epiretinal membrane in the study eye. * Ocular inflammation (including trace or above) in the study eye. * History of idiopathic or autoimmune uveitis in either eye. * Structural damage to the center of the macula in the study eye that is likely to preclude improvement in VA following the resolution of macular edema, including atrophy of the retinal pigment epithelium (RPE), subretinal fibrosis, or organized hard-exudate plaque. * Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization (CNV) of any cause (eg, age-related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia). * Concurrent disease in the study eye that would compromise visual acuity or require medical or surgical intervention during the study period. * Cataract surgery in the study eye within 3 months, yttrium-aluminum-garnet (YAG) laser capsulotomy within the past 2 months, or any other intraocular surgery within the 90 days preceding Day 0. * Aphakia or absence of the posterior capsule in the study eye. * Uncontrolled glaucoma or previous filtration surgery in the study eye. * Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia. * Evidence at examination of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye or current treatment for serious systemic infection. * Uncontrolled blood pressure. * History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0. * Uncontrolled diabetes mellitus. * Renal failure requiring dialysis or renal transplant. * Participation in an investigational trial within 30 days prior to screening that involved treatment with any drug (excluding vitamins and minerals) or device. * History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use an investigational drug, might affect interpretation of the results of the study, or renders the subject at high risk from treatment complications. * Pregnancy or lactation. * History of allergy to fluorescein. * History of allergy to ranibizumab injection or related molecule.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24 | Baseline to Month 24 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Months 24, 36, and 48 | VA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart. |
| Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Baseline to Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Baseline to Month 36 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. |
| Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Baseline to Month 48 | Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement. |
| Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Baseline to Month 36 | The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative \[NP\]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative \[P\]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy. |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Baseline to Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. |
| Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Baseline to Month 36 | The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3. |
| Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Baseline to Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. |
| Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48 | Month 36 to Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. |
| Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48 | Month 36 to Month 48 | BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. |
| Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48 | Month 36 to Month 48 | Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement. |
| Percentage of Patients With Resolution of Leakage at Month 24 | Baseline to Month 24 | Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center. |
Participant flow
Recruitment details
Patients were recruited from study sites in the United States, Argentina, Peru, Columbia, Chile, and Peru. There were 47 patients from the Latin American countries.
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata \[PRN\]) for up to 24 additional months. | 125 |
| Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata \[PRN\]) for up to 24 additional months. | 127 |
| Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. | 130 |
| Total | 382 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Study | Adverse Event | 3 | 1 | 1 |
| Core Study | Death | 3 | 5 | 10 |
| Core Study | Lost to Follow-up | 3 | 3 | 3 |
| Core Study | Physician Decision | 1 | 2 | 2 |
| Core Study | Subject needed other treatment | 1 | 3 | 2 |
| Core Study | Subject non-compliance | 5 | 2 | 1 |
| Core Study | Subject's decision | 12 | 11 | 10 |
| Open-label Extension Through Month 48 | Adverse Event | 0 | 0 | 1 |
| Open-label Extension Through Month 48 | Death | 1 | 3 | 3 |
| Open-label Extension Through Month 48 | Lost to Follow-up | 1 | 2 | 1 |
| Open-label Extension Through Month 48 | Sponsor's Decision to Terminate Study | 41 | 34 | 36 |
| Open-label Extension Through Month 48 | Subject Required Other Intervention | 2 | 1 | 0 |
| Open-label Extension Through Month 48 | Subject's Decision | 5 | 1 | 6 |
| Open-label Extension Through Month 60 | Adverse Event | 0 | 0 | 2 |
| Open-label Extension Through Month 60 | Death | 1 | 7 | 4 |
| Open-label Extension Through Month 60 | Lost to Follow-up | 1 | 3 | 1 |
| Open-label Extension Through Month 60 | Sponsor's Decision to Terminate Study | 75 | 70 | 69 |
| Open-label Extension Through Month 60 | Subject Required Other Intervention | 2 | 1 | 0 |
| Open-label Extension Through Month 60 | Subject's Decision | 7 | 1 | 6 |
Baseline characteristics
| Characteristic | Ranibizumab 0.3 mg | Ranibizumab 0.5 mg | Sham Injection | Total |
|---|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 11.1 | 61.8 years STANDARD_DEVIATION 10.1 | 63.5 years STANDARD_DEVIATION 10.8 | 62.7 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 52 Participants | 47 Participants | 64 Participants | 163 Participants |
| Sex: Female, Male Male | 73 Participants | 80 Participants | 66 Participants | 219 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 123 / 127 | 123 / 127 | 120 / 125 | 121 / 124 | 65 / 88 | 63 / 83 | 62 / 84 |
