ALA: Alpha Lipoic Acid in Geographic Atrophy

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT02613572
• Collaborator: (none)
• Enrollment: 68
• Locations: 5
• Arms: 7
• Duration (Months): 40
• Patients Per Site: 13.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Age-Related Macular Degeneration	Drug: alpha lipoic acid; Drug: Placebo	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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).
• Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: Feb 15, 2019
• Actual Study Completion Date: Mar 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: alpha lipoic acid (ALA) 600mg once daily x 5 days 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; Other Names: thioctic acid
Experimental: alpha lipoic acid 800mg once daily with meal x 5 days	Drug: alpha lipoic acid; Other Names: thioctic acid
Experimental: alpha lipoic acid 1200mg once daily x 5 days	Drug: alpha lipoic acid; Other Names: thioctic acid
Placebo Comparator: Placebo 600mg 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
Experimental: ALA 600 mg once daily with a meal for 2 weeks	Drug: alpha lipoic acid; Other Names: thioctic acid
Placebo Comparator: Placebo 1200mg Two 600mg capsules once daily with a meal for the entire remainder of the 18 month period of the study	Drug: Placebo
Experimental: ALA 1200mg Two 600mg capsules once daily with a meal for the entire remainder of the 18 month period of the study	Drug: alpha lipoic acid; Other Names: thioctic acid

Outcome Measures

Primary Outcome Measures

1. Phase I: Percentage of Participants With Adverse Events [15 days]

   The percent of adverse events that develop will be stratified by the alpha lipoic acid dose.

2. Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted [18 months]

   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.

3. Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted [18 months]

   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.

4. Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted [18 months]

   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.

5. Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted [18 months]

   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.

Secondary Outcome Measures

1. Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA) [18 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Iowa Hospitals and Clinics, Department of Ophthalmology & Visual Sciences	Iowa City	Iowa	United States	52242
2	NJ Retina	Teaneck	New Jersey	United States	07666
3	Oregon Regina. LLP	Eugene	Oregon	United States	97401
4	Retina Northwest, P.C.	Portland	Oregon	United States	97210
5	Scheie Eye Institute of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Study Chair: Benjamin J Kim, MD, University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 14, 2017

More Information

Publications

• Sarezky D, Raquib AR, Dunaief JL, Kim BJ. Tolerability in the elderly population of high-dose alpha lipoic acid: a potential antioxidant therapy for the eye. Clin Ophthalmol. 2016 Sep 29;10:1899-1903. eCollection 2016.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02613572
• Other Study ID Numbers: 822310; 822311; 201604726
• First Posted: Nov 24, 2015
• Last Update Posted: Aug 6, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Macular Degeneration; Geographic Atrophy; Atrophy; Thioctic Acid

Study Results

Participant Flow

Pre-assignment Detail	Phase I: 15 subjects took escalating ALA doses (600mg, 800mg, 1200mg). 1 subject withdrew after 800mg due to wanting to delay start of 1200mg dose beyond planned completion date. Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled.

Arm/Group Title	Alpha Lipoic Acid (ALA) 600, 800, 1200 mg	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg
Arm/Group Description	Phase I: All subjects 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.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
Period Title: Phase I: Tolerability, 600, 800, 1200 mg
STARTED	15	0	0
600 mg	15	0	0
800 mg	15	0	0
1200 mg	14	0	0
COMPLETED	14	0	0
NOT COMPLETED	1	0	0
Period Title: Phase I: Tolerability, 600, 800, 1200 mg
STARTED	0	27	26
COMPLETED	0	26	26
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	Alpha Lipoic Acid (ALA) 600, 800 &1200 mg	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg	Total
Arm/Group Description	Phase I: All subjects 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.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Total of all reporting groups
Overall Participants	15	27	26	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.7 (3.3)	79.0 (7.0)	80.6 (6.5)	77.8 (7.2)
Sex: Female, Male (Count of Participants)
Female	10 66.7%	16 59.3%	18 69.2%	44 64.7%
Male	5 33.3%	11 40.7%	8 30.8%	24 35.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 20%	0 0%	0 0%	3 4.4%
White	12 80%	26 96.3%	24 92.3%	62 91.2%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 3.7%	2 7.7%	3 4.4%
Region of Enrollment (participants) [Number]
United States	15 100%	27 100%	26 100%	68 100%
Bilateral Geographic Atrophy (Count of Participants)
Yes	0 0%	24 88.9%	23 88.5%	47 69.1%
No	0 0%	3 11.1%	3 11.5%	6 8.8%
Geographic Atrophy Lipoic Acid Study (GALA) Eligible Eyes (Count of Participants)
Unilateral	0 0%	17 63%	16 61.5%	33 48.5%
Bilateral	0 0%	10 37%	10 38.5%	20 29.4%

