A Multi-site Interventional Pilot Study Using Transorbital Alternating Current Stimulation for People With Glaucoma
Phase: NA
Conditions: Glaucoma
Sponsor: NYU Langone Health

 
 
Official Title: 
A Multi-site Interventional Pilot Study Using Transorbital Alternating 
Current Stimulation for People With Glaucoma   
NCT Number: 
NCT03188042 
Study Number: 
16-02005 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
April 19, 2023 
 
 

rtACS for people with glaucoma 
 
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This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
 
 
 
 
 
 
 
 
A MULTI-SITE INTERVENTIONAL PILOT STUDY USING 
TRANSORBITAL ALTERNATING CURRENT STIMULATION 
FOR PEOPLE WITH GLAUCOMA 
 
 
 
 
 
 
 
Principal Investigator 
Joseph F. Panarelli, M.D.Department of Ophthalmology 
222 East 41st Street 
New York, NY  10017 
Phone: 929.455.5030 
Joseph.panarelli@nyulangone.org  
Funding Sponsor: 
NYU Langone Health 
Department of Ophthalmology 
222 East 41st Street 
New York, NY  10017 
Phone: 212.263.2573 
 
Study Intervention: 
Repetitive transorbital alternating current stimulation to treat 
visual impairment in people with glaucoma  
IRB Number: 
s16-02005 
 
Initial version: 03.21.2017 
Amended: 
05.24.2017 
Amended: 
11.21.2017 
Amended: 
01.17.2018 
Amended: 
05.10.2018 
Amended: 
07.11.2018 
Amended: 
11.19.2018 
Amended: 
04.09.2019 
Amended: 
02.19.2020 
Amended: 
05.21.2020 
Amended:  
08.05.2020 
Amended: 
04.16.2021 
Amended: 
08.05.2021 
Amended: 
03.15.2023 
Amended:  
04.06.2023 
 
 
Clinical Research Protocol 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION .................................................................................................................................. 6 
1.1 
BACKGROUND ................................................................................................................................ 6 
1.1.1 
Glaucoma ................................................................................................................................ 6 
1.1.2 
Brain Electrical Connectivity .................................................................................................... 9 
1.1.3 
Alternating Current Stimulation ............................................................................................. 10 
1.1.4 
Clinical Data to Date: Repetitive, Transorbital Alternating Current Stimulation .................... 12 
1.2 
INVESTIGATIONAL DEVICE ............................................................................................................. 13 
1.3 
RESEARCH RISKS & BENEFITS ...................................................................................................... 13 
1.3.1 
Risk of Investigational Device ............................................................................................... 13 
1.3.2 
Other Risks of Study Participation......................................................................................... 14 
1.3.3 
Potential Benefits .................................................................................................................. 14 
2 
STUDY OBJECTIVES ....................................................................................................................... 14 
2.1 
PRIMARY OBJECTIVES .................................................................................................................. 15 
2.1.1 
Objective: Assessment of Ophthalmic Structure and Function ............................................. 15 
2.1.2 
Objective: Assessment of Functional Ability and QoL........................................................... 15 
2.2 
SECONDARY OBJECTIVE ............................................................................................................... 15 
2.2.1 
Objective: Assessment of Feasibility and Implementation of Procedures ............................ 15 
3 
STUDY DESIGN ................................................................................................................................. 15 
3.1 
GENERAL DESIGN ........................................................................................................................ 15 
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................ 17 
3.2.1 
Assessment of Ophthalmic Structure and Function .............................................................. 17 
3.2.2 
Assessment of Functional Ability and QoL ............................................................................ 19 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................... 20 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 21 
4.1 
INCLUSION CRITERIA .................................................................................................................... 21 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 21 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 22 
4.3.1 
Recruitment [NYU Langone Eye Center and New York Eye and Ear Infirmary of Mount Sinai]
 
