Clinical trial NCT02613572
Conditions: Age-Related Macular Degeneration
Sponsor: University of Pennsylvania
Start date: 2015-11-01; Completion date: 2019-03-01
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

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.

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.

Arms: arm 1: 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. arm 2: once daily with meal x 5 days arm 3: once daily x 5 days arm 4: 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 arm 5: once daily with a meal for 2 weeks arm 6: Two 600mg capsules once daily with a meal for the entire remainder of the 18 month period of the study arm 7: Two 600mg capsules once daily with a meal for the entire remainder of the 18 month period of the study
Interventions: intervention 1: alpha lipoic acid intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
 
Evaluation of Alpha Lipoic Acid as a Potential Treatment for 
Geographic Atrophy in subjects with Age-related Macular 
Degeneration 
 
Principal Investigator & 
Clinical and Scientific Expert 
Benjamin J. Kim, MD 
Assistant Professor of Ophthalmology at the Hospital of the 
University of Pennsylvania 
Scheie Eye Institute of the University of Pennsylvania 
Philadelphia, PA  19104 
215-662-8675 
Benjamin.kim@uphs.upenn.edu 
 
Sub-Investigator:  
Alexander J. Brucker, MD 
Professor of Ophthalmology  
Scheie Eye Institute of the University of Pennsylvania 
Philadelphia, PA  19104 
215-662-8675 
ajbrucke@mail.med.upenn.edu 
 
Collaborators: 
 
 
 
 
 
 
Joshua L. Dunaief, MD, PhD 
Adele Niessen Professor of Ophthalmology 
Scheie Eye Institute of the University of Pennsylvania 
Philadelphia, PA  19104 
215-898-5235 
jdunaief@mail.med.upenn.edu 
 
 
Regulatory Sponsor  
University of Pennsylvania 
Philadelphia, PA  19104 
 
Investigational Product: 
Alpha Lipoic Acid  
 
Protocol Number: 
822310, 0822311, 201604726 
IND/ IDE Number: 
126925 
 
ClinicalTrials.gov Number:      NCT02613572 
Document Date: 
14 November 2017 
 
 


Page ii of 32 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS......................................................................................................................... IV 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
INTRODUCTION ............................................................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ......................................................................................... 3 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT .............................................................. 4 
1.2.1 
Nonclinical Data ....................................................................................................................... 4 
1.2.2 
Clinical Data to Date ................................................................................................................ 4 
1.3 
DOSE RATIONALE .............................................................................................................................. 5 
2 
STUDY OBJECTIVES ............................................................................................................................ 5 
2.1 
PRIMARY OBJECTIVE.......................................................................................................................... 5 
2.2 
SECONDARY OBJECTIVES (IF APPLICABLE) .......................................................................................... 5 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 6 
3.1 
GENERAL DESIGN .............................................................................................................................. 6 
3.1.1 
Allocation to Interventional Group ............................................................................................ 6 
3.2 
STUDY ENDPOINTS ............................................................................................................................ 7 
3.2.1 
Primary Study Endpoints ......................................................................................................... 7 
3.2.2 
Secondary Study Endpoints ..................................................................................................... 7 
3.2.3 
Primary Safety Endpoints ........................................................................................................ 8 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................... 8 
4.1 
DOSE TOLERABILITY TEST (PHASE 1) ................................................................................................. 8 
4.1.1 
INCLUSION CRITERIA ....................................................................................................................... 8 
4.1.2 
EXCLUSION CRITERIA. ..................................................................................................................... 8 
4.1.3 
SUBJECT RECRUITMENT .................................................................................................................. 8 
4.1.4 
DURATION OF STUDY PARTICIPATION ............................................................................................... 8 
4.1.5 
TOTAL NUMBER OF SUBJECTS AND SITES ........................................................................................ 8 
4.1.6 
VULNERABLE POPULATIONS ............................................................................................................ 8 
4.2 
RANDOMIZED, DOUBLE-BLIND PLACEBO CONTROLLED TRIAL (PHASE 2) ................................................. 8 
4.2.1 
INCLUSION CRITERIA ....................................................................................................................... 8 
4.2.2 
EXCLUSION CRITERIA ...................................................................................................................... 9 
4.2.3 
SUBJECT RECRUITMENT ................................................................................................................ 10 
4.2.4 
DURATION OF STUDY PARTICIPATION ............................................................................................. 10 
4.2.5 
TOTAL NUMBER OF SUBJECTS AND SITES ...................................................................................... 10 
4.2.6 
VULNERABLE POPULATIONS .......................................................................................................... 10 
5 
STUDY INTERVENTION ...................................................................................................................... 10 
5.1 
DESCRIPTION OF STUDY MEDICATION ................................................................................................ 10 
5.2 
INTERVENTION REGIMEN .................................................................................................................. 10 
5.3 
RECEIPT .......................................................................................................................................... 10 
5.4 
STORAGE ........................................................................................................................................ 10 
5.5 
PREPARATION AND PACKAGING ........................................................................................................ 10 
5.6 
BLINDING......................................................................................................................................... 11 
5.7 
ADMINISTRATION AND ACCOUNTABILITY ............................................................................................ 11 
5.8 
SUBJECT COMPLIANCE MONITORING ................................................................................................ 11 
5.8.1 
Return or Destruction of Investigational Product ................................................................... 13 
6 
STUDY PROCEDURES, PHASE 1 ...................................................................................................... 13 


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CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
6.1 
SCREENING ..................................................................................................................................... 13 
6.2 
STUDY INTERVENTION AND FOLLOW-UP PHASE ................................................................................. 13 
6.3 
END OF STUDY ................................................................................................................................ 13 
6.4 
UNSCHEDULED VISITS ...................................................................................................................... 13 
6.5 
SUBJECT WITHDRAWAL .................................................................................................................... 14 
7 
STUDY PROCEDURES, PHASE 2 ...................................................................................................... 14 
7.1 
SCREENING (AT BASELINE) ............................................................................................................... 14 
7.2 
STUDY INTERVENTION PHASE ........................................................................................................... 15 
7.2.1 
6 Month, 12 Month, and 18 Month Visits ............................................................................... 15 
7.2.2 
Ophthalmic Procedures ......................................................................................................... 15 
7.2.3 
Photography ........................................................................................................................... 15 
7.3 
FOLLOW UP PHASE OF THE STUDY ................................................................................................... 17 
7.3.1 
End of Study Visit ................................................................................................................... 17 
7.4 
UNSCHEDULED VISITS ...................................................................................................................... 17 
7.5 
SUBJECT WITHDRAWAL .................................................................................................................... 17 
7.5.1 
Data Collection and Follow-up for Withdrawn Subjects ......................................................... 17 
7.6 
EARLY TERMINATION VISITS ............................................................................................................. 17 
8 
STATISTICAL PLAN ............................................................................................................................ 17 
8.1 
PRIMARY ENDPOINT ......................................................................................................................... 17 
8.2 
SECONDARY ENDPOINTS .................................................................................................................. 17 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ...................................................................................... 18 
8.4 
STATISTICAL METHODS .................................................................................................................... 18 
8.4.1 
Baseline Data ......................................................................................................................... 19 
8.4.2 
Safety Analysis ....................................................................................................................... 19 
9 
SAFETY AND ADVERSE EVENTS ..................................................................................................... 19 
9.1 
DEFINITIONS .................................................................................................................................... 19 
9.1.1 
Adverse Event ........................................................................................................................ 19 
9.1.2 
Serious Adverse Event .......................................................................................................... 19 
9.2 
RECORDING OF ADVERSE EVENTS .................................................................................................... 19 
9.3 
RELATIONSHIP OF AE TO STUDY ...................................................................................................... 20 
9.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................................... 20 
9.4.1 
Investigator reporting: notifying the study sponsor ................................................................ 20 
9.4.2 
INVESTIGATOR REPORTING: NOTIFYING THE LOCAL IRB ................................................................. 20 
9.4.3 
Sponsor reporting: Notifying the FDA .................................................................................... 21 
9.4.4 
Sponsor reporting: Notifying participating investigators......................................................... 21 
9.5 
UNBLINDING PROCEDURES ............................................................................................................... 21 
9.6 
MONITORING ................................................................................................................................... 21 
9.6.1 
Data and Safety Monitoring Plan ........................................................................................... 21 
10 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 21 
10.1 
CONFIDENTIALITY .......................................................................................................................... 21 
10.2 
DATA COLLECTION AND MANAGEMENT ........................................................................................... 22 
10.3 
RECORDS RETENTION .................................................................................................................... 22 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 22 
11.1 
STUDY MONITORING PLAN ............................................................................................................. 22 
11.2 
AUDITING AND INSPECTING ............................................................................................................. 23 
12 
ETHICAL CONSIDERATIONS........................................................................................................... 23 
12.1 
RISKS ........................................................................................................................................... 23 
12.2 
BENEFITS ...................................................................................................................................... 23 
12.3 
RISK BENEFIT ASSESSMENT ........................................................................................................... 24 
12.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ................................................................ 24 
13 
STUDY FINANCES ............................................................................................................................ 24 
13.1 
FUNDING SOURCE ......................................................................................................................... 24 