Outcome Measures

1. Primary Outcome

Title	Phase I: Percentage of Participants With Adverse Events
Description	The percent of adverse events that develop will be stratified by the alpha lipoic acid dose.
Time Frame	15 days

Outcome Measure Data

Analysis Population Description

Phase I: 15 subjects took escalating ALA doses (600mg, 800mg, 1200mg). 1 subject withdrew after 800mg due to wanting to delay start of 1200mg dose beyond planned completion date.

Arm/Group Title	Alpha Lipoic Acid (ALA) 600 mg	Alpha Lipoic Acid (ALA) 800 mg	Alpha Lipoic Acid (ALA) 1200 mg
Arm/Group Description	Phase I: All subjects 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.	Phase I: All subjects 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.	Phase I: All subjects 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.
Measure Participants	15	15	14
Count of Participants [Participants]	11 73.3%	10 37%	10 38.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpha Lipoic Acid (ALA) 600 mg, Alpha Lipoic Acid (ALA) 800 mg, Alpha Lipoic Acid (ALA) 1200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of Geographic Atrophy (mm2) - Unadjusted
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.

Arm/Group Title	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg
Arm/Group Description	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
Measure Participants	26	26
Mean (Standard Deviation) [mm^2/year]	1.21 (0.13)	1.71 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpha Lipoic Acid (ALA) 600 mg, Alpha Lipoic Acid (ALA) 800 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Mixed Models Analysis
	Comments

3. Primary Outcome

Title	Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Total Area of GA (mm2) - Adjusted
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.

Arm/Group Title	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg
Arm/Group Description	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
Measure Participants	26	26
Mean (Standard Deviation) [mm^2/year]	1.29 (0.23)	1.63 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpha Lipoic Acid (ALA) 600 mg, Alpha Lipoic Acid (ALA) 800 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Mixed Models Analysis
	Comments

4. Primary Outcome

Title	Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Unadjusted
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.

Arm/Group Title	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg
Arm/Group Description	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
Measure Participants	26	26
Mean (Standard Deviation) [mm/year]	0.28 (0.02)	0.31 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpha Lipoic Acid (ALA) 600 mg, Alpha Lipoic Acid (ALA) 800 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Mixed Models Analysis
	Comments

5. Primary Outcome

Title	Phase II: Mean Annual Growth of Geographic Atrophy (Fundus Autofluorescence) - Square Root of Area of GA (mm) - Adjusted
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.

Arm/Group Title	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg
Arm/Group Description	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
Measure Participants	26	26
Mean (Standard Deviation) [mm/year]	0.27 (0.04)	0.32 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpha Lipoic Acid (ALA) 600 mg, Alpha Lipoic Acid (ALA) 800 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Mixed Models Analysis
	Comments

6. Secondary Outcome

Title	Phase II: Mean Annual Change in Best-Corrected Visual Acuity (BCVA)
Description	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.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Phase II: 52 subjects randomized to placebo or 1200mg ALA. 1 subject died due to unrelated event and was replaced in study; thus, 53 total subjects were enrolled, but 52 subjects were analyzed in this outcome.