| serious Total, serious adverse events | 54 / 127 | 68 / 127 | 54 / 125 | 67 / 124 | 19 / 88 | 31 / 83 | 18 / 84 |
Outcome results
Primary
Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time frame: Baseline to Month 24
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24 | 33.6 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24 | 45.7 Percentage of patients |
| Sham Injection | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24 | 12.3 Percentage of patients |
p-value: <0.000195% CI: [11.4, 30.2]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [23.8, 42.8]Cochran-Mantel-Haenszel
Secondary
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time frame: Baseline to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 24 | 10.9 Letters | Standard Deviation 10.4 |
| Ranibizumab 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 48 (n=34,39,39,0) | 11.1 Letters | Standard Deviation 12 |
| Ranibizumab 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 36 | 10.6 Letters | Standard Deviation 12.9 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 24 | 12.0 Letters | Standard Deviation 14.9 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 48 (n=34,39,39,0) | 12.4 Letters | Standard Deviation 9.7 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 36 | 11.4 Letters | Standard Deviation 16.3 |
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 36 | NA Letters | — |
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 24 | 2.3 Letters | Standard Deviation 14.2 |
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 48 (n=34,39,39,0) | NA Letters | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 24 | NA Letters | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 48 (n=34,39,39,0) | 4.6 Letters | Standard Deviation 12.8 |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 | Month 36 | 4.7 Letters | Standard Deviation 13.3 |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: <0.000195% CI: [5.4, 11.5]ANOVA
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: <0.000195% CI: [6.4, 13.3]ANOVA
Secondary
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time frame: Baseline to Month 36
Population: Subgroup of the intent-to-treat population: All randomized patients with focal edema at baseline, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 24 | 10.5 Letters | Standard Deviation 11.9 |
| Ranibizumab 0.3 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 36 | 10.8 Letters | Standard Deviation 12.1 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 36 | 10.9 Letters | Standard Deviation 16.6 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 24 | 12.8 Letters | Standard Deviation 11 |
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 24 | 1.9 Letters | Standard Deviation 17 |
| Sham Injection | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 36 | NA Letters | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 24 | NA Letters | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline | Month 36 | 6.6 Letters | Standard Deviation 14.4 |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.p-value: 0.010295% CI: [2, 14.6]ANOVA
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.p-value: 0.000595% CI: [5.1, 17.3]ANOVA
Secondary
Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48
Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time frame: Baseline to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.3 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 24 | -259.8 µm | Standard Deviation 169.3 |
| Ranibizumab 0.3 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 48 (n=38,39,0,33) | -251.4 µm | Standard Deviation 173.8 |
| Ranibizumab 0.3 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 36 | -261.8 µm | Standard Deviation 180.8 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 24 | -270.7 µm | Standard Deviation 201.6 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 48 (n=38,39,0,33) | -291.6 µm | Standard Deviation 200.7 |
| Ranibizumab 0.5 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 36 | -266.7 µm | Standard Deviation 207.8 |
| Sham Injection | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 36 | NA µm | — |
| Sham Injection | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 24 | -125.8 µm | Standard Deviation 198.3 |
| Sham Injection | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 48 (n=38,39,0,33) | NA µm | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 24 | NA µm | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 48 (n=38,39,0,33) | -258.7 µm | Standard Deviation 182.3 |
| Sham Injection/Ranibizumab 0.5 mg | Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 | Month 36 | -213.2 µm | Standard Deviation 193.5 |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: <0.000195% CI: [-151.6, -72]ANCOVA
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: <0.000195% CI: [-169.7, -94.8]ANCOVA
Secondary
Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time frame: Month 36 to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.3 mg | Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48 | -0.9 Letters | Standard Deviation 8.3 |
| Ranibizumab 0.5 mg | Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48 | 0.3 Letters | Standard Deviation 10.7 |
| Sham Injection | Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48 | -2.6 Letters | Standard Deviation 8.8 |
Secondary
Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48
Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time frame: Month 36 to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.3 mg | Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48 | 46.1 µm | Standard Deviation 148.1 |
| Ranibizumab 0.5 mg | Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48 | 44.1 µm | Standard Deviation 86.3 |
| Sham Injection | Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48 | 9.6 µm | Standard Deviation 78.9 |
Secondary
Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36
The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3.