22 
4.3.2 
Recruitment [Other] ............................................................................................................... 23 
4.3.3 
Recruitment: Flyer ................................................................................................................. 24 
4.3.4 
Screening .............................................................................................................................. 24 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 26 
4.4.1 
When and How to Withdraw Subjects ................................................................................... 26 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 26 
5 
STUDY DEVICE ................................................................................................................................. 26 
5.1 
DESCRIPTION ............................................................................................................................... 26 
5.2 
TREATMENT REGIMEN .................................................................................................................. 26 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 27 
5.4 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 27 
5.5 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 27 
5.6 
PACKAGING ................................................................................................................................. 27 
5.7 
MASKING OF STUDY ..................................................................................................................... 27 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 27 

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5.8.1 
Receipt of Study Device ........................................................................................................ 27 
5.8.2 
Storage .................................................................................................................................. 28 
6 
STUDY PROCEDURES ..................................................................................................................... 28 
6.1 
VISIT: BASELINE ........................................................................................................................... 28 
6.1.1 
Process of Consent ............................................................................................................... 28 
6.1.2 
Assessments ......................................................................................................................... 28 
6.2 
VISIT: DAILY INTERVENTION SESSIONS 1-10................................................................................... 29 
6.3 
VISIT: POST-INTERVENTION .......................................................................................................... 29 
6.4 
VISIT: FOLLOW-UP ........................................................................................................................ 30 
7 
STATISTICAL PLAN ......................................................................................................................... 30 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 30 
7.2 
STATISTICAL METHODS ................................................................................................................ 30 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 31 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 31 
8.1 
DEFINITIONS ................................................................................................................................ 31 
8.2 
RECORDING OF ADVERSE DEVICE EFFECTS .................................................................................. 33 
8.3 
REPORTING OF ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS .................................. 33 
8.3.1 
Investigator Reporting: Notifying the IRB .............................................................................. 33 
8.4 
RECORDING AND REPORTING OF ANTICIPATED EFFECTS................................................................ 34 
8.5 
UNMASKING PROCEDURES ........................................................................................................... 35 
8.6 
MEDICAL MONITORING ................................................................................................................. 36 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 36 
9.1 
CONFIDENTIALITY ......................................................................................................................... 36 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 36 
9.3 
CASE REPORT FORMS.................................................................................................................. 37 
9.4 
RECORDS RETENTION .................................................................................................................. 37 
9.5 
ELECTRONIC MEDICAL RECORD AND RELEASE OF STUDY-RELATED INFORMATION .......................... 37 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 37 
10.1 
STUDY DATA AND SAFETY MONITORING PLAN ............................................................................... 37 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 38 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 38 
12 
STUDY FINANCES ............................................................................................................................ 38 
12.1 
FUNDING SOURCE ........................................................................................................................ 38 
12.2 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 38 
13 
PUBLICATION PLAN ........................................................................................................................ 38 
14 
REFERENCES ................................................................................................................................... 39 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
ACS = alternating current stimulation 
BOLD = blood-oxygen-level dependent  
CS = contrast sensitivity 
D-KEFS = Delis-Kaplan Executive Function System 
EEG = electroencephalography 
EST = electrical stimulation therapy 
ETDRS = Early Treatment Diabetic Retinopathy Study 
FDA = Food and Drug Administration 
fMRI = functional magnetic resonance imaging 
GAS = Geriatric Anxiety Scale 
HIPAA = Health Insurance Portability and Accountability Act 
HRQoL = health-related quality of life 
IOP = intraocular pressure 
IRB = Institutional Review Board 
LIFE-H = Assessment of Life Habits 
logMAR = logarithm minimal angle of resolution 
M = magnocellular  
MD = mean deviation 
MNRead = Minnesota Low Vision Reading Test 
MRI = magnetic resonance imaging 
NYULMC = NYU Langone Medical Center 
OCT = optical coherence tomography 
OCT-A = OCT angiography 
ON = optic nerve 
PERG = pattern electroretinography 
PI = principal investigator 
PSQI = Pittsburgh Sleep Quality Index 
QoL = quality of life 
RGC = retinal ganglion cell 
RNFL = retinal nerve fiber layer 
rtACS = repetitive transorbital alternating current stimulation 
SF-36 = 36-Item Short Form Survey 
TICS-m = Telephone Interview for Cognitive Status-modified 
VA = visual acuity 
VEP = visual evoked potential 
VF = visual field 
VFQ-39 = 39-item Visual Functioning Questionnaire 
VRQoL = vision-related quality of life 
WAIS-IV = Wechsler Adult Intelligence Scale-Fourth Edition 
 