Arm/Group Title	Placebo 1200mg	Alpha Lipoic Acid (ALA) 1200mg
Arm/Group Description	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.	Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
Measure Participants	26	26
Mean (Standard Deviation) [letters/year]	-3.8 (1.1)	-3.1 (1.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alpha Lipoic Acid (ALA) 600 mg, Alpha Lipoic Acid (ALA) 800 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	Phase I: 15 Days; Phase II: 18 Months
Arm/Group Title	Alpha Lipoic Acid (ALA) 600 mg		Alpha Lipoic Acid (ALA) 800 mg		Alpha Lipoic Acid (ALA) 1200 mg (Phase I)		Placebo 1200mg		Alpha Lipoic Acid (ALA) 1200mg (Phase II)
Arm/Group Description	Phase I: All subjects 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.		Phase I: All subjects 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.		Phase I: All subjects 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.		Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.		Phase II: All subjects in Phase II will be double blinded and randomized to either placebo or ALA. Each will take one 600 mg 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 entire remainder of the 18 month period of the study.
All Cause Mortality
	Alpha Lipoic Acid (ALA) 600 mg		Alpha Lipoic Acid (ALA) 800 mg		Alpha Lipoic Acid (ALA) 1200 mg (Phase I)		Placebo 1200mg		Alpha Lipoic Acid (ALA) 1200mg (Phase II)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		0/26 (0%)
Serious Adverse Events
	Alpha Lipoic Acid (ALA) 600 mg		Alpha Lipoic Acid (ALA) 800 mg		Alpha Lipoic Acid (ALA) 1200 mg (Phase I)		Placebo 1200mg		Alpha Lipoic Acid (ALA) 1200mg (Phase II)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/14 (0%)		5/27 (18.5%)		10/26 (38.5%)
Cardiac disorders
Coronary Artery Occlusion	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		0/26 (0%)
Cardio-Respiratory Arrest	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		0/26 (0%)
Eye disorders
Visual Acuity Reduced	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		1/26 (3.8%)
Infections and infestations
Sepsis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Bacteraemia	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Bronchitis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Injury, poisoning and procedural complications
Spinal Compression Fracture	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		0/26 (0%)
Hip fracture	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Subarachnoid Haemorrhage	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Nervous system disorders
Cerebrovascular Accident	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Aspiration	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Pulmonary Embolism	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Vascular disorders
Thrombosis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Alpha Lipoic Acid (ALA) 600 mg		Alpha Lipoic Acid (ALA) 800 mg		Alpha Lipoic Acid (ALA) 1200 mg (Phase I)		Placebo 1200mg		Alpha Lipoic Acid (ALA) 1200mg (Phase II)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/15 (73.3%)		10/15 (66.7%)		10/14 (71.4%)		24/27 (88.9%)		23/26 (88.5%)
Eye disorders
Angle Closure Glaucoma	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Blepharitis	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		0/26 (0%)
Blindness	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		3/26 (11.5%)
Cataract	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Macular Degeneration	0/15 (0%)		0/15 (0%)		0/14 (0%)		3/27 (11.1%)		1/26 (3.8%)
Retinal Haemorrhage	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Vision Blurred	0/15 (0%)		0/15 (0%)		0/14 (0%)		4/27 (14.8%)		1/26 (3.8%)
Visual Acuity Reduced	0/15 (0%)		0/15 (0%)		0/14 (0%)		6/27 (22.2%)		7/26 (26.9%)
Visual Disturbance	0/15 (0%)		0/15 (0%)		0/14 (0%)		3/27 (11.1%)		1/26 (3.8%)
Gastrointestinal disorders
Acid Reflux (Dyspepsia)	1/15 (6.7%)		1/15 (6.7%)		1/14 (7.1%)		1/27 (3.7%)		6/26 (23.1%)
Diarrhoea	2/15 (13.3%)		1/15 (6.7%)		1/14 (7.1%)		6/27 (22.2%)		2/26 (7.7%)
Loose Stools	0/15 (0%)		3/15 (20%)		1/14 (7.1%)		0/27 (0%)		0/26 (0%)