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CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
13.2 
CONFLICT OF INTEREST.................................................................................................................. 25 
14 
PUBLICATION PLAN ........................................................................................................................ 25 
15 
REFERENCES ................................................................................................................................... 25 
16 
APPENDICES .................................................................................................................................... 27 
17 
ADDITIONAL INFORMATION ........................................................................................................... 27 
17.1 
EXPEDITED FDA REPORTING REQUIREMENTS ................................................................................ 27 
17.2 
SOURCE DOCUMENTS (DEFINITION) ................................................................................................ 28 
17.3 
CASE REPORT FORMS (CRFS) (DEFINITION AND GUIDELINES) .......................................................... 28 
 
 
 
 
 
List of Abbreviations 
 
ALA: Alpha Lipoic Acid 
 
AMD: Age-related macular degeneration 
 
BCVA: Best-corrected visual acuity as measured by an electronic visual acuity (EVA) or ETDRS chart 
 
CPOB: Center for Preventive Ophthalmology and Biostatistics 
 
DA: Optic disc area 
 
EAE: Experimental autoimmune encephalomyelitis 
 
FAF: Fundus autofluorescence 
 
GA: Geographic atrophy is defined as one or more well-defined, more or less circular patches of loss of 
the RPE, typically with exposure of underlying choroidal blood vessels 
 
OCT: Spectral Domain Optical Coherence Tomography  
 
RPE: Retinal pigment epithelium 
 
 
 
 
 


Lipoic Acid in GA 
 
page 1 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
Study Summary 
Title 
Evaluation of Alpha Lipoic Acid as a Potential Treatment for Geographic 
Atrophy in subjects with Age-related Macular Degeneration 
 
Short Title 
Lipoic Acid in GA 
 
Protocol Number 
 
822310 
Clinical Trial Phase 
II 
 
Methodology 
Dose tolerability test (Phase 1) 
Randomized, double-blind, placebo-controlled (Phase 2 Pilot Study). 
 
Study Duration 
Phase 1: 15 days 
Phase 2: 31 months: 12 month enrollment period followed by an approximately 
1 month run-in period and then an 18 month study participation after 
randomization. (Final subject could have final study visit 31 months after first 
study subject was screened) 
 
Study Center(s) 
Phase 1: Single site (1 site); Phase 2: Multi-site (5 total) 
 
Objectives 
The objective of Phase 1 of this protocol is to ensure that oral Alpha Lipoic 
Acid doses of up to 1200 mg daily are well-tolerated in the elderly population.  
The objective of Phase 2 of this protocol is to determine the effects of ALA on 
the progression of GA in patients with AMD through a Phase II pilot clinical 
trial.  
 
Number of Subjects 
65 subjects (Phase 1: 15; Phase 2: 50) 
 
Main Inclusion 
Criteria 
• 
Age 55-90 
• 
Diagnosis of geographic atrophy from age-related macular degeneration in 
the study eye.  The largest GA lesion must be a minimum of 0.5 DA (1.25 
mm2) and no more than 6 DA in size. GA is defined as one or more well-
defined, usually more or less circular patches of loss of the 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. 
• 
BCVA between 20/20 and 20/400 in the study eye.  
• 
Presence of hyperfluorescence at the edge of GA on autofluorescence 
imaging. 
 
Investigational 
Product  
 
Alpha Lipoic Acid (ALA), also known as Thioctic Acid.   
Duration of 
administration 
 
Phase 1: 15 days 
Phase 2: 18 months from the time of randomization 
 
Reference therapy 
The reference is a placebo. 
 


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CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
Statistical 
Methodology 
 
For Phase 1 of this protocol, the percent of adverse events and serious 
adverse events that developed in the study group will be determined.  For 
Phase 2 of this protocol, the mean change in the total area of GA within study 
eyes over 18 months will be compared between subjects receiving the active 
ALA dose and placebo supplementation; a square root transformation will be 
applied to the area measurements to mitigate the dependence of growth rate 
on initial size. 
 
Safety Evaluations  
For Phase 1 of this protocol, the primary safety outcome is the percent of 
subjects that develop a serious adverse event while taking ALA.  For Phase 2 
of this protocol, the primary safety outcome will be a visual acuity decrease of 
≥ 3 lines (15 letters) between baseline and 18 months after randomization. 
 
Data and Safety 
Monitoring Plan  
Monitoring is risk based.   
  
 
 
 


Page 3 of 32 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance with University of Pennsylvania Research Policies, 
Procedures, Federal and State regulations, and in accordance with international standards of Good 
Clinical Practice (GCP).   
Introduction 
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) for which 
there is currently no available treatment.  Damage to the retina secondary to oxidative stress is thought to 
be a significant factor in the pathogenesis of GA.1-3  Recently, the Dunaief Lab at the University of 
Pennsylvania has found that alpha lipoic acid (ALA), a potent antioxidant and iron chelator, is extremely 
retina-protective in a light damage mouse model.4 ALA, a naturally occurring substance made by the 
body, is an excellent candidate drug because it has proven to be safe and effective during decades of use 
for the treatment of diabetic peripheral neuropathy.5-8 The objective of this study is to determine the 
effects of ALA on the progression of GA in patients with AMD through a Phase II clinical trial.  The central 
hypothesis is that oral ALA supplementation reduces the rate of enlargement of GA in AMD patients.  The 
rationale is that the antioxidant and iron chelating effects of ALA will slow down one of the major 
pathways responsible for GA progression.   
1.1 
Background and Relevant Literature  
Age-related macular degeneration (AMD) is a complex, degenerative, and progressive eye disease that 
can result in severe loss of central vision. It is the leading cause of blindness among those 60 years or 
older in the Western hemisphere.9-10 Geographic atrophy (GA), an advanced form of AMD, is responsible 
for approximately 20% of the legal blindness cases in North America.1 Based on United States 
(US) Census Bureau data from the year 2000 and AREDS (Age Related Eye Disease Study) data, there 
are at least an estimated 824,000 individuals in the US of at least 55 years of age with geographic 
atrophy.11 Presently, this number is likely higher given the population growth in this age 
category.  Similarly, there are at least 8 million individuals in the US with monocular or binocular 
intermediate AMD or monocular advanced AMD, and thus at risk for progression to advanced AMD in one 
of their eyes.  The major mechanisms involved in AMD progression include oxidative stress, inflammation 
with abnormalities in the complement system, accumulation of lipid peroxidation end products, and the 
production of other toxic metabolic byproducts from the visual cycle.1,12-15 Iron potentially contributes to 
the oxidative damage seen in AMD.16-18 
 
AMD is characterized by a progressive degeneration of the macula, leading to a severe decrease in 
central vision.  An early sign of AMD is the appearance of drusen, which are yellow, extracellular deposits 
that accumulate below the retinal pigment epithelium (RPE) and are known to be risk factors for 
developing choroidal neovascularization (CNV).  Depending on the number and size of drusen at the 
macula, a subject may be categorized as intermediate AMD.19 Some of these subjects may progress to 
advanced AMD.  There are two types of advanced AMD: GA and exudative (neovascular) AMD.  GA can 
be defined as one or more well-defined, more or less circular patches of loss of the RPE, typically with 
exposure of underlying choroidal blood vessels.  GA can be multifocal or unifocal.  Areas of GA are 
atrophic, nonfunctioning retina, and each area of GA leads to a scotoma in the subject’s visual field.  
Exudative AMD is defined as the presence of abnormal vessels, referred to as choroidal 
neovascularization, under the retina or retinal pigment epithelium.  These vessels can leak fluid and 
bleed, leading to acute and severe vision loss.  The current standard-of-care treatment of exudative AMD 
is intravitreal injection therapy with anti-VEGF (vascular endothelial growth factor) agents.20 For eyes with 
geographic atrophy, 2 – 18% may develop CNV over the course of two years, and CNV in the fellow eye 
is a risk factor for this development.21  There currently is no treatment to prevent or slow the progression 
of GA.  
 
Several Phase I and Phase II clinical trials have evaluated agents targeting the mechanisms of GA,22-26 
but there has been very limited success.  Stem cell therapy holds promise but is an area where more 
work is needed to clearly show safety and efficacy in humans.27-28 Thus far, the only therapeutic agent 
that has progressed to a Phase III trial is lampalizumab, an inhibitor of complement factor D, and this trial 


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CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
is estimated to be complete in 2018.29-30 If lampalizumab is shown to be an effective treatment for GA, 
then there is still a significant need for other treatments for GA that may add to its effect or reduce its 
treatment burden, especially since lampalizumab may require intravitreal injection every 4 or 6 weeks.  
Thus, there is a critical need to find a treatment for GA that can slow its progression or prevent its onset.  
In the absence of such a treatment, a tremendous number of people will continue to become legally blind.   
 