 
 

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Study Summary 
Title 
A Multi-site Interventional Pilot Study Using Transorbital Alternating 
Current Stimulation for People with Glaucoma 
Short Title 
rtACS for people with glaucoma  
IRB Number 
s16-02005 
Methodology 
Prospective, randomized controlled (active versus sham repetitive alternating 
current stimulation [rtACS]) double-masked pilot study. 
Participants and interventionist masked to group. 
Study Duration 
February 2017 to December 2021 
Study Center(s) 
NYU Langone Eye Center 
New York Eye and Ear Infirmary of Mount Sinai  
Objectives 
(1) Determine an effect of rtACS on ophthalmic structure and function (from 
eye to visual brain) 
(2) Assess the methodology of procedures for assessment of people’s 
functional ability and quality of life to determine an effect of rtACS 
(3) Assess the feasibility and implementation of the pilot study protocol for a 
larger multi-site, randomized controlled trial 
Number of Subjects 
n = 16 
Diagnosis and Main 
Inclusion Criteria 
Adults with moderate to severe stage glaucoma, absent ocular and certain 
systemic comorbidities 
Study Intervention 
rtACS to treat visual impairment in people with glaucoma  
Reference therapy 
Sham stimulation 
Statistical 
Methodology 
Descriptive statistics, multivariate analyses, and estimates of effect and 
variance for between and within groups (active versus sham rtACS) analyses 
 

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1 Introduction 
This document is a clinical research protocol for a human clinical research study. This study will be 
conducted in compliance with the written protocol and in accordance with U.S. federal research 
regulations, Good Clinical Practices standards, and NYU Langone Medical Center (NYULMC) institutional 
research policies and procedures. 
 
The proposed pilot study will test the preliminary efficacy and feasibility of an intervention protocol for 
repetitive transorbital alternating current stimulation (rtACS) for the treatment of visual impairment in 
people with glaucoma. We will evaluate a study protocol to use in future clinical trials to test the 
effectiveness of rtACS to ameliorate the progressive effects of vision loss both structurally and 
functionally in the eye, the visual pathway, and in regard to people’s independence (i.e., functional ability). 
1.1 Background  
Vision is the dominant sense1 humans use to interact with and understand the many facets of everyday 
life. Vision is integral within other sensory systems as well (e.g., vestibular system). The health of 
people’s visual system influences how they learn, communicate, work, engage in leisure, and interact with 
the environment that surrounds them. Vision changes as a normal part of aging. Aging Americans are 
living longer; the generation of Americans living into older age (i.e., Baby Boomers) is a larger population 
cohort than previous generations. The number of Americans aged 65 years and older, ages when people 
are more vulnerable to vision loss due to age-related eye diseases, is projected to increase from 
approximately 47.8 million (2015) to 98.2 million (2060).2 Visual impairment is one of the 10 most 
common causes of disability in the U.S.3 In a 2014 population survey, 11.3% of adults aged 45 to 64 
years and 13.5% of adults aged 65 years and older reported some form of vision-related difficulty.2,4 
 