Nausea	0/15 (0%)		0/15 (0%)		1/14 (7.1%)		1/27 (3.7%)		7/26 (26.9%)
Stomach Discomfort	0/15 (0%)		0/15 (0%)		1/14 (7.1%)		1/27 (3.7%)		5/26 (19.2%)
Colitis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Constipation	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		3/26 (11.5%)
Gastrointestinal Pain	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Gastrooesophageal Reflux Disease	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		2/26 (7.7%)
Giardiasis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Haemorrhoids	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		0/26 (0%)
Vomiting	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		6/26 (23.1%)
General disorders
Fatigue	1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/27 (0%)		0/26 (0%)
Weakness (Asthenia)	0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/27 (0%)		0/26 (0%)
Influenza Like Illness	0/15 (0%)		0/15 (0%)		0/14 (0%)		4/27 (14.8%)		2/26 (7.7%)
Infections and infestations
Bronchitis	0/15 (0%)		0/15 (0%)		0/14 (0%)		4/27 (14.8%)		0/26 (0%)
Cellulitis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Fungal Infection	0/15 (0%)		0/15 (0%)		0/14 (0%)		3/27 (11.1%)		0/26 (0%)
Gastroenteritis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Nasopharyngitis	0/15 (0%)		0/15 (0%)		0/14 (0%)		6/27 (22.2%)		2/26 (7.7%)
Pneumonia	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Tooth Abscess	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		0/26 (0%)
Urinary Tract Infection	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		5/26 (19.2%)
Injury, poisoning and procedural complications
Back Injury	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Fall	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		3/26 (11.5%)
Investigations
Weight Decreased	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		5/26 (19.2%)
Metabolism and nutrition disorders
Hyperglycemia	1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/27 (0%)		0/26 (0%)
Decreased Appetite	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		4/26 (15.4%)
Musculoskeletal and connective tissue disorders
Leg (Muscle) Cramps	0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/27 (0%)		0/26 (0%)
Arthritis	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Muscle Spasms	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Musculoskeletal Pain	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		2/26 (7.7%)
Nervous system disorders
Dizziness	0/15 (0%)		0/15 (0%)		1/14 (7.1%)		3/27 (11.1%)		4/26 (15.4%)
Ageusia	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Lethargy	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		1/26 (3.8%)
Psychiatric disorders
Insomnia	1/15 (6.7%)		0/15 (0%)		1/14 (7.1%)		2/27 (7.4%)		0/26 (0%)
Depression	0/15 (0%)		0/15 (0%)		0/14 (0%)		1/27 (3.7%)		3/26 (11.5%)
Renal and urinary disorders
Abnormal Urine Odor	8/15 (53.3%)		7/15 (46.7%)		7/14 (50%)		0/27 (0%)		3/26 (11.5%)
Dysuria	0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/27 (0%)		0/26 (0%)
Increased Urinary Frequency	0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/27 (0%)		0/26 (0%)
Urinary Urgency	0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/27 (0%)		0/26 (0%)
Hypertonic Bladder	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Proteinuria	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		2/26 (7.7%)
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Bronchial Obstruction	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		0/26 (0%)
Cough	0/15 (0%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		3/26 (11.5%)
Dyspnoea	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		0/26 (0%)
Skin and subcutaneous tissue disorders
Rash	1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/27 (0%)		1/26 (3.8%)
Precancerous Skin Lesion	0/15 (0%)		0/15 (0%)		0/14 (0%)		2/27 (7.4%)		0/26 (0%)
Vascular disorders
Flushing	0/15 (0%)		1/15 (6.7%)		1/14 (7.1%)		0/27 (0%)		0/26 (0%)
Hot Flashes	1/15 (6.7%)		0/15 (0%)		1/14 (7.1%)		0/27 (0%)		0/26 (0%)
Hypertension	0/15 (0%)		0/15 (0%)		0/14 (0%)		3/27 (11.1%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.