1.2 
Name and Description of the Investigational Product  
Alpha lipoic acid (ALA) is also known as thioctic acid.  Placebo product is also used in this study.  ALA is 
a potent antioxidant that was approved many years ago in Germany for the treatment of diabetic 
peripheral neuropathy.5-8 ALA is created endogenously by plants and animals.  It is available in the diet 
through potatoes, spinach, broccoli, tomatoes, peas, brussel sprouts, and rice bran.31 It can already be 
purchased as an over-the-counter supplement and is manufactured by several companies.  ALA is an 
important cofactor for mitochondrial enzyme complexes and is involved in the metabolic process that 
converts carbohydrates into energy.32 The functions of ALA also include the restoration of diminished 
levels of other antioxidants, acting as a potent chelator of metal ions such as iron, stimulating glucose 
uptake, and increasing insulin sensitivity.32  
1.2.1 
Nonclinical Data 
Recently, the Dunaief Lab of the University of Pennsylvania found that ALA, a potent antioxidant and iron 
chelator, is extremely retina-protective in a light damage mouse model.4  While there is no animal model 
that exactly replicates GA from AMD, the mouse model of light-induced retinal degeneration is a good 
model for studying the development of retinal atrophy.  The Dunaief Lab found that intraperitoneal ALA 
given daily at 100 mg/kg had a significant protective effect in a mouse model of light-induced retinal 
degeneration. ALA, a naturally occurring substance made by the body, is an excellent candidate drug 
because it has proven to be safe and effective during decades of use for the treatment of diabetic 
peripheral neuropathy.5-8 ALA is widely available over the counter.  Additionally, animal model data has 
shown that ALA potentially restores tear production and, thus, may be of benefit for the treatment of dry 
eye disease and its symptoms.33 
1.2.2 
Clinical Data to Date 
ALA has been approved for the treatment of diabetic peripheral neuropathy for many years in Germany.5-8  
It also has been studied in clinical trials for a variety of diseases including cardiovascular disease, 
diabetes, schizophrenia, and others.34  It is commonly used at doses of 200-600 mg and is already 
available over-the-counter.   
 
The safety of ALA has been extensively evaluated. ALA is metabolized by the liver and is known to be 
safe in both hepatic and renal disease.  The primary side effects from oral ALA are gastrointestinal and 
occur at doses of 1200 mg or higher.  These gastrointestinal side effects predominantly involve an upset 
stomach, gastric reflux, nausea, and can be minimized if ALA is taken in divided doses or with a meal, 
although concurrent food ingestion may partially reduce the bioavailability.35-37 There can also be a 
malodorous urine and headache.  Rare complications that may be related to ALA include one subject that 
developed an allergic rash, fever, and mild thrombocytopenia that resolved after stopping ALA and 
reports of a rare occurrence of insulin autoimmune syndrome.38-39 Insulin autoimmune syndrome is 
treatable and resolves within a few months after cessation of ALA. Most of these published studies on the 
safety and tolerability of ALA at doses of 1200 mg or higher involve adults that are not elderly. 
1.2.3      Human Pharmacokinetics 
ALA is both water and fat-soluble.  Importantly, it is known to cross the blood-brain barrier and is 
therefore capable of reaching the target ocular tissues.40-41 There are two enantiomers (R and S) of ALA, 
and the R form is the naturally occurring form.42 Many clinical studies have used the racemic form of ALA 
and biological activity has been shown with oral ingestion of the racemic form.5,36,43 When the oral form is 
ingested, gastrointestinal absorption is roughly 30%.44 Yadav et al. and other groups have reported 
pharmacokinetic data on oral, racemic ALA from different companies, including ALA from Pure 
Encapsulations (Sudbury, MA), a subsidiary of Atrium Innovations Inc. (Westmount, Canada).  They 


Page 5 of 32 
 
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
showed that when ALA is taken with food, maximum blood levels are achieved 30-60 minutes after 
ingestion.35,42 Peak levels in the cortex, retina, and optic nerve are achieved around the same time.45-46 
Doses of 600 mg twice daily led to median serum levels of 0.2 µg/mL (range 0 - 3.7 µg/mL), while median 
serum levels of ALA after placebo ingestion were negligible (all values < 1 µg/mL).36 Doses of 1200 mg 
daily or twice daily led to median serum levels of 4.8 µg/mL (range 0 – 19 µg/mL).  When taking 1200 mg 
daily, blood levels of ALA are undetectable approximately 5 hours after ingestion.35  
1.3 
Dose Rationale  
The Dunaief Lab found that intraperitoneal ALA given daily at 100 mg/kg had a significant protective 
effect in a mouse model of light-induced retinal degeneration.4 Others have shown oral ALA at similar 
doses to be protective of retinal ganglion cells in a mouse model of glaucoma.45 Yadav et al. found that 
subcutaneous injections of ALA at 50 mg/kg/day was an effective dose at suppressing experimental 
autoimmune encephalomyelitis (EAE) in mice.  They then found that 1200 mg of oral ALA taken daily with 
a meal led to a comparable peak serum level as the peak serum level seen in mice when EAE is 
suppressed by ALA, and they concluded that 1200 mg daily with a meal would be an effective and 
tolerable dose to test for multiple sclerosis.35  With concurrent food ingestion, the potential gastrointestinal 
side effects are minimized.  Thus, 1200 mg daily with a meal has the potential to be efficacious, safe, and 
well tolerated. This study will be conducted in two parts. The first part is the dose tolerability test (Phase 
1). In Phase 1, doses of 600 mg daily, 800 mg daily, and 1200 mg daily of oral ALA will be tested in 
subjects in the elderly population, as most safety/tolerability data for higher doses of ALA is not specific to 
the elderly population. Once the first Phase is complete a randomized, double-blind placebo controlled 
trial (Phase 2) will be conducted.  In Phase 2, doses of 1200mg will be administered to subjects for 18 
months, 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. 
 
2 
Study Objectives 
The objective of Phase 1 of this protocol is to determine if doses of 600 mg, 800 mg, and 1200 mg of ALA 
are well-tolerated in the elderly population as each dose is taken for 5 days.   
 
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.   
2.1 
Primary Objective 
The primary objective is to investigate ALA’s effect on the rate of change over time (18 months) in area of 
GA in the study eye, as determined by masked digital grading of fundus photography.  The primary 
endpoint will be determined using fundus autofluorescence (FAF).  The study will utilize the Scheie Eye 
Institute Reading Center to grade the photographs. 
2.2 
Secondary Objectives  
The secondary objectives investigate the effect of ALA on the following: 
• 
Change in best-corrected visual acuity (BCVA) 
• 
Three line or more worsening from baseline BCVA 
• 
Absolute and relative change in area of GA as measured on FAF 
• 
Rate of change over time (18 months from the time of randomization) in area of GA in the study 
eye as measured on color fundus photos. 
• 
Absolute and relative change in area of GA as measured on color fundus photos 
• 
Ocular safety outcomes of ALA as indicated by changes in visual acuity, development of 
uveitis, or any other ocular changes not consistent with the natural progression of GA 
 


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CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
The following exploratory endpoints will be of interest to the study: 1) Change in drusen volume based on 
OCT and change in the number of drusen seen on color fundus photos; 2) Change in score on the Ocular 
Surface Disease Index (OSDI)47;3) Change in best distance corrected near visual acuity. 
 
3 
Investigational Plan  
3.1 
General Design 
 
Phase 1: Dose tolerability test 
This is a single site dose tolerability test. We plan to enroll 15 subjects (ages 65-90) in a single site drug 
tolerability test. 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 2: 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 12 months.  The 
primary endpoint is the mean rate of change of the area of GA in the study eye from baseline to 18 
months (from the time of randomization) 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.48  
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. 
3.1.1 
Allocation to Interventional Group  
Phase 1- Tolerability 
For the tolerability test (Phase 1), 15 subjects will each take ALA at doses of 600 mg, 800 mg, and 1200 
mg daily.  There is no randomization for the tolerability test.  The 15 subjects will receive the ALA after 
consenting to the tolerability study at the Scheie Eye Institute of the University of Pennsylvania. 
 
Phase 2 
Screening/Run-In Phase 
After the clinician determines the patient meets preliminary eligibility for the trial and the patient signs the 
consent form, the screening data will be entered into the data management system.  Coordinating Center 
staff will verify the patient is eligible for the study; correction or confirmation will be performed as 
needed.   The Clinical and Scientific Expert and the Scheie Eye Institute Reading Center will also review 
the patient’s information and retinal images to confirm eligibility prior to randomization and complete a 
form confirming eligibility that is entered into the data management system.   
 
At the screening visit, all subjects will be provided with a postage-paid mailing envelope.  Those subjects 
that do not meet inclusion and exclusion criteria will be contacted and informed that they did not meet all 
of the screening criteria.  Those subjects that are meeting inclusion and exclusion criteria will be 
instructed to start the 10 day run-in phase, once they receive the medication bottle in the mail.    The 
UPenn Investigational Drug Service will mail a medication bottle with 10 placebo capsules to the subject. 
The shipment will include instructions for taking the capsules and a form for providing the first and last 
dates of taking the capsules.   After completing the 10 days of the run-in phase, the subject will use the 
postage-paid mailing envelope to mail back the medication bottle,any remaining contents, and the form to 
the clinical site.  The subject is not informed of whether the study capsules for the run-in phase are 
placebo or ALA. 


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Subjects who demonstrate compliance by taking ≥ 80% of the provided capsules and mailing the 
medication bottle within 40 days of the screening visit will be eligible to continue in the study.  If an 
investigator did not receive a mailed medication bottle but believes the subject followed instructions and 
the medication bottle was lost in the mail, then that subject may get screened again for the study. In this 
instance, the subject will have to repeat the screening visit and the run-in phase.   
 
 
Intervention Phase 
The Coordinating Center is responsible for random assignment of patients to one of the two treatment 
groups.  Random treatment allocation schedules will be generated using a randomized block design and 
stratified by clinical center. All baseline procedures must be performed within 40 days of the day of 
randomization. 
 
For subjects who have successfully completed the run-in phase, the clinical site will inform the 
Coordinating Center that that all inclusion and exclusion criteria have been met. Coordinating Center staff 
will issue the next randomized treatment assignment from the clinical site’s schedule for the patient .  A 
Coordinating Center staff member notifies the clinical site Investigator  that the randomization has been 
completed and the Investigator will fax/send a prescription for study medication (ALA or placebo), signed 
by the Principal or Sub-Investigator, to the University of Pennsylvania’s Investigational Drug Service 
(IDS). A Coordinating Center staff member will notify IDS of the treatment assignment.    
 