The number of Americans with major chronic eye diseases is increasing5 and visual health is increasingly 
a major public health concern.6 Adults with degenerative eye diseases, who are at greater risk for 
progressive vision loss, live with an uncertainty that their vision may deteriorate over time and that 
currently there is no cure or means to reverse the progression. Vision loss is associated with a higher 
prevalence of chronic conditions,7 death,8 falls and injuries,9 depression and social isolation.10,11 People 
with visual impairment have higher odds of receiving informal care and lower odds of reporting a 
favorable health status than people without visual impairment.12 Glaucoma is one of the most prevalent 
causes of progressive visual impairment and is a leading cause of irreversible blindness.13 
1.1.1 Glaucoma 
Glaucoma affects people’s capabilities to perform daily living tasks (i.e., functional ability)14-19 and their 
quality of life (QoL),20-22 even when people were unaware of their diagnosis.21 The prevalence of 
glaucoma is increasing. In the U.S. the estimated number of Americans with glaucoma will more than 
double from 2.7 million (2010) to 7.3 million in 2050.23 As many as 50% of affected people with glaucoma 
are unaware of their diagnosis.24 The estimated U.S. direct medical costs for glaucoma-related health 
care are approximately $2.9 billion annually,25 an estimated $748 million for Medicare beneficiaries.26 
However, these financial estimates do not account for indirect costs of financial burden on individuals, 
caregivers, and non-governmental healthcare payers. 
The silent burden of glaucoma is its insidious nature. The pathophysiology of glaucoma is not well 
understood; factors contributing to its progression include mechanical, vascular, and biochemical 
mechanisms.27 The structures in the eye affected by glaucoma are neural (e.g., retinal ganglion cells), 
vascular (e.g., central artery and vein), and connective (e.g., trabecular meshwork) tissues. Glaucoma is 
typically characterized by increased intraocular pressure (IOP), retinal nerve fiber layer (RNFL) and optic 
nerve (ON) damage, and progressive loss of visual fields (VFs). Glaucoma is a chronic optic neuropathy 
that manifests through damage (degeneration) to the ON and death of retinal ganglion cells (RGCs). 
RGCs are neurons in the eye that transmit visual information from the retina to the brain via the ON.  
In glaucoma, secondary damage to and death of RGCs result in visual function deficits, such as VF 
defects and diminished contrast sensitivity (CS).28,29 These secondary damages are attributed to primary 
damage at the ON head and lamina cribrosa, a vulnerable area where the ON connects with the axons of 

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RGCs (Figure 1). In the visual system, information about the visual world is acquired, processed, and 
conveyed from the retina to visual centers in the brain by distinct, parallel information pathways (e.g., 
parvocellular and magnocellular pathways). These pathways represent different types of RGCs, thus play 
different roles in visual function. Glaucoma appears to selectively affect the magnocellular (M) pathway; 
this fact is important in understanding how degenerative changes in glaucoma that affect M cells result in 
selective loss of particular visual functions. While RGCs are selectively affected by glaucoma, 
glaucomatous damage extends beyond the retina to upstream cortical networks30-34 employed in vision.  
 
 
Figure 1. A. The optic disc is composed of neural, vascular, and connective tissues. The convergence of the axons of 
retinal ganglion cells (RGCs) at the optic disc creates the neuroretinal rim; the rim surrounds the cup, a central shallow 
depression in the optic disc. RGC axons exit the eye through the lamina cribrosa (LC) forming the optic nerve, and 
travel to the left and right lateral geniculate nucleus, the thalamic relay nuclei for vision. B. Glaucomatous optic 
neuropathy involves damage and remodeling of the optic disc tissues and LC that lead to vision loss. With elevated 
intraocular pressure, the LC is posteriorly displaced and thinned, leading to deepening of the cup and narrowing of the 
rim. Distortions within the LC may initiate or contribute to the blockade of axonal transport of neurotrophic factors within 
the RGC axons followed by apoptotic degeneration of the RGCs. Strain placed on this region also causes molecular 
and functional changes to the resident cell population in the optic nerve (e.g., astrocytes, microglia), remodeling of the 
extracellular matrix, alterations of the microcirculation and to shrinkage and atrophy of target relay neurons in the lateral 
geniculate nucleus.35 
1.1.1.1 Glaucoma Treatment 
By the time glaucoma is diagnosed there is irreversible impairment to eye structures; there are no 
interventions to restore function or reverse damage. The mainstay of treatment is management of IOP 
(Figure 2), pharmaceutically and/or surgically, because IOP is the only modifiable risk factor to date, 
though it is only one of the multiple contributors to glaucoma (e.g., loss of neurotrophic factors, localized 
ischemia, excitotoxicity). Beyond IOP, there is no clinical treatment for neuronal tissue loss associated 
with glaucoma progression. And herein lies a large focus in research: how do we intervene at the neural 
level to prevent further disease progression and treat the damage that neural tissue has already 
sustained? Two approaches are neuroprotection and neuroplasticity. 

