Age Related Macular Degeneration, Choroidal Neovascular Membrane, Macular Degeneration, Subfoveal Neovascular Age-Related Macular Degeneration, Wet Age-Related Macular Degeneration
Conditions
Keywords
Antibodies, Monoclonal, Immunologic Factors, Eye Diseases, Retinal Degeneration, Macular Degeneration, Pharmacologic Actions, Retinal Diseases
Brief summary
The purpose of this study is to determine whether 2.0mg Ranibizumab is effective in the treatment of recurrent fluid.
Detailed description
This is an open-label, Phase I/II study of intravitreally administered 2.0 mg ranibizumab in subjects with persistent fluid or recurrent fluid on OCT after having received at least nine ranibizumab injections in the past twelve months. Consented, enrolled subjects will receive have monthly ETDRS BCVA, ophthalmic examination and OCTs evaluation using Stratus, Cirrus and Spectralis machines. Fluorescein angiography and autofluorescence will be done at BSL, and Months 6 and 12. DNA samples for genetic analysis will be collected at baseline. Subjects will receive open-label intravitreal injections of 2.0 mg ranibizumab administered every 28 days for 3 months: Following the three loading doses, all patients will receive a minimum capped PRN treatment (all patients will receive 2.0 mg intravitreal ranibizumab quarterly). Dosing should not occur earlier than 22 days after the previous treatment. Study visits should be scheduled to occur every 30 (±7) days relative to the date of the first injection (Day 0). Subjects will be randomized into two re-treatment cohorts for additional re-treatment, if needed: * Cohort A - Subjects can receive re-treatment every 4 weeks if there is persistent or recurrent intraretinal, subretinal ,or sub-RPE fluid on any OCT modality, or any evidence of hemorrhage on clinical evaluation. * Cohort B - Subjects can receive re-treatment every 6 weeks if there is persistent or recurrent intraretinal, subretinal ,or sub-RPE fluid on any OCT modality, or any evidence of hemorrhage on clinical evaluation. Every 6 weeks regimen will test potential longer duration of action of 2.0 mg ranibizumab.
Interventions
DRUGRanibizumab
Intravitreal Injection of 2.0mg formulation
Sponsors
Genentech, Inc.
David M. Brown, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Willingness to provide signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization * Age ≥ 50 years * For sexually active women of childbearing potential, agreement to the use of an appropriate form of contraception (or abstinence) for the duration of the study * Although no birth control method is 100% effective, the following are considered effective means of contraception: surgical sterilization, use of oral contraceptives, barrier contraception using either a condom or diaphragm with spermicidal gel, an intrauterine device, or contraceptive hormone implant or patch. A patient's primary care physician, obstetrician, or gynecologist should be consulted regarding an appropriate form of birth control. * Ability and willingness to return for all scheduled visits and assessments Study eyes must meet the following criteria for entry into the SAVE trial: * The last treatment with Ranibizumab is ≥ 28 days * To have received at least 9 injections of Ranibizumab in the past 12 months * Any CNVM lesion (Occult, Minimally Classic or Classic) (i.e., leakage on fluorescein angiography or subretinal, intraretinal, or sub-RPE fluid on Spectral Domain OCT) secondary to age-related macular degeneration. * Best corrected visual acuity in the study eye, using e-ETDRS testing, between 20/25 and 20/320 (Snellen equivalent), inclusive. * Only one eye will be enrolled in the Study. If both eyes are eligible study investigator will select the eye for entry. * The total area of subretinal hemorrhage and fibrosis must comprise less than 50% of the total lesion. * Clear ocular media and adequate pupillary dilation to permit good quality fundus imaging
Exclusion criteria
* 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. * Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated * Participation in another simultaneous medical investigation or trial Ocular
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in ETDRS BCVA at Month 12 (Fixed Interval Dosing Primary Endpoint After 3 Monthly Doses. Variable Interval Dosing Primary Endpoint at 1 Year.) | 1 Year | Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) was used to quantify visual acuity. BCVA is measured using an eye chart and is reported as the number of letters read correctly using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. |
Secondary
| Measure | Time frame |
|---|---|
| Determine Number of Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12 and Month 12 in ETDRS BCVA | 1 year |
| Determine Number of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12 in ETDRS BCVA. | 1 year |
| Evaluate the Incidence and Severity of Ocular and Non-ocular Adverse Events (AEs) Through Month 12 | 1 year |
| Assess Number of Ranibizumab Injections in Each of the Two Doses Required Through Month 12 | 1 year |
| Evaluate the Relationship Between Specific Genetic Polymorphisms Associated With AMD, Disease Characteristics and Processes, and Response to Intravitreal Ranibizumab | 1 year |
| Evaluate Mean Change in Central Retinal Thickness Over Time Through Month12 as Assessed by All Three OCTs (Stratus, Cirrus, and Spectralis) | 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 4 Week Re-treatment Subjects can receive re-treatment every 4 weeks if there is persistent or recurrent intraretinal, subretinal, or sub-RPE fluid on any OCT modality, or any evidence of hemorrhage on clinical evaluation. Subjects will go no longer than 12 weeks without treatment.
