Age-Related Macular Degeneration
Conditions
Brief summary
This is a prospective, single-blind, randomized study to evaluate intravitreal aflibercept injection (IAI) versus sham as prophylaxis against conversion to neovascular age-related macular degeneration (AMD) in high-risk subjects.
Detailed description
128 subjects will be enrolled in the trial and randomized in a 1:1 ratio to receive either IAI every three months for 24 months or sham injections. Enrollment will be stratified in order to ensure a balance between the two treatment groups for subjects who were diagnosed with exudative AMD within the past two years versus those diagnosed more than two years prior to Baseline. Study assessments will be conducted at required visits every three months and include manifest refraction and ETDRS visual acuity testing, slit lamp exam and dilated fundus exam, spectral-domain optical coherence tomography (SD-OCT) using Avanti device, and OCT angiography using Avanti AngioVueTM, and fluorescein angiography. Fundus photography will also be performed at Baseline, Month 12 and Month 24 visits. In the event of conversion to neovascular AMD in the study eye at any point during the study, the Investigator will treat the subject with IAI at a frequency per his/her discretion.
Interventions
Intravitreal aflibercept injection
DRUGPlacebo
Sham injection
Sponsors
Regeneron Pharmaceuticals
Jeffrey S Heier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Study eye must have a diagnosis of non-exudative age-related degeneration characterized by the presence of many intermediate sized drusen, 1 or more large drusen, and/or hyperpigmentary changes. Fellow (non-study) eye must have CNV lesion (i.e., leakage on fluorescein angiography and/or subretinal, intraretinal, or sub-RPE fluid on OCT) secondary to age-related macular degeneration OR history of CNV lesion secondary to age-related macular degeneration, as confirmed by current or past treatment or current or past diagnostic imaging. * Subject must be willing and able to comply with clinic visits and study-related procedures. * Subject must provide signed informed consent. * Subject must be able to understand and complete study-related questionnaires. In order to participate in the home monitoring sub-study, subjects must have an approved wireless device (i.e. iPhone, iPad, or iPod running iOS 6.0 or later) or be willing to use a loaned device and have access to a wireless Internet connection for the duration of the study.
Exclusion criteria
* Evidence of neovascular AMD in the study eye at time of enrollment or anytime in the past. The reading center must confirm that there is no evidence of neovascular AMD in the study eye prior to enrollment. * Serous PED of any size in the study eye, as determined by the reading center. * Previous treatment with verteporfin PDT, anti-VEGF therapy, laser, external beam radiation or other AMD therapy in the study eye. * History of macular hole in study eye. * History of vitrectomy in study eye. * Lens extraction or implantation within the last 3 months. * Capsulotomy within the last 1 month. * Lens or other media opacity that would preclude good fundus photography or angiography within the next 2 years. * Macular edema or signs of diabetic retinopathy more severe than 10 red dots (microaneurysms or blot hemorrhages). * Retinal changes related to high myopia and/or myopic correction greater than 8.00 diopters spherical equivalent. * Any progressive ocular disease that would affect visual acuity within the next 2 years. * Previous participation in any studies of investigational drugs likely to have ocular effects within 30 days preceding the initial study treatment. * Concurrent use of systemic anti-VEGF agents. * Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in the study eye. * Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. * For subjects who have undergone prior refractive or cataract surgery in the study eye, the preoperative refractive error in the study eye cannot exceed 8 diopters of myopia. * Uncontrolled glaucoma in the study eye (defined as intraocular pressure greater than 25 mmHg) despite treatment with anti-glaucoma medication). * Subjects who are unable to be photographed to document CNV due to known allergy to fluorescein dye, lack of venous access or cataract obscuring the CNV. * Subjects with other ocular diseases that can compromise the visual acuity of the study eye such as amblyopia and anterior ischemic optic neuropathy. * Current treatment for active systemic infection. * Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders. * History of recurrent significant infections or bacterial infections. * Inability to comply with study or follow-up procedures. * Pregnancy (positive pregnancy test) or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Converting to Exudative AMD at 24 Months. | 24 months | Percentage of subjects converting to exudative AMD at 24 months as confirmed by independent masked reading center. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Converted to Exudative AMD Who Had Exudative AMD in Fellow Eye ≤ 2 Years at Baseline. | up to Month 24 | Percentage of patients converted to exudative AMD in study eye who had exudative AMD in fellow eye ≤ 2 years at Baseline. |
| Percentage of Patient Converted to Exudative AMD Based on Presence of Nonexudative CNV. | up to Month 24 | Percentage of patients converted to exudative AMD compared to all patients with presence of nonexudative CNV in the study eye at Month 24, as confirmed by independent reading center evaluation of OCT angiography images. |
| Mean Change in Best-corrected Visual Acuity at 24 Months Compared to Baseline | 24 months | Mean change in best-corrected visual acuity (BCVA) at 24 months compared to baseline according to ETDRS protocol. BCVA is evaluated by counting the number of letters correctly read by the patient on an ETDRS eye chart. A higher value indicates that the patient read more letter correctly which indicates a better outcome. |
| Mean Change in Growth of Geographic Atrophy. | 24 months | Mean change in growth of geographic atrophy from baseline to Month 24. |
Countries
United States
Participant flow
Pre-assignment details
Of 128 patients enrolled, 127 (63 in the IAI group and 64 in the sham group) were included in the analysis. This is because shortly after enrollment of the excluded patient, it was determined that they should not have been enrolled due to not meeting eligibility criteria at screening.
