Age-Related Macular Degeneration, AMD, Geographic Atrophy
Conditions
Keywords
Retinal Pigment Epithelium, Dynamic Light Scattering (DLS), Visual Acuity Decrease, Intra-ocular Pressure, Autofluorescence of Retina, Age-Related Macular Degeneration, AMD
Brief summary
Othera Pharmaceuticals' Othera (OT)-551 antioxidant eye drop has the potential for chronic treatment of the dry form of age-related macular degeneration. This pilot study of up to 10 eye drop tolerant participants with bilateral geographic atrophy is designed to characterize the effect of 0.45% concentration of OT-551 eye drops given 3 times a day on the progression of geographic atrophy area over a two-year period. Participants will have one eye randomized to receive the eye drop and the fellow eye will be observed only.
Detailed description
Age-related macular Degeneration (AMD), the leading cause of blindness in people over age 55 in the U.S., is a heterogeneous clinical entity in which retinal degeneration occurs predominantly in the macula in the context of aging and leads to impairment primarily of central visual acuity. AMD occurs in two general forms, one of which involves subchoroidal neovascularization with subsequent formation of a disciform scar. A second form, and the subject of this study, is termed dry or atrophic macular degeneration and involves a constellation of clinical features that can include drusen, pigment clumping and/or retinal pigment epithelium (RPE) dropout, and geographic atrophy. Geographic atrophy can begin as a thinning of the RPE with involvement of the underlying choriocapillaris and lead subsequently to an atrophic change in the macula. The only therapy for persons with atrophic AMD is an oral supplement containing high doses of antioxidants and zinc, which was tested by the National Eye Institute (NEI) in a large, multicenter, double-masked, placebo-controlled clinical trial with average participant follow-up of about 6 years. This antioxidant therapy was shown to modestly retard the progression of dry AMD from an intermediate stage to the advanced stages and demonstrated the benefit of antioxidant therapy in this disease. In this study, we will evaluate Othera Pharmaceuticals' OT-551 antioxidant eye drop for chronic treatment of the dry form of AMD. This single-center, open-label, study of up to 10 participants with bilateral geographic atrophy is designed to characterize the safety of 0.45 percent concentration of OT-551 eye drops, given 3 times a day, on participants with geographic atrophy area for up to three years. Participants will have one eye randomized to receive the eye drop and the fellow eye will be observed.
Interventions
DRUGOT-551 antioxidant eye drop
0.45% concentration of OT-551 eye drops were given three times a day on participants with geographic atrophy area for up to three years. Participants had one eye randomized to receive the eye drop and the fellow eye was observed.
Sponsors
National Eye Institute (NEI)
Othera Pharmaceuticals
National Institutes of Health Clinical Center (CC)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant must understand and sign the protocol's informed consent document (if the participant's vision is impaired to the point where it is not possible to read the informed consent document, the informed consent document will be read in its entirety to the participant). 2. Participant must be able to administer the eye drops or have a caretaker administer the eye drops. 3. Participant must have geographic atrophy (GA) present in both eyes compatible with age-related macular degeneration (AMD). GA is defined as one or more well-defined, usually more or less circular patches of partial or complete depigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appears to be preserved and large choroidal vessels are not visible, a round-ish patch of RPE partial depigmentation may still be classified as early GA. The GA in each eye must be able to be photographed in their entirety and not contiguous with any areas of peripapillary atrophy, which can complicate area measurements. 4. Participant must have a steady fixation in the study eye in the foveal or parafoveal area and media clear enough for good quality photographs. 5. Female participants of child bearing potential (those who are not post-menopausal or surgically sterile) may participate if they are not lactating and if they agree to adequate birth control methods. 4.5
Exclusion criteria