Ranibizumab: Intravitreal Injection of 2.0mg formulation | 46 |
| 6 Week Re-treatment Subjects can receive re-treatment every 6 weeks if there is persistent or recurrent intraretinal, subretinal, or sub-RPE fluid on any OCT modality, or any evidence of hemorrhage on clinical evaluation. Every 6 weeks regimen will test potential longer duration of action of 2.0 mg ranibizumab. Subjects will go no longer than 12 weeks without treatment.
Ranibizumab: Intravitreal Injection of 2.0mg formulation | 42 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study drug no longer available | 3 | 6 |
Baseline characteristics
| Characteristic | 6 Week Re-treatment | 4 Week Re-treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 39 Participants | 44 Participants | 83 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Continuous | 77 years | 76 years | 76.1 years |
| Gender Female | 21 Participants | 25 Participants | 46 Participants |
| Gender Male | 21 Participants | 21 Participants | 42 Participants |
| Region of Enrollment United States | 42 participants | 46 participants | 88 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 46 | 8 / 42 |
| serious Total, serious adverse events | 7 / 46 | 10 / 42 |
Outcome results
Primary
Mean Change From Baseline in ETDRS BCVA at Month 12 (Fixed Interval Dosing Primary Endpoint After 3 Monthly Doses. Variable Interval Dosing Primary Endpoint at 1 Year.)
Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) was used to quantify visual acuity. BCVA is measured using an eye chart and is reported as the number of letters read correctly using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved.
Time frame: 1 Year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 4 Week Re-treatment | Mean Change From Baseline in ETDRS BCVA at Month 12 (Fixed Interval Dosing Primary Endpoint After 3 Monthly Doses. Variable Interval Dosing Primary Endpoint at 1 Year.) | 4.1 ETDRS BCVA Letters | Standard Error 1.4 |
| 6 Week Re-treatment | Mean Change From Baseline in ETDRS BCVA at Month 12 (Fixed Interval Dosing Primary Endpoint After 3 Monthly Doses. Variable Interval Dosing Primary Endpoint at 1 Year.) | 4.1 ETDRS BCVA Letters | Standard Error 1 |
Secondary
Assess Number of Ranibizumab Injections in Each of the Two Doses Required Through Month 12
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 4 Week Re-treatment | Assess Number of Ranibizumab Injections in Each of the Two Doses Required Through Month 12 | 11.6 number of injection | Standard Deviation 1.1 |
| 6 Week Re-treatment | Assess Number of Ranibizumab Injections in Each of the Two Doses Required Through Month 12 | 8.6 number of injection | Standard Deviation 0.8 |
Secondary
Determine Number of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12 in ETDRS BCVA.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4 Week Re-treatment | Determine Number of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12 in ETDRS BCVA. | 5 participants |
| 6 Week Re-treatment | Determine Number of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12 in ETDRS BCVA. | 3 participants |
Secondary
Determine Number of Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12 and Month 12 in ETDRS BCVA
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4 Week Re-treatment | Determine Number of Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12 and Month 12 in ETDRS BCVA | 1 participants |
| 6 Week Re-treatment | Determine Number of Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12 and Month 12 in ETDRS BCVA | 0 participants |
Secondary
Evaluate Mean Change in Central Retinal Thickness Over Time Through Month12 as Assessed by All Three OCTs (Stratus, Cirrus, and Spectralis)
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 4 Week Re-treatment | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month12 as Assessed by All Three OCTs (Stratus, Cirrus, and Spectralis) | -59.2 micrometer | Standard Deviation 107.8 |
| 6 Week Re-treatment | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month12 as Assessed by All Three OCTs (Stratus, Cirrus, and Spectralis) | -31.8 micrometer | Standard Deviation 87.2 |
Secondary
Evaluate the Incidence and Severity of Ocular and Non-ocular Adverse Events (AEs) Through Month 12
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 4 Week Re-treatment | Evaluate the Incidence and Severity of Ocular and Non-ocular Adverse Events (AEs) Through Month 12 | Ocular Events | 18 Incidents |
| 4 Week Re-treatment | Evaluate the Incidence and Severity of Ocular and Non-ocular Adverse Events (AEs) Through Month 12 | Serious Non-Ocular Events | 7 Incidents |
| 6 Week Re-treatment | Evaluate the Incidence and Severity of Ocular and Non-ocular Adverse Events (AEs) Through Month 12 | Ocular Events | 8 Incidents |
| 6 Week Re-treatment | Evaluate the Incidence and Severity of Ocular and Non-ocular Adverse Events (AEs) Through Month 12 | Serious Non-Ocular Events | 10 Incidents |
Secondary
Evaluate the Relationship Between Specific Genetic Polymorphisms Associated With AMD, Disease Characteristics and Processes, and Response to Intravitreal Ranibizumab
Time frame: 1 year
Population: Given lack of clinical benefit of 2.0 mg ranibizumab, as demonstrated in the HARBOR trial \[Busbee BG, et al. (2013) Ophthalmology 120(5), 1046-1056\], further secondary analyses were suspended.