Once IDS receives both the prescription from the Investigator and the treatment assignment from the 
Coordinating Center, IDS will send a supply of study drug to the subject’s home.   Subsequent study 
medication also will be mailed by IDS directly to the subject’s home. 
 
For both study Phases, prior to starting the medication, the subject will be instructed on how to take the 
medication, and what signs and symptoms to monitor and report.  For Phase 2 of the protocol, each 
subject will be contacted approximately two weeks after randomization to verify that the study drug has 
been received and that each subject is taking the study medication per instructions. 
3.2 
Study Endpoints  
3.2.1 
Primary Study Endpoints 
For Phase 1 of this protocol, the primary endpoint is the percent of adverse events that develop in the 
study group.   
 
For Phase 2 of this protocol, the primary endpoint is the rate of change over time (18 months from the 
time of randomization) in area of GA in the study eye. This is determined by masked grading of FAF, in 
participants randomized to placebo or 1200 mg once daily of ALA. 
3.2.2 
Secondary Study Endpoints 
The secondary endpoints will investigate the effect of ALA on the following: 
• 
Absolute and relative change in area of GA as measured on FAF 
• 
Rate of change over time (18 months from the time of randomization) in area of GA in the 
study eye as measured on color fundus photos 
• 
Absolute and relative change in area of GA as measured on color fundus photos  
• 
Ocular safety outcomes of ALA as indicated by changes in visual acuity, development of 
uveitis, or any other ocular changes not consistent with the natural progression of GA 
 
The following exploratory endpoints will be of interest to the study:  1) Change in drusen volume based on 
OCT and change in the amount of drusen on color fundus photos; 2) Change in score on the Ocular 
Surface Disease Index (OSDI).47; 3) Change in best distance corrected near visual acuity.  


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3.2.3 
Primary Safety Endpoints 
The primary safety endpoint is a change in best-corrected visual acuity (BCVA) that involves a loss of 
three lines or more from baseline. 
4 
Study Population and Duration of Participation  
4.1 
Dose Tolerability Test (Phase 1) 
4.1.1 
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. 
 
4.1.2 
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 Phase 2 of this trial. 
 
4.1.3 
Subject Recruitment 
Subjects will be recruited from the investigator’s site (Scheie Eye Institute of the University of 
Pennsylvania) 
 
4.1.4 
Duration of Study Participation 
Subjects will participate in the ALA tolerability test for 15 days. 
 
4.1.5 
Total Number of Subjects and Sites 
15 subjects will be recruited from a single site (Scheie Eye Institute of the University of 
Pennsylvania) for the ALA tolerability test. 
 
4.1.6 
Vulnerable Populations 
No vulnerable populations will be involved with this study. 
4.2 
Randomized, double-blind placebo controlled trial (Phase 2) 
4.2.1 
Inclusion Criteria 
• 
Age 55-90 
• 
Diagnosis of geographic atrophy from age-related macular degeneration in the study eye.   
The largest GA lesion must be a minimum of 0.5 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 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. 
• 
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. 


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• 
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. 
4.2.2 
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 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 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 any of the individual components of the 
AREDS vitamins at doses consistent with the AREDS formula (instead of taking the 
AREDS vitamins) is 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. 


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• 
History of severe, chronic gastric reflux such that it causes discomfort several times a 
week (within the past 6 months). 
• 
Male subjects who refuse to use acceptable contraceptive methods. 
4.2.3 
Subject Recruitment  
Subjects will be recruited from the investigators’ clinical practice as well as from referring clinical 
practices on site.  We may plan to utilize Penn media services to increase subject recruitment. 
4.2.4 
Duration of Study Participation 
Subjects will participate in the study for an 18 month period (from the time of randomization). 
4.2.5 
Total Number of Subjects and Sites  
Recruitment for screening visits will end after 50 subjects are randomized.  If there are subjects that 
were already screened and consented at the time the 50th subject is randomized, then eligible 
patients will be allowed to proceed to the Run-In period and randomization (if the subject passes the 
Run-In requirements).  This would not be expected to be more than a few subjects.  It is expected 
that approximately 10-15  subjects per site will be enrolled in order to produce 50 evaluable subjects.  
4.2.6 
Vulnerable Populations 
No vulnerable populations will be involved with this study. 
5 
Study Intervention 
Please refer to sections 6.2. 
5.1 
Description of study medication 
Study medication is comprised of ALA 600mg capsules or placebo capsules. 
5.2 
Intervention Regimen 
Subjects 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 remainder of the 18 
month period of the study.   
 
For the tolerability test (Phase 1), see section 3.1.1.  The 800 mg oral ALA dose will consist of two 400 
mg capsules of ALA.   
5.3 
Receipt  
The ALA is provided by Pure Encapsulations (Sudbury, MA).  It is received, stored, handled, and 
distributed to investigators by the University of Pennsylvania Investigational Drug Service. 
5.4 
Storage 
Active and placebo capsules will be stored, labeled and distributed to Investigators or directly mailed to 
the subject’s home by the University of Pennsylvania Investigational Drug Service.  All drugs (active drug 
and placebo) must be stored at room temperature.   
5.5 
Preparation and Packaging 
In order to maintain the study blind, the Perelman School of Medicine Investigational Drug Service (IDS) 
will manufacture a placebo capsule to match the active ALA 600mg capsule provided by Pure 
Encapsulations Inc.  A white, semi-opaque Size 0 pharmaceutical grade capsule shell will be filled with a 
combination of microcrystalline cellulose NF (approximately 600mg) plus trace amounts of coloring 
agents in order to closely mimic the appearance of the powder inside the active ALA capsule.  Both 
placebo and ALA will be light yellow. 
 
For dispensing, capsules will be hand-counted and placed into white opaque Type 2 HDPE 


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pharmaceutical rounds which comply with USP<671> specifications, in either 120mL or 250mL capacity, 
with a PS-22 tamper-evident liner and a child-resistant cap.  A non-child-resistant cap may be provided to 
the clinician on request, for the subject to switch to after dispensing if he/she has difficulty opening bottles 
and has no young children living at home.  Bottles will include labeling compliant with FDA regulation, 21 
CFR 312.6. 
5.6 
Blinding 
Blinding only applies to Phase 2 of this protocol.  A master file of subject assignments will be kept by the 
data coordinating center.  The research team and the subject will be blinded and will not know the 
investigational product contained each capsule. The blind may be broken in the case of an emergency. 
5.7 
Administration and Accountability    
When dispensing bottles of study run-in capsules, a member of the study team will record information 
onto the drug inventory logs.  The Investigational Drug Service provides an “ALA for GA Study Medication 
Ordering, Distribution, and Accountability Manual” to each clinical center.  Outdated supplies will be 
recalled by the Investigational Drug Service or destroyed on site and replacement supplies provided. 
 
At each visit after the baseline visit and when run-in bottles are returned, unused study drug will be 
collected.  Returned drug must be stored in the returned bottle in a secured location.  The date the bottles 
are returned are noted on a drug accountability log. 
 
All drug storage facilities and medication dispensing and collection records will be made available for 
inspection. 
5.8 
Subject Compliance Monitoring 
Each Investigator must make visits as pleasant as possible by minimizing wait time and providing 
comfortable waiting and examination facilities.  The Investigator for each Clinical Center will continually 
educate the subjects as to the nature of the study, the need for the subject’s continued participation, and 
answer questions concerning geographic atrophy and the use of ALA.   
 
In Phase 2, subjects will be contacted to remind them of a follow up visit within the week of the 
appointment.  The contact can be by telephone or email and a subject response is necessary.  To ensure 
subject compliance for scheduled visits, early morning, evening, or weekend hours may be provided.  
Every effort must be made by the Investigator to remain in contact with subjects, even if they do not want 
to return to be examined or follow the protocol.  After subjects enrolled in Phase 2 are randomized, they 
will be contacted at week 2 and months 1, 3, 9, and 15 months to ensure study drug compliance and to 
inquire about any difficulties with the study drug. 
 
If a subject cannot tolerate the study medication (ALA or placebo) because of gastric reflux or symptoms 
thought to be from gastric reflux, they will be encouraged to prevent their symptoms by taking an over-
the-counter gastrointestinal medication for reflux such as ranitidine or omeprazole.  The investigator will 
make the determination that the symptoms are consistent with reflux and make the recommendation for 
gastrointestinal prophylaxis on a case-by-case basis.  The investigator may choose to involve an internist 
in making this decision.  Any use of gastrointestinal prophylaxis medications will be recorded.  If ranitidine 
is desired to treat such symptoms at no cost to the subject because of reflux presumed to be related to 
the study medication, then a prescription may be sent (fax/email) to the UPenn IDS and the ranitidine will 
be mailed to the subject.  The study’s Clinical and Scientific Expert must be notified and approve of this 
action within one week and prior to sending the ranitidine prescription to the Penn IDS. 
 
