Alpha Lipoic Acid in Geographic Atrophy

Study Overview
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Brief Summary
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Because of its iron-chelating and antioxidant properties, alpha lipoic acid may be a treatment for geographic atrophy (GA) secondary to age-related macular degeneration. There is ample published data about the safety and pharmacokinetics of alpha lipoic acid in adults. However, there is not much data on the safety and tolerability of higher doses of alpha lipoic acid in the elderly population. The purpose of Phase I of this protocol is to determine if there are safety/tolerability concerns seen when higher doses of alpha lipoic acid are taken by subjects 65 years of age or older. The objective of Phase 2 of this protocol is to determine the effects of ALA on the progression of GA in subjects with AMD. The central hypothesis, based on the existing literature, is that oral ALA reduces the rate of enlargement of GA in AMD subjects. The rationale is that the antioxidant and iron chelating effects of ALA will slow down one of the major pathways responsible for GA progression.

Detailed Description
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Phase I (Apr 2016 completed): 15 subjects, 65 years of age or older will take alpha lipoic acid on the following schedule: 600 mg once daily with a meal for 5 days. If tolerated, then the subject will then take 800 mg once daily with a meal for 5 days. If tolerated, then the subject will then take 1200 mg once daily with a meal for 5 days. Phase II: Randomized, double-blind placebo controlled pilot trial. Upon the completion of the dose tolerability test, we plan to enroll 50 subjects into a randomized, double-blind, placebo-controlled trial. Subjects will be randomized (1:1) into one of two study arms: placebo capsules and ALA 1200 mg orally once daily, assuming that 1200 mg is well tolerated by subjects in Phase 1. If 1200 mg is not well-tolerated based on Phase 1 data, then the highest tolerable dose will be used. Four clinical sites are planned and the enrollment period is estimated to be 6 months. The primary endpoint is the mean rate of change of the area of GA in the study eye from baseline to 18 months as evaluated by fundus autofluorescence. Subjects will have a refracted electronic visual acuity and dilated exam at baseline, 6 months, 12 months, and 18 months. The study will be conducted on an outpatient basis and study visits will last approximately 2-3 hours. Two weeks after the 18 months study visit, the subject will be contacted to share with the investigators adverse events that developed after completing the 18 month visit. The Investigator shall ensure each subject has a follow-up eye exam scheduled within 6 months.

Official Title
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Evaluation of Lipoic Acid as a Treatment for Geographic Atrophy Secondary to Age-Related Macular Degeneration (AMD): Phase I- Tolerability Study and Phase II Pilot- Determine the Effects of ALA on the Progression of Geographic Atrophy (GA) in Patients With Age-related Macular Degeneration (AMD).