1. Participant is \> 60 years of age (to minimize fundus changes from causes other than AMD). 2. Participant is in another investigational study and actively receiving study therapy. 3. Participant is unable to comply with study procedures or follow-up visits. 4. Participant has evidence of ocular disease other than AMD in either eye that may confound the outcome of the study (e.g., diabetic retinopathy, uveitis, etc.). 5. Participant has a chronic requirement (e.g., ≥ four weeks at a time) for ocular medications for diseases, that in the judgment of the examining physician, are vision threatening or may affect the primary outcome (artificial tears are permitted). 6. Participant has evidence of pseudovitelliform macular degeneration that may confound the outcome of the study in either eye. 7. Participant with evidence of vitreo-retinal traction maculopathy that may confound the outcome of the study in either eye. 8. Participant has a history of laser, photodynamic therapy (PDT), intravitreal injection of any agent (e.g., anti-VEGF, triamcinolone, etc.), or any previous treatment for AMD other than AREDS or equivalent supplement formulation in the study eye. 9. Participant has had a vitrectomy, penetrating keratoplasty, trabeculectomy or trabeculoplasty. 10. Participant has undergone lens removal in the last three months. 11. Participant is on chemotherapy. 12. Participant is on ocular or systemic medications known to be toxic to the lens, retina, or optic nerve. 13. Participant with a history of malignancy that would compromise the 2-year study survival. 14. Participant with a history of ocular Herpes simplex virus. 15. Participant with a history of or demonstration of allergy to benzakonium chloride, a preservative agent used in the eye drop.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Best-corrected Visual Acuity (BCVA) From Baseline to Year 2 for All Participants. | 2 years | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. This acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters the Snellen measurement is 20/20. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Geographic Atrophy (GA), as Measured on Fundus Autofluorescence Imaging Using a Confocal Scanning Ophthalmoscope (HRA FAF) From Baseline to Year 2. | 2 years | Geographic Atrophy (GA), or the death of photoreceptors and surrounding cells in the retina, is a common condition in patients with Age-Related Macular Degeneration (AMD). The death of these photoreceptors results in lesions that cause vision loss. The amount of GA is measured from images produced via a non-invasive technique called Fundus Autofluorescence Imaging, which uses a Confocal Scanning Ophthalmoscope to detect the naturally-fluorescing lipofuscin (the waste that is left behind by dead photoreceptors and digested by surrounding cells) that is prevalent at the border of the lesion. |
| The Change in GA, as Measured on Stereoscopic Color Fundus Photography (CFP) From Baseline to Year 2. | 2 years | GA was also measured using Stereoscopic Color Fundus Photography (CFP), which produces color images of the inside of the eye. |
| The Change in Contrast Sensitivity as Measured by the Pelli-Robson Chart From Baseline to Year 2. | 2 years | The Pelli-Robson Chart is comprised of 10 groups of 3 large letters with levels of contrast ranging from 100% (black against white) to 1% (very light gray against white). Each eye is assigned a score based on the contrast of the last group in which two or three letters were correctly read. A score of 2 log units, which represents a normal sensitivity contrast, indicates that the eye was able to detect two of the three letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2). |
| Number of Participants With an Increase in the Number of Scotomatous Points Between Study and Fellow Eyes From Baseline to Year 2. | 2 years | Scotomatous points are testing points on microperimetry examination that are centered on the macula and report a lack of retinal sensitivity within the range tested. |
| The Change in Total Drusen Area From Baseline to Year 2. | Baseline, 2 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participant Information | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Participant Information |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 76.91 years STANDARD_DEVIATION 7.85 |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 11 |
| serious Total, serious adverse events | 0 / 11 |
Outcome results
Primary
The Change in Best-corrected Visual Acuity (BCVA) From Baseline to Year 2 for All Participants.
Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. This acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters the Snellen measurement is 20/20.
Time frame: 2 years
Population: Data collected from the 10 participants that completed the 24-month follow-up visit were analyzed.~Ten study eyes and 10 fellow eyes were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Eye: OT-511 Antioxidant Eye Drop | The Change in Best-corrected Visual Acuity (BCVA) From Baseline to Year 2 for All Participants. | 0.2 ETDRS Letters | Standard Deviation 13.3 |
| Fellow Eye | The Change in Best-corrected Visual Acuity (BCVA) From Baseline to Year 2 for All Participants. | -11.3 ETDRS Letters | Standard Deviation 7.6 |
Secondary
Number of Participants With an Increase in the Number of Scotomatous Points Between Study and Fellow Eyes From Baseline to Year 2.
Scotomatous points are testing points on microperimetry examination that are centered on the macula and report a lack of retinal sensitivity within the range tested.