If a subject cannot tolerate the study medication (ALA or placebo) for the reasons detailed below, then the 
subject will be asked if he/she is willing to take one capsule twice daily instead of two capsules once 
daily: 
• 
there are uncomfortable gastrointestinal symptoms that do not resolve with medication for reflux,  
• 
there are gastrointestinal symptoms and the subject does not want to take any prophylactic 
gastrointestinal medication, or  


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• 
there are other symptoms causing intolerability of the study dose  
 
If the subject cannot tolerate or does not want to take one capsule twice daily, then the subject will be 
asked if he/she is willing to take one capsule once daily.  If the subject cannot tolerate one capsule once 
daily or does not want to take one capsule once daily, then the subject will be asked to at least remain in 
the study.  All changes to the schedule of study medication dosing will be documented.  
 
The study subjects will be asked to provide urine samples at the 12 months study visit.  The urine will be 
tested for a metabolite of ALA to determine the subject’s compliance. The samples will be tested in the 
Metabolomic Core Laboratory directed by Dr. Itzhak Nissim at the Children’s Hospital of Philadelphia 
(CHOP).   Please follow the instructions below for shipping of urine samples from each site to the Scheie 
Eye Institute lab for storage before analysis.   
 
Instructions for shipping and handling of urine analysis samples:  
Samples must be frozen (in a -20 ºC freezer, shipping labels will be provided, samples must be shipped 
frozen on dry ice  via overnight carrier to:  
 
Dr. Josh Dunaief Laboratory  
University of Pennsylvania 
305B Stellar Chance 
422 Curie Blvd 
Philadelphia, PA 19104 
 
Contact Information: 
Office: 215-898-5235 
Email: jdunaief@pennmedicine.upenn.edu 
 
 
 
Urine samples will be stored in a freezer in the Dunaief Laboratory at -20 ºC or less. The temperature of 
this freezer should not drop below -20 ºC.   
The collected urine samples will be transferred on dry ice to: 
 
The Children’s Hospital of Philadelphia (CHOP) Abramson Research Center (ARC) 5TH Floor, 
Lab # 515 (A-D), 513 Metabolomic Core 
3615 Civic Center Boulevard 
Philadelphia, PA 19104-4318, USA 
 
 
Contact information:  
Ilana Nissim,   
Email: NISSIMI@email.chop.edu  
Tel: 215 590 3389 
or 
Evgueni Daikhin,   
Email: DAIKHIN@email.chop.edu 
 Tel: 215 590 1675 
ssitz@mail.med.upenn.edu 
For questions please contact: 
Itzhak Nissim, Ph.D 
Metabolomic Core Director 
Email: Nissim@email.chop.edu 
 
The samples will be transferred from the Dunaief lab to the Nissim lab in a total 2-3 batches with the first 
batch sent after 35% or more of samples have been collected. 


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5.8.1 
Return or Destruction of Investigational Product 
Completion of the study is met when a study subject completes the follow-up visits as specified by the 
subject’s allotted study Phase.  At this point, all remaining study medication will be collected.  The amount 
of remaining capsules (if any) will be counted by study team personnel and reported to the coordinating 
center.  The remaining study medication will be disposed of at the clinical site. 
6 
Study Procedures, Phase 1 
6.1 
Screening 
At the baseline screening visit, a complete medical history list will be elicited from the subject and 
extracted from available medical records.  Data to be collected include: age, gender, ethnicity, medical 
history, medications, allergies, ocular diseases, ocular surgeries, and non-ocular surgeries.  A blood 
pressure and pulse will also be checked and documented at this visit.  Based on all of this data, it will be 
confirmed that the patient meets all inclusion and exclusion criteria.   
 
After signing the informed consent document, the ALA will be dispensed to the subject.  Data will be 
directly collected onto case report forms, which will be considered the source data.   
6.2 
Study Intervention and Follow-up Phase 
15 subjects (ages 65-90) will take 600 mg of oral ALA once daily with a meal for 5 days.  This medication 
will be placed in a red-banded medication bottle (#1) with clear instructions.  Each subject will be 
monitored by the study physician, who will record a history of any side effects or tolerability issues, 
including a complete review of systems.  If well-tolerated, each subject will then take 800 mg of oral ALA 
once daily with a meal for 5 days.  This medication will be placed in a green-banded medication bottle 
(#2) with clear instructions.  Each subject will be monitored by the study physician who will record a 
history of any side effects or tolerability issues, including a complete review of systems.  If 800 mg of oral 
ALA is well-tolerated, then these subjects will be asked to take 1200 mg of oral ALA daily again for 5 days 
with a concurrent meal.  This medication will be placed in a blue-banded medication bottle (#3) with clear 
instructions.  Each of these subjects will be monitored by the study physician who will record a history of 
any side effects or tolerability issues, including a complete review of systems.  Patients will be contacted 
by the study physician every 5 days to check on tolerability issues and to determine if the patient can 
safely proceed to the next dose of ALA. 
6.3 
End of Study 
At the time of the final phone call, the subject will be asked to discontinue the ALA.  A final review of 
systems will be recorded.  If there are no urgent issues, then the subjects will be asked to maintain 
continued care with their primary care physician and ophthalmologist. 
 
The enrolled subjects will be provided an envelope (with postage cost already paid).  This envelope will 
be mailed to the subject’s home or given to him/her at the time of their enrollment visit.  Using the 
envelope, the subject will be asked to mail all of the study medication bottles to the Scheie Eye Institute.  
There will be documentation of the received medication bottles and the amount of any unused study 
medication within them.    Unused study medication will then be destroyed at the Scheie Eye Institute. 
6.4 
Unscheduled Visits 
Unscheduled visits will be handled as typical standard of care visits by the treating ophthalmologist.  Any 
exams and tests at unscheduled visits will be billed to the subject’s insurance per the usual practices of 
that ophthalmologist.  At the next scheduled study phone call, any adverse events related to the need for 
the unscheduled visits will be recorded.  If there is a significant change in exam or a new diagnosis noted 
at the time of the unscheduled visit (i.e. new choroidal neovascularization, retinal vein or artery occlusion, 
vitreous hemorrhage, etc.) the Sponsor will be notified. 


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6.5 
Subject Withdrawal 
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to intervention or 
study procedures or visit schedules, AEs, or due to other concerns.  The Investigator or the Sponsor may 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the clinical study. 
 
The enrolled subjects will be provided an envelope (with postage cost already paid).  This envelope will 
be mailed to the subject’s home or given to him/her at the time of their enrollment visit.  In the event of 
subject withdrawal, the subject will be asked to mail all of the study medication bottles to the Scheie Eye 
Institute using the provided envelope.  There will be documentation of the received medication bottles and 
the amount of any unused study medication within them.    Unused study medication will then be 
destroyed at the Scheie Eye Institute. 
7 
Study Procedures, Phase 2 
 
 
Baseline Visit 
6 months visit 
12 months visit 
18 months visit 
EVA/ETDRS 
Refraction 
X 
X 
X 
X 
Distance Corrected 
Near Visual Acuity 
(ETDRS) 
X 
X 
X 
X 
Dilated Exam 
X 
X 
X 
X 
Fundus Photos 
X 
X 
X 
X 
Autofluorescence 
X 
X 
X 
X 
OCT 
X 
X 
X 
X 
Pulse, BP, BW  
X 
X 
X 
X 
Urine Test 
 
 
X 
 
Medical Review 
X 
X 
X 
X 
Ocular Surface 
Disease Index 
X 
X 
X 
X 
7.1 
Screening (at baseline) 
At the baseline screening visit, the informed consent document is signed by the subject.  A complete 
medical history list will be elicited from the subject and extracted from available medical records.  Data to 
be collected include: age, gender, ethnicity, medical history, medications, allergies, ocular diseases, 
ocular surgeries, and non-ocular surgeries.  The subject will be given the option of completing the Ocular 
Surface Disease Index (OSDI).47  A dilated eye examination will be performed.  A blood pressure, pulse, 
and body weight will also be checked and documented at the baseline, 6 month, 12 month, and 18 month 
visit as part of a routine safety assessment.  Based on all of this data, it will be confirmed that the subject 
meets inclusion and exclusion criteria.   
 
Run-In Period: The subject will be mailed a medication bottle with the instructions to take one capsule 
once daily for 10 days and a form to record the starting and stopping dates.  The medication bottle will 
contain the placebo but the subject will not be informed that the medication bottle contains placebo or 
ALA.  After taking the capsule for 10 days, the subject will mail the medication bottle, including any 
remaining capsules, and form back to the clinical site using a postage-paid envelope provided at the time 
of the baseline screening visit.  Those subjects that have demonstrated compliance by taking ≥ 80% of 
the provided capsules and mailing the medication bottle within 40 days of the screening visit will now 
have met all inclusion and exclusion criteria.  The subject will then be randomized and study medication 
will be mailed to the subject by the Penn IDS (see section 3.1.1 Allocation to Intervention Group).  If an 
investigator did not receive a mailed medication bottle but believes the subject followed instructions and 
the medication bottle was lost in the mail, then that subject may get screened again for the study. In this 
instance, the subject will have to repeat the screening visit and the run-in period.   


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Subjects that participated in the Run-In but did not demonstrate an ability to take ≥ 80% of the 
capsules will be notified within two weeks that they cannot continue in the study and that they received 
placebo capsules during the Run-In.  Subjects that continue to randomization will be informed after the 
study is completed that they received placebo capsules for the Run-In and whether they were randomized 
to placebo or ALA. 
After signing the informed consent document and within 45 days before study treatment 
administration, all screening procedures, including OCT, FAF, fundus photography, BCVA, and the 10 
day run-in phase must be performed. 
 
