OT-551 Antioxidant Eye Drops to Treat Geographic Atrophy in Age-Related Macular Degeneration

• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00306488
• Collaborator: National Eye Institute (NEI) (NIH), Othera Pharmaceuticals (Industry)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 48
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Geographic Atrophy; Age-Related Macular Degeneration; AMD	Drug: OT-551 antioxidant eye drop	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of OT-551 Antioxidant Eye Drop in Participants With Bilateral Geographic Atrophy Associated With Age-Related Macular Degeneration
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OT-551 antioxidant eye drop The fellow eye was treated with OT-551 antioxidant eye drops over the course of the study.	Drug: OT-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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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).

4. 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.

5. The Change in Total Drusen Area From Baseline to Year 2. [Baseline, 2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institutes of Health Clinical Center (CC)
• National Eye Institute (NEI)
• Othera Pharmaceuticals

Investigators

• Principal Investigator: Wai Wong, MD, PhD, National Eye Institute (NEI)

Study Documents (Full-Text)

None provided.

More Information

Publications

• Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct;119(10):1417-36. Erratum in: Arch Ophthalmol. 2008 Sep;126(9):1251.
• Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997 Jan;104(1):7-21.
• Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992 Jun;99(6):933-43.

• Responsible Party: National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00306488
• Other Study ID Numbers: 060116; 06-EI-0116
• First Posted: Mar 23, 2006
• Last Update Posted: Jul 14, 2020
• Last Verified: Aug 1, 2011

• Keywords provided by National Institutes of Health Clinical Center (CC): Retinal Pigment Epithelium; Dynamic Light Scattering (DLS); Visual Acuity Decrease; Intra-ocular Pressure; Autofluorescence of Retina; Age-Related Macular Degeneration; AMD
• Additional relevant MeSH terms: Macular Degeneration; Geographic Atrophy; Atrophy; Ophthalmic Solutions; Antioxidants

Study Results

Participant Flow

Arm/Group Title	OT-511 Antioxidant Eye Drop
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day. The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Period Title: Overall Study
STARTED	11
COMPLETED	10
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Participant Information
Arm/Group Description
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 9.1%
>=65 years	10 90.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	76.91 (7.85)
Sex: Female, Male (Count of Participants)
Female	7 63.6%
Male	4 36.4%
Region of Enrollment (participants) [Number]
United States	11 100%

Outcome Measures

1. Primary Outcome

Title	The Change in Best-corrected Visual Acuity (BCVA) From Baseline to Year 2 for All Participants.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Study Eye: OT-511 Antioxidant Eye Drop	Fellow Eye
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day.	The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Measure Participants	10	10
Measure Eyes	10	10
Mean (Standard Deviation) [ETDRS Letters]	0.2 (13.3)	-11.3 (7.6)

2. Secondary Outcome

Title	The Change in Geographic Atrophy (GA), as Measured on Fundus Autofluorescence Imaging Using a Confocal Scanning Ophthalmoscope (HRA FAF) From Baseline to Year 2.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Study Eye: OT-511 Antioxidant Eye Drop	Fellow Eye
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day.	The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Measure Participants	10	10
Measure Eyes	10	10
Mean (Standard Deviation) [mm^2]	2.17 (0.83)	2.24 (0.91)

3. Secondary Outcome

Title	The Change in GA, as Measured on Stereoscopic Color Fundus Photography (CFP) From Baseline to Year 2.
Description	GA was also measured using Stereoscopic Color Fundus Photography (CFP), which produces color images of the inside of the eye.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

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/Group Title	Study Eye: OT-511 Antioxidant Eye Drop	Fellow Eye
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day.	The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Measure Participants	10	10
Measure Eyes	10	10
Mean (Standard Deviation) [mm^2]	2.46 (1.25)	2.47 (0.73)

4. Secondary Outcome

Title	The Change in Contrast Sensitivity as Measured by the Pelli-Robson Chart From Baseline to Year 2.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Study Eye: OT-511 Antioxidant Eye Drop	Fellow Eye
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day.	The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Measure Participants	10	10
Measure Eyes	10	10
Mean (Standard Deviation) [Log Units]	0.075 (0.33)	-0.15 (0.27)

5. Secondary Outcome

Title	Number of Participants With an Increase in the Number of Scotomatous Points Between Study and Fellow Eyes From Baseline to Year 2.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Study Eye: OT-511 Antioxidant Eye Drop	Fellow Eye
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day.	The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Measure Participants	8	8
Number [participants]	7 63.6%	7 NaN

6. Secondary Outcome

Title	The Change in Total Drusen Area From Baseline to Year 2.
Time Frame	Baseline, 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Eye: OT-511 Antioxidant Eye Drop	Fellow Eye
Arm/Group Description	The study eye was treated with one drop (40µL) of 0.45% OT-551 antioxidant eye drops three times a day.	The fellow eye was not treated with the study medication (OT-511 antioxidant eye drops).
Measure Participants	10	10
Mean (Standard Error) [mm^2]	-0.09 (0.22)	-0.06 (0.14)

Adverse Events

Time Frame	Adverse event data were collected between December 2006 through May 2010.
Arm/Group Title	Participant Adverse Event Information
Arm/Group Description
All Cause Mortality
	Participant Adverse Event Information
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Participant Adverse Event Information
	Affected / at Risk (%)	# Events
Total	0/11 (0%)
Other (Not Including Serious) Adverse Events
	Participant Adverse Event Information
	Affected / at Risk (%)	# Events
Total	10/11 (90.9%)
Endocrine disorders
Hypothyroidism	1/11 (9.1%)	1
Eye disorders
Retinal haemmorhage	4/11 (36.4%)	5
Cataract subcapsular	1/11 (9.1%)	1
Basal cell carcinoma	1/11 (9.1%)	1
Vision blurred	1/11 (9.1%)	1
Eye pain	1/11 (9.1%)	1
Visual acuity reduced	1/11 (9.1%)	1
Eyelid oedema	1/11 (9.1%)	1
Gastrointestinal disorders
Oedema mouth	1/11 (9.1%)	1
Immune system disorders
Allergy to arthropod sting	1/11 (9.1%)	1
Infections and infestations
Upper respiratory tract infection	1/11 (9.1%)	1
Candidiasis	1/11 (9.1%)	2
Tooth abscess	1/11 (9.1%)	1
Herpes zoster	1/11 (9.1%)	1
Injury, poisoning and procedural complications
Joint injury	1/11 (9.1%)	1
Nerve root injury cervical	1/11 (9.1%)	1
Investigations
Intraocular pressure increased	1/11 (9.1%)	2
Blood cholesterol increased	1/11 (9.1%)	1
Metabolism and nutrition disorders
Hypercholesterolaemia	1/11 (9.1%)	1
Start of new cholesterol-lowering medication	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
Muscle spasms	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamas cell carcinoma	2/11 (18.2%)	2
Nervous system disorders
Transient ischaemic attack	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Dry throat	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Skin haemorrhage	1/11 (9.1%)	1
Dry skin	1/11 (9.1%)	1
Surgical and medical procedures
Mole excision	1/11 (9.1%)	1
Knee arthoplasty	1/11 (9.1%)	1
Spinal laminectomy	1/11 (9.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.