Time frame: 2 years
Population: Data were only collected in 8 of the 10 participants that completed the full 24 months. Eight study eyes and eight fellow eyes were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Eye: OT-511 Antioxidant Eye Drop | Number of Participants With an Increase in the Number of Scotomatous Points Between Study and Fellow Eyes From Baseline to Year 2. | 7 participants |
| Fellow Eye | Number of Participants With an Increase in the Number of Scotomatous Points Between Study and Fellow Eyes From Baseline to Year 2. | 7 participants |
Secondary
The Change in Contrast Sensitivity as Measured by the Pelli-Robson Chart From Baseline to Year 2.
The Pelli-Robson Chart is comprised of 10 groups of 3 large letters with levels of contrast ranging from 100% (black against white) to 1% (very light gray against white). Each eye is assigned a score based on the contrast of the last group in which two or three letters were correctly read. A score of 2 log units, which represents a normal sensitivity contrast, indicates that the eye was able to detect two of the three letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2).
Time frame: 2 years
Population: Data collected from the ten participants that completed the full twenty-four months of the study were analyzed.~Ten study eyes and ten fellow eyes were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Eye: OT-511 Antioxidant Eye Drop | The Change in Contrast Sensitivity as Measured by the Pelli-Robson Chart From Baseline to Year 2. | 0.075 Log Units | Standard Deviation 0.33 |
| Fellow Eye | The Change in Contrast Sensitivity as Measured by the Pelli-Robson Chart From Baseline to Year 2. | -0.15 Log Units | Standard Deviation 0.27 |
Secondary
The Change in GA, as Measured on Stereoscopic Color Fundus Photography (CFP) From Baseline to Year 2.
GA was also measured using Stereoscopic Color Fundus Photography (CFP), which produces color images of the inside of the eye.
Time frame: 2 years
Population: Data collected from the ten participants that completed the full twenty-four months of the study were analyzed.~Ten study eyes and ten fellow eyes were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Eye: OT-511 Antioxidant Eye Drop | The Change in GA, as Measured on Stereoscopic Color Fundus Photography (CFP) From Baseline to Year 2. | 2.46 mm^2 | Standard Deviation 1.25 |
| Fellow Eye | The Change in GA, as Measured on Stereoscopic Color Fundus Photography (CFP) From Baseline to Year 2. | 2.47 mm^2 | Standard Deviation 0.73 |
Secondary
The Change in Geographic Atrophy (GA), as Measured on Fundus Autofluorescence Imaging Using a Confocal Scanning Ophthalmoscope (HRA FAF) From Baseline to Year 2.
Geographic Atrophy (GA), or the death of photoreceptors and surrounding cells in the retina, is a common condition in patients with Age-Related Macular Degeneration (AMD). The death of these photoreceptors results in lesions that cause vision loss. The amount of GA is measured from images produced via a non-invasive technique called Fundus Autofluorescence Imaging, which uses a Confocal Scanning Ophthalmoscope to detect the naturally-fluorescing lipofuscin (the waste that is left behind by dead photoreceptors and digested by surrounding cells) that is prevalent at the border of the lesion.
Time frame: 2 years
Population: Data collected from the ten participants that completed the full twenty-four months of the study were analyzed.~Ten study eyes and ten fellow eyes were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Eye: OT-511 Antioxidant Eye Drop | The Change in Geographic Atrophy (GA), as Measured on Fundus Autofluorescence Imaging Using a Confocal Scanning Ophthalmoscope (HRA FAF) From Baseline to Year 2. | 2.17 mm^2 | Standard Deviation 0.83 |
| Fellow Eye | The Change in Geographic Atrophy (GA), as Measured on Fundus Autofluorescence Imaging Using a Confocal Scanning Ophthalmoscope (HRA FAF) From Baseline to Year 2. | 2.24 mm^2 | Standard Deviation 0.91 |
Secondary
The Change in Total Drusen Area From Baseline to Year 2.
Time frame: Baseline, 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Eye: OT-511 Antioxidant Eye Drop | The Change in Total Drusen Area From Baseline to Year 2. | -0.09 mm^2 | Standard Error 0.22 |
| Fellow Eye | The Change in Total Drusen Area From Baseline to Year 2. | -0.06 mm^2 | Standard Error 0.14 |