Data will be directly collected onto case report forms, which will be considered the source data.  There is 
no restriction on the number of subjects to be enrolled by a particular site. 
7.2 
Study Intervention Phase 
7.2.1 
6 Month, 12 Month, and 18 Month Visits 
Fundus photographs, OCT and FAF images will all be collected at enrollment (baseline), 6, 12, and 18 
month visits only.  Both eyes will be imaged.  These will be collected by ophthalmic photographers 
certified for clinical trial imaging.  The Scheie Eye Institute Reading Center will provide detailed grading of 
FAFs, color fundus photographs, and OCTs for determination of study outcomes. Color fundus 
photographs, FAF and OCT images will be submitted to the Scheie Image Reading Center at enrollment 
(baseline), 6, 12, and 18 months.  At each of these visits, the subject will be given the option of 
completing the Ocular Surface Disease Index (OSDI).47 
 
Study visits must fit the recommended time frame as much as possible.  All follow-up study visits must at 
least be within 3 months (+/- 3 months) of the recommended date of the study visit. 
7.2.2 
Ophthalmic Procedures 
Best-Corrected Visual Acuity (BCVA)/Refraction (Distance Measurement) 
BCVA measurement should be performed on both eyes using the Electronic ETDRS (E-ETDRS) Visual 
Acuity Testing Protocol.48 These will be performed by a study certified examiner.  Traditional ETDRS 
charts may be used if the E-ETDRS chart is not available. BCVA and refraction will be done via protocol 
by a study certified examiner. 
 
Best Distance-Corrected Near Visual Acuity (Near Measurement) 
In order to evaluate the potential of ALA to improve presbyopia, a distance-corrected near visual acuity 
will be measured with a near vision ETDRS style chart.  Using the distance correction (based on 
refraction), the near visual acuity will be measured for each eye with the near vision chart held at 16 
inches (40 cm).  This should be done regardless of the eye being phakic or pseudophakic. 
    
Ophthalmoscopic Examination 
Intraocular pressures (IOP) will be measured at each study visit.  Pupils will be dilated with two sets each 
of 2.5% Neo-Synephrine and 1% Mydriacyl, or equivalent.  A complete anterior and posterior segment slit 
lamp exam will be performed by the study certified ophthalmologist including a lens assessment.  This will 
be done with both a slit lamp and dilated ophthalmoscopy.  
7.2.3 
Photography   
Keratometry 
Automated or manual keratometry measurements will be made at the baseline screening visit.  The 
corneal radius of curvature for each eye of each subject will be entered into the Heidelberg Spectralis 
machine.  From the keratometry measurements, the average keratometry reading (K) for each eye is 
calculated [(K1 + K2)/2].  Then, the corneal radius of curvature (mm) can be calculated using the formula 


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and the average K measurement: r = 337.5/K.  Keratometry measurements will be re-measured and 
updated within the Spectralis if a subject has had any ophthalmic surgery or history of corneal suture 
removal since the last study visit.  
 
Fundus Photography 
A photographic field between 30 and 40 degrees is required. Stereo color photographs of standard fields 
1, 2 and modified 3 will be obtained. Photographs from baseline, months 6, 12, and 18 will be read by the 
Scheie Image Reading Center for an independent assessment.  Fundus photos should be acquired 
before fundus autofluorescence images are acquired. 
 
 
 
 
 
Spectral Domain Optical Coherence Tomography (OCT) 
All OCT images from enrollment (baseline) and months 6, 12, and 18 months will be read by the Scheie 
Image Reading Center for additional outcomes.  These images will be acquired with the Heidelberg 
Spectralis (Carlsbad, CA).   
 
 
 
 
Fundus Autofluorescence (FAF) 
The areas of geographic atrophy will be evaluated from FAF images taken with the Heidelberg Spectralis 
(Carlsbad, CA) using the Blue Peak Blue Laser Autofluorescence mode.  The FAF images should be 
taken after the color fundus photos and OCT imaging.  
 
All FAF images from enrollment (baseline) and months 6, 12, and 18 will be read by the Scheie Image 
Reading Center.  
 
 
 
 
 
Geographic Atrophy 
Geographic atrophy (GA) will be assessed from the color fundus photographs and FAF images. On color 
photographs, GA is observed as one of more sharply defined, more or less circular patches of absence of 
the RPE, typically with exposure of underlying large choroidal blood vessels. At a minimum, at least two 
of the aforementioned  characteristics (sharp edges, more or less circular shape and visibility of 
underlying choroidal vessels) with a minimum size of ≥ 175 microns in longest linear dimension are 
required for a lesion to be categorized as GA.49 While a minimum size of ≥ 175 microns in longest linear 
dimension is required for a lesion to be categorized as GA for grading once an eye is in the study, the GA 
size requirements for study eye inclusion stated in section 4.2.1 (Inclusion Criteria) still stand. 
 
Once geographic atrophy has been identified on the color photographs and FAF by the grader, the grader 
will use the Region Finder semi-automated software of the Heidelberg Spectralis to measure the areas of 
geographic atrophy at the macula of the study eye.  While the color photographs are used to categorize a 
lesion as GA, the primary measure of GA area will be taken from the FAF images.  The color photos can 
also be used to assist in the interpretation of the FAF images.  GA appears as well defined 
hypoautofluorescent patches in FAF images.  All areas of GA at the macula of the study eye will be 
measured. 
 


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7.3 
Follow Up Phase of the Study  
7.3.1 
End of Study Visit 
Two weeks following the 18 months visit, the subject will be contacted to determine if there have been 
any adverse events following the completion of the study and to ensure that the subject has a follow-up 
eye examination (outside of the study) with an ophthalmologist.  
7.4 
Unscheduled Visits 
Unscheduled visits will be handled as typical standard of care visits by the treating ophthalmologist.  Any 
exams and tests at unscheduled visits will be billed to the subject’s insurance per the usual practices of 
that ophthalmologist.  At the next scheduled study visit, any adverse events related to the need for the 
unscheduled visits will be recorded.  If there is a significant change in exam or a new diagnosis noted at 
the time of the unscheduled visit (i.e. new choroidal neovascularization, retinal vein or artery occlusion, 
vitreous hemorrhage, etc.), the Sponsor will be notified   
7.5 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to intervention or 
study procedures or visit schedules, AEs, or due to other concerns.  The Investigator or the Sponsor may 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the clinical study. 
Subjects who wish to withdraw early will be asked to have one final visit to collect investigational product 
and to follow up regarding adverse events before formal withdrawal of consent.  
7.5.1 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects who wish to withdraw consent to participate in the study will be asked to have one final visit to 
collect the investigational product. During this visit they will be asked for permission to have the study 
team look into their survival status via publically available means.   
7.6 
Early Termination Visits   
If a subject terminates the study early, a follow-up visit will be scheduled to assess subject safety and 
collect unused drug.  The reason for early termination will be recorded on the case report form.  AEs and 
SAEs will be recorded.  The Investigator will ensure that the subject has a follow-up standard-of-care visit 
scheduled with an ophthalmologist for their continued eye care.  
8 
Statistical Plan 
8.1 
Primary Endpoint 
For Phase 1 of this protocol, the primary endpoint is the percent of adverse events that develop in the 
study group at each studied dose of ALA.   
 
For Phase 2 of this protocol, the primary endpoint is the mean rate of change of the area of GA in the 
study eye from baseline to 18 months (from the time of randomization) as evaluated by fundus 
autofluorescence.  
8.2 
Secondary Endpoints 
 
A secondary endpoint for Phase I is the percent of subjects that think they could tolerate each studied 
dose of ALA for a duration of 18 months.  If 4 or more (out of 15) subjects state that they could not 
imagine taking a particular dose for 18 months, then that dose will not be used in the Phase 2 Trial. 
 
The secondary endpoints for Phase 2 include: 
• 
The change in best corrected visual acuity (BCVA) from baseline to 18 months from the time of 
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• 
The proportion of subjects with three lines or more worsening in BCVA 
• 
Absolute and relative change in area of GA as measured on FAF 
• 
Rate of change over time (18 months from the time of randomization) in area of GA in the study 
eye as measured on color fundus photos. 
• 
Absolute and relative change in area of GA as measured on color fundus photos 
• 
Change in drusen volume based on OCT and change in the number of drusen seen on color 
fundus photos (exploratory endpoint) 
• 
Change in score on the Ocular Surface Disease Index (OSDI)47 (exploratory endpoint) 
• 
Change in best distance corrected near visual acuity (exploratory endpoint) 
 
• 
Ocular and systemic safety outcomes for these doses of ALA 
8.3 
Sample Size and Power Determination 
Phase 1: It is expected that a sample size of 15 subjects will adequately determine if there is a significant 
intolerance of the tested doses of ALA in the elderly population.   
 
Phase 2:  In addition to assessing the safety profile of ALA and the feasibility of study procedures, one of 
the major goals of the proposed study is to determine if additional, larger scale assessments of efficacy 
are warranted.  For pilot studies, it is appropriate to use a confidence interval approach to evaluate 
outcomes and pre-specify a clinically important threshold to determine if further investigation is justified.50-
51 If we decide to halt investigation if the observed growth rate in the actively treated group is greater than 
in the placebo group, then it is reasonable to use a one-sided confidence interval.  With 50 total 
subjects, we can be 90% confident (one-sided) that the “effect size” of ALA in reducing the GA growth 
rate  is 0.4 or less.  This number assumes that 15% of subjects dropout.  An example of an effect size of 
0.4 would be a growth rate of 0.40 mm in the placebo group and a growth rate of 0.32 (20% reduction) in 
the ALA group when the standard deviation of the annual growth rate is 0.20 mm.52 Interventions with 
less efficacy than this may not be worth pursuing. 
 