Participants by arm
| Arm | Count |
|---|---|
| Intravitreal Aflibercept Injection Subjects will be randomized to receive intravitreal aflibercept injection every three months for 24 months.
Intravitreal aflibercept injection: Intravitreal aflibercept injection | 63 |
| Placebo Subjects will be randomized to receive sham injection every three months for 24 months.
Placebo: Sham injection | 64 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Intravitreal Aflibercept Injection |
|---|---|---|---|
| Age, Continuous | 76.9 years STANDARD_DEVIATION 8.8 | 76.5 years STANDARD_DEVIATION 8.1 | 76.1 years STANDARD_DEVIATION 7.4 |
| Duration of Fellow Eye nvAMD < 2 Years | 31 Participants | 61 Participants | 30 Participants |
| Mean BCVA | 77.3 letters read on ETDRS eye chart STANDARD_DEVIATION 10.1 | 78.0 letters read on ETDRS eye chart STANDARD_DEVIATION 9.45 | 78.7 letters read on ETDRS eye chart STANDARD_DEVIATION 8.8 |
| Non-exudative Macular NV | 6 Participants | 10 Participants | 4 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 32 Participants | 59 Participants | 27 Participants |
| Sex: Female, Male Male | 32 Participants | 68 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 63 | 5 / 64 |
| other Total, other adverse events | 9 / 63 | 8 / 64 |
| serious Total, serious adverse events | 14 / 63 | 27 / 64 |
Outcome results
Primary
Percentage of Subjects Converting to Exudative AMD at 24 Months.
Percentage of subjects converting to exudative AMD at 24 months as confirmed by independent masked reading center.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravitreal aflibercept injection | Percentage of Subjects Converting to Exudative AMD at 24 Months. | 6 Participants |
| Placebo | Percentage of Subjects Converting to Exudative AMD at 24 Months. | 7 Participants |
Secondary
Mean Change in Best-corrected Visual Acuity at 24 Months Compared to Baseline
Mean change in best-corrected visual acuity (BCVA) at 24 months compared to baseline according to ETDRS protocol. BCVA is evaluated by counting the number of letters correctly read by the patient on an ETDRS eye chart. A higher value indicates that the patient read more letter correctly which indicates a better outcome.
Time frame: 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intravitreal aflibercept injection | Mean Change in Best-corrected Visual Acuity at 24 Months Compared to Baseline | 2.8 number of letters read on eye chart |
| Placebo | Mean Change in Best-corrected Visual Acuity at 24 Months Compared to Baseline | 0.2 number of letters read on eye chart |
Secondary
Mean Change in Growth of Geographic Atrophy.
Mean change in growth of geographic atrophy from baseline to Month 24.
Time frame: 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intravitreal aflibercept injection | Mean Change in Growth of Geographic Atrophy. | 0.34 millimeters squared |
| Placebo | Mean Change in Growth of Geographic Atrophy. | 0.43 millimeters squared |
Secondary
Percentage of Patient Converted to Exudative AMD Based on Presence of Nonexudative CNV.
Percentage of patients converted to exudative AMD compared to all patients with presence of nonexudative CNV in the study eye at Month 24, as confirmed by independent reading center evaluation of OCT angiography images.
Time frame: up to Month 24
Population: Number of subjects with nonexudative CNV present at Month 24 based on OCT angiography.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravitreal aflibercept injection | Percentage of Patient Converted to Exudative AMD Based on Presence of Nonexudative CNV. | 3 Participants |
| Placebo | Percentage of Patient Converted to Exudative AMD Based on Presence of Nonexudative CNV. | 4 Participants |
Secondary
Percentage of Patients Converted to Exudative AMD Who Had Exudative AMD in Fellow Eye ≤ 2 Years at Baseline.
Percentage of patients converted to exudative AMD in study eye who had exudative AMD in fellow eye ≤ 2 years at Baseline.
Time frame: up to Month 24
Population: Patients with a history of exudative AMD in their fellow eye no longer than 2 years at Baseline by treatment group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravitreal aflibercept injection | Percentage of Patients Converted to Exudative AMD Who Had Exudative AMD in Fellow Eye ≤ 2 Years at Baseline. | 4 Participants |
| Placebo | Percentage of Patients Converted to Exudative AMD Who Had Exudative AMD in Fellow Eye ≤ 2 Years at Baseline. | 5 Participants |