Conditions
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Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: alpha lipoic acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Phase I Inclusion Criteria: Ages 65-90 Female participants must be menopausal. Male participants are required to use contraception. Able to give informed consent For the study duration (15 days), the subject must remain in the country, remain within 4 hours of travel time (by car or airplane), have access to medical care if needed, and provide contact information so the subject can be reached as needed. Exclusion Criteria: Blood Pressure greater than 190/100 at the baseline visit Pulse greater than 100 at the baseline visit Acute and ongoing systemic infection History of dementia Participant has a condition that, in the opinion of the investigator, gives them an unstable medical status. Participant has geographic atrophy and the investigator believes the participant is a candidate for enrollment into the planned Phase 2 trial for geographic atrophy. Phase II Inclusion Criteria Age 55-90 Diagnosis of geographic atrophy from age-related macular degeneration in the study eye. The largest geographic atrophy (GA) lesion must be a minimum of 0.5 optic disk area (DA) (1.25 mm2) and no more than 6 DA in size (15.0 mm2). GA is defined as one or more well-defined, usually more or less circular patches of loss of the retinal pigment epithelium (RPE), typically with exposure of underlying choroidal blood vessels. If the GA is multifocal and the largest lesion is < 0.5 DA, then there should be at least 3 lesions ≥ 250 microns in greatest linear diameter. Best-Corrected Visual Acuity (BCVA) between 20/20 and 20/400 in the study eye. Female participants must be menopausal. Male participants are required to use contraception and cannot donate sperm during study participation. Presence of hyperfluorescence at the edge of GA on autofluorescence imaging. Ability to give informed consent. If a subject has two eligible eyes, then both eyes can be enrolled into the study. Subject must have mailed back the medication bottle after the 10 day run-in phase, demonstrating that they have taken ≥ 80% of the capsules. Exclusion Criteria Evidence of ocular disease other than AMD in the study eye that may confound the study outcomes (e.g., History of myopic degeneration, choroidal neovascularization, central serous chorioretinopathy, severe diabetic retinopathy, uveitis, vitelliform dystrophy, or macular edema). Presence of geographic atrophy that is already touching clearly defined beta peripapillary atrophy or is already touching the optic disc. Beta peripapillary atrophy is defined as peripapillary atrophy in which either the sclera or choroidal vessels are clearly visible. Any history of intravitreal injection in the study eye for AMD or choroidal neovascularization. However, if a subject develops choroidal neovascularization in the study eye during the study, then the subject will receive the standard of care intravitreal injection treatments per the investigator. The subject will continue to stay in the study. Treatment of choroidal neovascularization (CNV) or other diseases in the non-study eye is at the investigator's discretion. History of intravitreal injection of any agent (e.g., triamcinolone) other than anti-VEGF (vascular endothelial growth factor) in the study eye within the last four months prior to study enrollment. History of laser treatment (including photodynamic therapy) to the macula for the study eye. History of intraocular surgery within 90 days. for the study eye. History of anterior segment laser (laser peripheral iridotomy, laser to trabecular meshwork, YAG capsulotomy) within 90 days for the study eye. Media opacity (corneal scar, cataract) that would prevent adequate fundus imaging for the study eye. Any history of participation in another therapeutic clinical trial for GA. Participation currently or within the past 30 days in another therapeutic clinical trial in which a systemic or ocular study medication is received by the subject. GA in the study eye due to a cause other than AMD History of prior use of ALA. AREDS (Age Related Eye Disease Study) vitamins taken at standard doses are not considered an exclusion criterion. Taking a standard multivitamin is not considered an exclusion criterion. However, the multivitamin should not contain alpha lipoic acid (also known as thioctic acid). Taking antioxidant supplements other than a standard multivitamin (such as bilberry, vitamin C that is not part of a multivitamin or taken at higher doses than the AREDS formula, vitamin E that is not part of a multivitamin or taken at higher doses than the AREDS formula, or other similar antioxidants) within one month of enrollment is an exclusion criteria; these patients should discontinue the antioxidant supplement one month before enrollment in order to participate. Taking a supplement that has antioxidant potential that is recommended by a physician as standard-of-care medical management is not an exclusion criterion.). Participant has a condition that, in the opinion of the investigator, would preclude participation in the study for 18 months (e.g., unstable medical status including blood pressure and glycemic control, unstable psychiatric history, moving and not able to return for all planned study visits). History of a formal diagnosis of dementia by a neurologist. History of gastric ulcer within the past 5 years. History of irritable bowel syndrome within the past 5 years.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: alpha lipoic acid (ALA) 600mg once daily x 5 days<br>All 15 patients recruited to the Phase I part will take escalating doses of alpha lipoic acid (ALA) open label. Each enrolled subject will take 600 mg of oral ALA once daily with a meal for 5 days. If well-tolerated, each subject will then take 800 mg of oral ALA once daily with a meal for 5 additional days. If 800 mg of oral ALA is well-tolerated, then subjects will then take 1200 mg of oral ALA once daily with a meal for 5 days. | Drug: alpha lipoic acid<br> <br> * Other names: thioctic acid;|
| Experimental: alpha lipoic acid 800mg<br>once daily with meal x 5 days | Drug: alpha lipoic acid<br> <br> * Other names: thioctic acid;|
| Experimental: alpha lipoic acid 1200mg<br>once daily x 5 days | Drug: alpha lipoic acid<br> <br> * Other names: thioctic acid;|
| Placebo Comparator: Placebo 600mg<br>All 50 subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600mg capsule of ALA (or placebo) once daily with a meal for 2 weeks and then increase to two 600 mg capsules of ALA (or placebo) once daily with a meal for the | Drug: Placebo<br> <br> |
| Experimental: ALA 600 mg<br>once daily with a meal for 2 weeks | Drug: alpha lipoic acid<br> <br> * Other names: thioctic acid;|
| Placebo Comparator: Placebo 1200mg<br>Two 600mg capsules once daily with a meal for the entire remainder of the 18 month period of the study | Drug: Placebo<br> <br> |
| Experimental: ALA 1200mg<br>Two 600mg capsules once daily with a meal for the entire remainder of the 18 month period of the study | Drug: alpha lipoic acid<br> <br> * Other names: thioctic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Percentage of Participants With Adverse Events | The percent of adverse events that develop will be stratified by the alpha lipoic acid dose. | 15 days | 
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. | 18 months | 
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. | 18 months | 
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence (FAF) by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. For square root transformed data, the square root of area was used. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. | 18 months | 
| Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted | The rate of change over time in area of Geographic Atrophy (GA) in the study eye. This is determined by masked grading of Fundus Autofluorescence (FAF) by an image reading center, in participants randomized to placebo or 1200 mg once daily of ALA. The values represent the annualized change from baseline to 18 months. Mean annual geographic atrophy growth rate was calculated by taking the total atrophy area at 18 months minus the baseline area. This value was then divided by 18 months and then multiplied by 12 months to get the annual growth rate. For square root transformed data, the square root of area was used. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA) | Unit of Measure. Mean annual change in best-corrected visual acuity was calculated by taking the letter score at 18 months minus the baseline letter score. This value was then divided by 18 months and then multiplied by 12 months to get the mean annual change in visual acuity. Timepoints for the study were baseline, 0, 6, 12, and 18 months. The baseline and 18 month timepoints were used for the annualized calculations as noted below. | 18 months |