Based on current data, it is possible that approximately 25% of subjects randomized to the ALA arm may 
not tolerate 1200 mg of ALA.  Instead of 1200 mg once daily of ALA, some of these patients may elect to 
take 600 mg twice daily or 600 mg once daily.  An intention to treat analysis will be performed on all 
subjects randomized to 1200 mg ALA in comparison to the placebo group.  Subgroup analyses will be 
performed on those subjects remaining at 1200 mg and subjects at a lower dose of ALA.  After 25 
subjects have enrolled in the study, we will perform interim analyses of the numbers of subjects in these 
subgroups without evaluating any outcomes data.  Depending on the status of enrollment, drop-out rates, 
and the size of the subgroup consistently taking 1200 mg subgroup, the study sample size may be 
increased at this time so that the 1200 mg subgroup has a number equal to or nearly equal to 22 subjects 
available for analyses. 
8.4 
Statistical Methods 
Phase 1: Percentages of adverse events will be calculated. 
 
Phase 2: As a preliminary analysis, the mean change in the total area of GA within study eyes over 18 
months (from the time of randomization) will be compared between eyes receiving the active ALA dose 
and placebo supplementation; a square root transformation will be applied to the area measurements to 
mitigate the dependence of growth rate on initial size.53-54 Also, mean change in visual acuity over 18 
months, the proportion with a decrease of 15 letters (3 lines) of visual acuity, and the proportions with 
serious adverse events will also be compared. Variants of the independent t-test and chi-square tests of 
proportions that account for the correlation between eyes of subjects who have two study eyes will be 
used to make comparisons.  
 
The main analysis for comparing treatment groups will compare the rates of change in total area of GA 
using a mixed effects linear model.  Use of this model allows including all patients in the analysis and  
requires less stringent assumptions than a complete cases analysis regarding the association of 


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missingness with the outcome variable and does not introduce bias into the estimation of the slope 
parameter as a “last observation carried forward (LOCF)” approach does when area changes with time.  
Both subject and eye will be considered random effects.  A sensitivity analysis using multiple imputation 
for missing values will be used for the analysis of mean change between baseline and 18 months and for 
the mixed effects linear model of total area.  
 
Similar analytic methods using mixed effects models will be used for the other outcome measures. 
 
8.4.1 
Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive statistics (including 
mean and standard deviation for continuous variables such as age and standard percentages for 
categorical variables such as gender). 
8.4.2 
Safety Analysis  
Phase 1: All subjects entered into the study will have detailed information collected on adverse events for 
the overall study safety analysis.  Symptoms reported will be graded as mild, moderate, or severe in 
nature.   
 
Phase 2: All subjects entered into the study and randomized at the baseline visit will have detailed 
information collected on adverse events for the overall study safety analysis 
9 
Safety and Adverse Events 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Abnormal results of diagnostic procedures are considered to be 
adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with new clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
9.1.2 
Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that results 
in any of the following outcomes:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. Example, loss of 6 lines of visual acuity on the ETDRS chart 
• A congenital anomaly or birth defect 
9.2 
Recording of Adverse Events 
At each contact with a subject, an Investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 


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form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though they should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each event 
will be followed until resolution, stabilization, or until it has been determined that the study intervention or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
9.3 
Relationship of AE to Study  
Principal Investigators will determine the relationship of each adverse event to the study procedures or 
study drug.  The relationship will be classified as any of the following: 
• 
Definitely related 
• 
Probably related 
• 
Possibly related 
• 
Unlikely or unrelated 
9.4 
Reporting of Adverse Events and Unanticipated Problems 
The Data Coordinating Center receives notification of Serious Adverse Events (SAEs) via a specific form 
completed by the investigator and submitted within 24 hours.  An assessment of all incoming SAEs is 
made to determine whether the event needs to be reported to the FDA.  The Coordinating Center sends 
an electronic copy of each Serious Adverse Event Report Form, as well as baseline medical history, 
medications reported at baseline and follow-up, and other supporting documentation as needed  to the 
Sponsor within 24 hours.  The Coordinating Center also sends all AEs to the Sponsor.  All SAEs are 
reviewed by the Sponsor as required by regulation.  
9.4.1 
Investigator reporting: notifying the study sponsor 
Any serious adverse event will be reported to the study Sponsor within 24 hours of the event.  To report 
such events, a Serious Adverse Event (SAE) form will be completed by the Investigator and sent to the 
Sponsor, via the Data Coordinating Center, within 24 hours.  The Investigator will keep a copy of each 
SAE form on file at the study site.  Report serious adverse events to: 
 
Clinical Trials Coordinating Center 
Center for Preventive Ophthalmology and Biostatistics 
3535 Market Street Suite 700 
Philadelphia, PA.  19104-3309 
215-615-1505 
215-615-1531 (fax) 
 
Within the following 24 hours, the Investigator will provide further information on the serious adverse 
event in the form of a written narrative.  This should include a copy of the completed Serious Adverse 
Event form and any other information that will assist the understanding of the event.  Significant new 
information for ongoing serious adverse events should be provided promptly to the study sponsor. 
9.4.2 
Investigator Reporting: Notifying the local IRB  
Each Principal Investigator will follow his/her IRB’s reporting requirements.  The University of 
Pennsylvania Investigator will report AEs at least annually to the University of Pennsylvania IRB.  
Investigators will promptly report any unexpected and related AEs to the IRB, including suspected 
adverse reactions. Other prompt reporting requirements will include: changes, violation, or deviation to 
the protocol without prior IRB and Sponsor review to eliminate immediate hazard to a study subject, 
complaint of a subject when the complaint indicates unexpected risks or the complaint cannot be resolved 
by the research team, breach of confidentiality, and premature completion of the study. For the UPenn 
site, an unanticipated problem that includes risk to other subjects must be reported to the IRB within 10 


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working days.  If an SAE involves death and other subjects are at risk, the UPenn Investigator must 
submit a report to the UPenn IRB within 3 days.  
9.4.3 
Sponsor reporting: Notifying the FDA   
This protocol is being conducted under an FDA IND. The Sponsor will report all adverse events to the 
FDA in the Annual Report and all unanticipated, related and serious adverse events to the FDA per 
regulation. 
9.4.4 
Sponsor reporting: Notifying participating investigators  
In addition to reporting to the FDA, the Sponsor shares SAEs with participating Investigators.  
9.5 
Unblinding Procedures 
The unblinding of the research team will only be performed if there is an emergency or time-sensitive 
event for which unblinding would help manage the event.  In this case, the Coordinating Center will 
provide documentation of whether the subject received placebo or ALA within 24 hours of the request to 
the Coordinating Center.  If possible, the study subject will remain blinded.  However, if deemed 
necessary and appropriate by both the site investigator and the Sponsor, the subject can be provided 
documentation of whether he/she received placebo or ALA within 24 hours of this request. 
9.6 
Monitoring 
9.6.1 
Data and Safety Monitoring Plan 
 
Phase 1: After a subject has taken a study dose for 5 days, a study physician will contact the subject and 
do a complete review of systems to document any adverse events.  Symptoms reported will be graded as 
mild, moderate, or severe and this data will be recorded.  If a subject does not feel comfortable 
proceeding to the next higher dose, then that subject will stop participation in the study at that point.  If 
after review of the adverse event(s) (and their quality) that a subject experienced at a particular dose, 
then the study physician also may stop the subject's participation in the study if their is any safety 
concern.  If 4 or more (out of 15) subjects state that they could not imagine taking a particular dose for 18 
months, then that dose will not be used in the Phase 2 Trial.  Adverse events, the severity of adverse 
events, and the percent of subjects that think they could take a particular dose of ALA for 18 months will 
be reported to the University of Pennsylvania IRB before proceeding with Phase 2.  A Data and Safety 
Monitor (DSM) will also independently review all adverse events as outlined in the DSM Charter. 
 
Phase 2: While each Principal Investigator has safety oversight of the study conducted at their site, there 
will also be a Data and Safety Monitor (DSM).  Review of known risks from ALA has suggested that ALA 
is relatively safe and well tolerated (see Section 1.2.2).A Drug Safety Monitoring Plan has been 
developed based on risk.  
10 Study Administration, Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 


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permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
10.2 Data Collection and Management  
Phase 1: For the ALA tolerability test, data will be entered onto case report forms by the Research 
Coordinator or Physician Investigator.  There will be no electronic records for the tolerability test. 
 
Phase 2: Data will be directly collected onto case report forms in real time by the study-certified clinic 
coordinator or examining ophthalmologist.  The case report forms will be considered the source data.  
Data will be entered by study certified clinic coordinators into a central database using the Research 
Electronic Data Capture (REDCap) system.55 REDCap is a secure, web-based application designed to 
support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) 
audit trails for tracking data manipulation and export procedures; 3) automated export procedures for 
seamless data downloads to common statistical packages; and 4) procedures for importing data from 
external sources. 
 
Clinical examination data are recorded directly onto the CRFs during the clinic visit and are considered 
the source documentation.  Each item entered by the clinic coordinator is checked for valid codes, 
legitimate ranges, legal dates, etc. and invalid entries are flagged.  Validation of data occurs during and 
after the data entry session.  Electronic logs of the completion status of each form and assessment are 
tracked by the Coordinating Center to determine the status of data collection for each registered 
participant.  Form revisions and additions are accommodated by having data management staff at the 
Sponsor modify or create the appropriate data definition.   
 