Time frame: Baseline to Month 36
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab 0.3 mg | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 24 | 0.7 Treatments | Standard Deviation 1.4 |
| Ranibizumab 0.3 mg | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 36 | 0.9 Treatments | Standard Deviation 1.8 |
| Ranibizumab 0.5 mg | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 36 | 0.4 Treatments | Standard Deviation 0.9 |
| Ranibizumab 0.5 mg | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 24 | 0.3 Treatments | Standard Deviation 0.7 |
| Sham Injection | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 24 | 1.6 Treatments | Standard Deviation 1.6 |
| Sham Injection | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 36 | NA Treatments | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 24 | NA Treatments | — |
| Sham Injection/Ranibizumab 0.5 mg | Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 | Month 36 | 1.7 Treatments | Standard Deviation 1.6 |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.p-value: <0.000195% CI: [-1.3, -0.5]ANOVA
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.p-value: <0.000195% CI: [-1.6, -1]ANOVA
Secondary
Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time frame: Baseline to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Month 36 | 36.8 Percentage of patients |
| Ranibizumab 0.3 mg | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Month 48 (n=39,39,34) | 48.7 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Month 36 | 40.2 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Month 48 (n=39,39,34) | 41.0 Percentage of patients |
| Sham Injection | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Month 36 | 19.2 Percentage of patients |
| Sham Injection | Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 | Month 48 (n=39,39,34) | 17.6 Percentage of patients |
Secondary
Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time frame: Baseline to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | 97.4 Percentage of patients |
| Ranibizumab 0.3 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 24 | 98.4 Percentage of patients |
| Ranibizumab 0.3 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 36 | 96.8 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | 97.4 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 36 | 96.1 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 24 | 96.1 Percentage of patients |
| Sham Injection | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 24 | 91.5 Percentage of patients |
| Sham Injection | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 36 | NA Percentage of patients |
| Sham Injection | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | NA Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | 94.1 Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 24 | NA Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 | Month 36 | 92.3 Percentage of patients |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: 0.011995% CI: [1.7, 12.6]Cochran-Mantel-Haenszel
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: 0.138495% CI: [-1.2, 10.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48
BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time frame: Month 36 to Month 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48 | 92.3 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48 | 97.4 Percentage of patients |
| Sham Injection | Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48 | 88.2 Percentage of patients |
Secondary
Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36
The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative \[NP\]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative \[P\]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy.
Time frame: Baseline to Month 36
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 24 | 1.7 Percentage of patients |
| Ranibizumab 0.3 mg | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 36 | 0.9 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 36 | 0.8 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 24 | 0 Percentage of patients |
| Sham Injection | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 24 | 5.6 Percentage of patients |
| Sham Injection | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 36 | NA Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 24 | NA Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 | Month 36 | 3.2 Percentage of patients |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.p-value: 0.085395% CI: [-9.3, 0.8]Cochran-Mantel-Haenszel
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.p-value: 0.007395% CI: [-9.8, -1.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48
VA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart.
Time frame: Months 24, 36, and 48
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 24 | 54.4 Percentage of patients |
| Ranibizumab 0.3 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | 64.1 Percentage of patients |
| Ranibizumab 0.3 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 36 | 55.2 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 24 | 62.2 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | 56.4 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 36 | 59.1 Percentage of patients |
| Sham Injection | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 36 | NA Percentage of patients |
| Sham Injection | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 24 | 34.6 Percentage of patients |
| Sham Injection | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | NA Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 24 | NA Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 48 (n=39,39,0,34) | 47.1 Percentage of patients |
| Sham Injection/Ranibizumab 0.5 mg | Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 | Month 36 | 42.3 Percentage of patients |
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: 0.000295% CI: [10.8, 31.9]Cochran-Mantel-Haenszel
Comparison: The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.p-value: <0.000195% CI: [16.4, 37.9]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients With Resolution of Leakage at Month 24
Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center.
Time frame: Baseline to Month 24
Population: Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab 0.3 mg | Percentage of Patients With Resolution of Leakage at Month 24 | 17.1 Percentage of patients |
| Ranibizumab 0.5 mg | Percentage of Patients With Resolution of Leakage at Month 24 | 30.7 Percentage of patients |
| Sham Injection | Percentage of Patients With Resolution of Leakage at Month 24 | 2.3 Percentage of patients |
p-value: 0.000295% CI: [6.8, 21.1]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [20.2, 36.4]Cochran-Mantel-Haenszel