Central Retinal, Hemi Retinal & Brach Retinal Vein Occlusions
Conditions
Keywords
CRVO, BRVO, HRVO, Macular edema, vein occlusion
Brief summary
To see if Lucentis 0.5mg combined with Targeted Pan Retinal photocoagulation will decrease the total number of intravitreal injections in a year for ischemic central retinal vein occlusion, hemi-retinal vein occlusions and branch retinal vein occlusions compared to standard of care
Detailed description
The WAVE trial is a phase IV, open label, 12-month trial of intravitreal ranibizumab 0.5 mg in patients (n=30) with ischemic CRVO, HRVO and BRVO who have been previously treated with ranibizumab or any other anti-VEGF intravitreal injection therapy, who are incomplete responders to 2 or more consecutive intravitreal anti-VEGF injections in the past 4 months. Randomization is 1:4, 1=control, ranibizumab only, 4=treatment arm. In total, 6 subjects will be randomized to control and 24 randomized to treatment arm. Cohort 1- 24 Subjects previously treated Patients will receive 6 doses of ranibizumab 0.5 mg, followed by PRN intravitreal injection of ranibizumab 0.5 mg based on pre-defined retreatment criteria for up to 11 total injections. Wide field angiography guided peripheral targeted-retinal photocoagulation (TRP), will be divided into 2 sessions if needed, one at the 2 weeks post injection visit and another later at M4/V7, if repeat wide field angiogram indicates areas not sufficiently treated in the first TRP session Cohort 2- 6 Subjects, previously treated patients will receive 6 doses of ranibizumab 0.5 mg, followed by PRN intravitreal injection of ranibizumab 0.5 mg based on pre-defined retreatment criteria for up to 11 total injections.
Interventions
intravitreal injections
Targeted Pan Retinal Photocoagulation based on wide field angiography
Sponsors
Genentech, Inc.
Charles C Wykoff, PhD, MD
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 years * Visual acuity between 20/25 and 20/800, ETDRS best corrected visual acuity * Ability to provide written informed consent and comply with study assessments for the full duration of the study Patients previously treated with any ITV anti-VEGF: • With at least 2 consecutive monthly intravitreal injections of anti-VEGF medications with presence of persistent or recurrent macular edema in the past 4 months
Exclusion criteria
* IOP over 30 mm Hg * Any previous retinal laser photocoagulation to the study eye * Previous intravitreal injection in the study eye of any corticosteroid treatment * Previous vitrectomy in study eye (posterior or anterior associated with vitreous loss in cataract surgery) * Intracapsular cataract extraction * Any previous radiation treatments to head/neck that the principal or sub investigator feels is clinically relevant * Inability to assess iris or angle neovascularization (corneal opacity precluding gonioscopy) * Significant cardiovascular disease or cancer that would prevent follow-up visits or completion of the 12 month study * Significant diabetic retinopathy in the fellow eye (diabetic macular edema, proliferative diabetic retinopathy, or high-risk non-proliferative diabetic retinopathy) * Participation in another simultaneous medical investigator or trial * Ocular disorders or concurrent disease in the study eye that may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention, including history of retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., DME, AMD, ocular histoplasmosis, or pathologic myopia) * Structural damage to the center of the macula in the study eye prior to CRVO, HRVO and BRVO likely to preclude improvement in visual acuity following the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s) * Vitreomacular traction or clinically significant epiretinal membrane in the study eye evident biomicroscopically or by OCT (vitreomacular attachment OK) * Infectious blepharitis, keratitis, scleritis, or conjunctivitis (in either eye) or current treatment for serious systemic infection * Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia (For patients who have had refractive or cataract surgery in the study eye, preoperative spherical equivalent refractive error of more than -8 diopters myopia is not allowed) * Uncontrolled Blood pressure: defined as systolic pressure \> 180mmHg and/or diastolic pressure of \>110 mm Hg (sitting) during the screening period * Uncontrolled diabetes mellitus * Renal failure requiring dialysis or renal transplant * Pregnancy (positive pregnancy test) or lactation * Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or patch. * History of other disease, metabolic dysfunction, physical examination finding, or other findings 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 render the subject at high risk from treatment complications * History of allergy to fluorescein, not amenable to treatment * Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed by the principal investigator (PI) and/or the sub-investigator. * History of allergy to humanized antibodies or any component of the ranibizumab formulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Intravitreal Injections Over a 12 Month Period | 12 months | Assess the number of intravitreal injections over 12 months. |
| Visual Acuity | 12 month period | Evaluate the mean change from baseline in ETDRS best-corrected visual acuity at 12 months. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 12 months | Incidence and severity of adverse events (ocular and non-ocular). |
| Neovascularization of the Iris, Optic Nerve and Elsewhere | 12 months | Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere. |
| Retinal Ischemia | 12 month period | Quantify change in area of perfused and ischemic retina. |
| Aqueous VEGF Levels | 12 Months | VEGF, other cytokines and ranibizumab levels in aqueous and serum samples at randomization and at the exit or early termination visit. |
| Visual Field | 6 and 12 Months | Goldman Visual Field changes at 6 and 12 months from baseline. Goldmann perimetry is a method used to map a patient's field of vision (central and peripheral). Changes will be assessed by manual digital quantification of GVF plots. |
| Central Foveal Outcome | 12 months | Mean change in Central Foveal Volume on High Resolution OCT. |
| Foveal Avascular Zone | 12 months | Assess change in foveal avascular zone area and largest diameter, measured during the early phase of the angiogram |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.