Data that have been entered into REDCap are subject to additional consistency checking involving more 
complex logic than implemented during data entry checking.  Often these post-entry checks involve 
several different forms and visits. The Center for Preventive Ophthalmology and Biostatistics (CPOB) 
biostatitician will develop the logic for these checks and the comments to be associated with the resulting 
data queries.  The Clinic Coordinator reviews edit messages and the corresponding data forms. If 
necessary, the Clinic Coordinator corrects the paper form, initials and dates the form, and updates the 
online database.  The updated data records are again subjected to the entire data checking system.  
When extraordinary circumstances arise in which the query may never be able to be resolved to meet the 
requirements of the edit logic, the biostatistician may, with the approval of the Director, flag specific items 
on specific forms as exempt from further edit.  The REDCap system generates an entry into a log of 
changes after every record correction so that a fully verifiable audit trail is created.  
 
Records Retention  
REDCap databases are backed up on a regularly scheduled basis. The backup data files are kept in 
a secured environment and are available for recovery. Data files that reside on the CPOB file server 
are backed up nightly.  In addition, all CPOB personnel are required to keep copies of key documents 
such as forms, correspondence, and reports on the file server, which is on an automatic backup 
schedule.  Files of the data system as of the time of each data freeze and for each publication are also 
archived. 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
Phase 1: After a subject has taken a study dose for 5 days, a study physician will contact the subject and 
do a complete review of systems to document any adverse events.  Symptoms reported will be graded as 
mild, moderate, or severe and this data will be recorded.  If a subject does not feel comfortable 
proceeding to the next higher dose, then that subject will stop participation in the study at that point.  If 
after review of the adverse event(s) (and their quality) that a subject experienced at a particular dose, 
then the study physician also may stop the subject's participation in the study if there is any safety 
concern.  If 4 or more (out of 15) subjects state that they could not imagine taking a particular dose for 18 
months, then that dose will not be used in the Phase 2 Trial. 


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Phase 2: Both the Sponsor and the Principal Investigators ensure safety and compliance.  There will be a 
Data and Safety Monitor (DSM).  A Data Safety Monitoring Plan has been developed based on risk.  At 
this time there is no Data Safety Monitoring Board as this is low risk study. 
 
The Investigators will allocate adequate time for monitoring with regards to accurate and confidential 
record keeping, appropriate reporting of adverse events by all sites, The investigators will ensure that the 
monitor or other compliance or quality assurance reviewer is given access to all the above noted study-
related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
adequate space to conduct the monitoring visit.  
11.2 Auditing and Inspecting 
The Investigator will permit study-related monitoring, audits, and inspections by the IRB, the Sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The Investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
12 Ethical Considerations 
This study is to be conducted in accordance with applicable US regulations, international standards of 
Good Clinical Practice, and applicable institutional research policies and procedures. 
 
The protocol and any amendments will be submitted by each PI to his/her Institutional Review Board 
(IRB).  The decision of the IRB concerning the conduct of the study will be made in writing to the 
Investigator and a copy of each decision will be provided to the Sponsor before changes are implemented 
in the study.  
12.1 Risks 
Risks of Eye Examination Procedures and Tests 
There is a very rare risk of an allergic response to the topical medications used to anesthetize the eye (for 
eye pressure measurement) or dilate the pupil.  This occurs in less than 1% of eyes. Dilating drops rarely 
could cause an acute angle closure glaucoma attack (less than 1 in 1000).56 
 
There are no known risks associated with OSDI survey, OCT, autofluorescence, or fundus photographs.  
 
Risks of study investigational medicines: Alpha Lipoic Acid (ALA) and placebo 
ALA and placebo study drug risk is low.  ALA is available over-the-counter and is approved in Germany 
for the treatment of diabetic peripheral neuropathy.5-8 The safety of ALA has been extensively evaluated. 
ALA is metabolized by the liver and is known to be safe in both hepatic and renal disease.  The primary 
side effects from oral ALA are gastrointestinal and occur at doses of 1200 mg or higher.  These 
gastrointestinal side effects predominantly involve an upset stomach, gastric reflux, nausea, and can be 
minimized if ALA is taken in divided doses or with a meal, although concurrent food ingestion may 
partially reduce the bioavailability.35-37 There can also be a malodorous urine and headache.  Rare 
complications that may be related to ALA included one patient who developed an allergic rash, fever, and 
mild thrombocytopenia that resolved after stopping ALA and reports of a rare occurrence of insulin 
autoimmune syndrome.38-39 Most of these published studies on the safety and tolerability of ALA at doses 
of 1200 mg or higher involve adults that are not elderly. 
12.2 Benefits 
A key benefit is believed to be a reduction in GA enlargement in patients with AMD. Our central 
hypothesis, based on the existing literature and our own preliminary data, is that oral lipoic acid 
supplementation reduces the rate of enlargement of GA in AMD patients.  Subjects may not directly 


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benefit from participation in this study.  Nevertheless, subjects who participate in this study will receive 
medical care and monitoring.  Furthermore, information from this study may help subjects and others with 
geographic atrophy secondary to AMD receive better care in the future. 
 
Depending on funding availability, some subjects may be provided financial assistance with 
transportation costs at the discretion of the principal investigator.  
 
Depending on funding availability, subjects may be provided a $40 gift card at each of the follow-
up study visits and a $100 gift card at the final study visit. 
 
For the tolerability test (Phase 1), it is not expected that subjects will receive any direct benefit.  However, 
information from the tolerability test will help to confirm the dose chosen for the Randomized, double-blind 
placebo controlled trial (Phase 2).  
12.3 Risk Benefit Assessment 
The risks of participating in the study are outweighed by the potential benefits of participating in the study 
as there is little risk of serious adverse events occurring and the potential benefit is a reduction of vision 
loss for participants.  
 
For the tolerability test, there is unlikely to be any direct benefit to the subjects, but the risk of serious 
adverse events is considered low.   
 
12.4 Informed Consent Process / HIPAA Authorization  
Written informed consent must be obtained before any of the baseline procedures are performed. An 
explanation of the trial and discussion of the possible risks and discomforts will be given by the 
Investigators and/or study staff.  Only those patients who fulfill all eligibility criteria will be entered into the 
trial. Informed consent will take place as an ongoing dialogue between the Investigator/study staff and 
subjects during the entire duration of their participation.  Patients that are unable to read the study 
consent and/or do not have the opportunity to take home and review with family/friends or do not present 
in the clinic with a family member will have the consent read to them by a study team member in the 
presence of a non-partial person that will verify the consent has been read in full to the patient. Phase 1 
and Phase 2 will have separate ICFs.   
12.4.1.1 Waiver of Consent (In some cases for screening/portions of that study that qualify as 
minimal risk, a waiver of documentation of consent may be permissible per IRB SOPs) 
No waiver requested. 
12.4.1.2 Waiver of Written Documentation of Consent 
No waiver requested. 
12.4.1.3 Waiver of Written Documentation of Consent where the research is subject to FDA 
regulations 
No waiver requested. 
12.4.1.4 Waiver of HIPAA Authorization 
No waiver requested.  
13 Study Finances 
13.1 Funding Source 
This study is financed primarily through a grant from the Bright Focus Foundation.  There is additional 
support provided by the Pennsylvania Lions Sight Conservation and Eye Research Foundation and the 
Scheie Eye Institute (University of Pennsylvania).  


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13.2 Conflict of Interest 
All Investigators will follow their University policies on conflict of interest.  There are no subject payments 
or stipends. 
14 Publication Plan 
The primary responsibility for publication is held by the University of Pennsylvania study chair.   
Investigators that have contributed meaningfully to the project or have recruited a significant number of 
subjects will be involved in the manuscript preparation.  Pure Encapsulations, Inc. (a subsidiary of Atrium 
Innovations Inc.) will be given the opportunity to review and comment on manuscripts prior to publication.  
Pure Encapsulations, Inc., may, at its sole discretion, request to be disclosed as the supplier of ALA in the 
“Materials and Methods” or some similar format when data are presented or published.  Pure 
Encapsulations, Inc. may request that their company name or the ALA product name is disclosed in 
abstracts.  
15 References 
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16 Appendices 
• Appendix 1, Sample Consent Form (Phase 2) 
• Appendix 2, Sample Consent Form (Phase 1) 
17 Additional Information  
17.1 Expedited FDA Reporting Requirements  
The Sponsor is required to report certain study events in an expedited fashion to the FDA.  These written 
notifications of adverse events are referred to as IND/ IDE safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated 
type of event: 
 


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This material is the property of the University of Pennsylvania.   
Within 7 calendar days 
Any study event that is all: 
• 
associated with the use of the study drug, and 
• 
unexpected, and  
• 
fatal or life-threatening, 
 
Within 15 calendar days 
Any study event that is: 
• 
associated with the use of the study drug, and 
• 
unexpected, and 
• 
serious, but not fatal or life-threatening 
• 
A previous adverse event that was not initially deemed reportable but is later found to fit 
the criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
• 
Any finding from non-clinical studies that suggest a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Sponsor will assess all SAEs and perform an aggregate analysis on all AEs as per regulation. 
 
Reporting Process 
Applicable events will be reported to the FDA using Form FDA3500A. 
17.2 Source Documents (definition) 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
17.3 Case Report Forms (CRFs) (definition and guidelines) 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it.