0.5mg Ranibizumab: intravitreal injections
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography | 24 |
| Ranibizumab 0.5mg Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.
0.5mg Ranibizumab: intravitreal injections | 6 |
| Total | 30 |
Baseline characteristics
| Characteristic | Total | Ranibizumab 0.5mg | Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab |
|---|---|---|---|
| Age, Continuous | 64.1 years | 63.8 years | 64.1 years |
| Central Retinal Thickness | 514 micrometers | 471 micrometers | 525 micrometers |
| ETDRS BCVA Letters | 52.4 ETDRS BCVA Letters | 55.3 ETDRS BCVA Letters | 51.7 ETDRS BCVA Letters |
| Prior Anti-VEGF Injections | 10.1 injections | 10.0 injections | 10.2 injections |
| RVO Subtype BRVO | 11 Participants | 2 Participants | 9 Participants |
| RVO Subtype CRVO | 17 Participants | 4 Participants | 13 Participants |
| RVO Subtype HRVO | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 15 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 15 Participants | 2 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 24 | 2 / 6 |
| serious Total, serious adverse events | 2 / 24 | 0 / 6 |
Outcome results
Primary
Total Number of Intravitreal Injections Over a 12 Month Period
Assess the number of intravitreal injections over 12 months.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Total Number of Intravitreal Injections Over a 12 Month Period | 8.7 injections |
| Ranibizumab 0.5mg | Total Number of Intravitreal Injections Over a 12 Month Period | 9.5 injections |
Primary
Visual Acuity
Evaluate the mean change from baseline in ETDRS best-corrected visual acuity at 12 months. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning.
Time frame: 12 month period
Population: 1 patient withdrew from the study before month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Visual Acuity | 14.9 ETDRS BCVA Letters | Standard Error 3.4 |
| Ranibizumab 0.5mg | Visual Acuity | 10.7 ETDRS BCVA Letters | Standard Error 4.4 |
Secondary
Adverse Events
Incidence and severity of adverse events (ocular and non-ocular).
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Adverse Events | Notable Ocular Events | 17 Participants |
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Adverse Events | Serious Non-Ocular Events | 2 Participants |
| Ranibizumab 0.5mg | Adverse Events | Notable Ocular Events | 2 Participants |
| Ranibizumab 0.5mg | Adverse Events | Serious Non-Ocular Events | 0 Participants |
Secondary
Aqueous VEGF Levels
VEGF, other cytokines and ranibizumab levels in aqueous and serum samples at randomization and at the exit or early termination visit.
Time frame: 12 Months
Population: Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.
Secondary
Central Foveal Outcome
Mean change in Central Foveal Volume on High Resolution OCT.
Time frame: 12 months
Population: 1 patient withdrew from the study before month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Central Foveal Outcome | -0.15 cubic millimeters | Standard Deviation 0.21 |
| Ranibizumab 0.5mg | Central Foveal Outcome | -0.15 cubic millimeters | Standard Deviation 0.2 |
Secondary
Foveal Avascular Zone
Assess change in foveal avascular zone area and largest diameter, measured during the early phase of the angiogram
Time frame: 12 months
Population: Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.
Secondary
Neovascularization of the Iris, Optic Nerve and Elsewhere
Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Neovascularization of the Iris, Optic Nerve and Elsewhere | 8.33 percentage of patients |
| Ranibizumab 0.5mg | Neovascularization of the Iris, Optic Nerve and Elsewhere | 0 percentage of patients |
Secondary
Retinal Ischemia
Quantify change in area of perfused and ischemic retina.
Time frame: 12 month period
Population: Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.
Secondary
Visual Field
Goldman Visual Field changes at 6 and 12 months from baseline. Goldmann perimetry is a method used to map a patient's field of vision (central and peripheral). Changes will be assessed by manual digital quantification of GVF plots.
Time frame: 6 and 12 Months
Population: Patients who completed GVF testing at baseline, M6, and M12 with adequate fixation and cooperation during testing were included in GVF analyses (n=14)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Visual Field | Month 6 | -1269 square degrees | Standard Error 180 |
| Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab | Visual Field | Month 12 | -1628 square degrees | Standard Error 353 |
| Ranibizumab 0.5mg | Visual Field | Month 6 | 102 square degrees | Standard Error 423 |
| Ranibizumab 0.5mg | Visual Field | Month 12 | -1875 square degrees | Standard Error 326 |