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Figure 2. Aqueous humor drainage pathways of healthy (A) and glaucomatous (B, C) eyes as it relates to elevated 
intraocular pressure.35 
1.1.1.1.1 Neuroprotection 
Neuroprotection refers to the relative preservation of neuronal integrity (i.e., neuronal structure and/or 
function) to slow or prevent disease progression. Measuring the neuronal morphology of key structures 
affected by glaucoma (e.g., RNFL), even with current imaging technology, remains limited; no imaging 
tools are able to distinguish between complete versus partial defects versus healthy RGCs. Some RGCs 
survive even within damaged retinal regions.36 Thus, one focal point of neuroscience is to develop 
therapeutic methods called neuroprotective therapies. Neuroprotection involves recovery, regeneration, 
or inhibiting specific biochemical pathways that influence neuronal health. Specific to glaucoma, 
neuroprotection involves targeted treatment of neurons of the visual pathway, but primarily RGC axons.37 
There is limited evidence that neuroprotective therapies are clinically effective in glaucoma.27,37-39 
Neuroprotective effects in the central nervous system are transient40 and only delayed the progression of 
neuronal degeneration in animal studies.41,42 
1.1.1.1.2 Neuroplasticity 
Another promising area of neuroscience gaining attention in vision research is neuroplasticity. 
Neuroplasticity is the brain’s ability to reorganize itself during normal aging, disease, or following injury; it 

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is the ability of the brain to change its functional architecture by modulating synaptic efficacy so that the 
neurons in the brain compensate and adapt their functions in response to change. With innovative 
imaging technologies, it will be possible to advance human studies research of the neuroplasticity of the 
visual pathway.  
One conceptualization of neuroplasticity, the residual vision activation theory,43 suggests that there are 
areas of residual visual capabilities in the retina within the areas that are damaged by disease or injury. 
Essentially, areas of residual vision may exist either on the border of the damaged areas of the retina 
(i.e., border of the scotoma) or within the impaired VF. A portion of cells may survive within a damaged 
structure; thus, some degree of function exists. Given the parallel processing and retinotopic nature of the 
visual system network, disease or injury that occurs at the site of early visual processing affects upstream 
neuronal networks.30-34,44,45 The integrity of the surviving neurons determines how much information 
reaches higher cortical regions. The idea that there is residual potential within damaged structures means 
that there may be a potential to alter the surviving neural tissue at the site of the defect and thus influence 
brain network connectivity (i.e., neuroplasticity). 
 
The residual vision activation theory also suggests that there is therapeutic value in regions of the VF 
where respondents demonstrate reduced stimulus detection thresholds or in areas where they respond 
less reliably or slowly to the stimulus presentations. The partially damaged areas may be more 
susceptible to sensitivity changes, attention, and fatigue, all factors generally thought to be negative, that 
influence the inherent nature of subjective measurement of visual function. However, while these areas 
may be viewed as variable outcomes or less severely affected, they may be a critical target for 
intervention because these regions may represent only partially damaged function. Studies reported a 
non-linear relationship between structural damage in the eye and visual function;43 the visual system 
involves many brain mechanisms and networks that include feedback loops with higher-order, top-down 
processes of cognition that influence visual function. For example, typically people with glaucoma 
consciously notice VF defects later than clinicians identify structural impairment of the retina (see 
Attachment 1). 
 
The goal of intervention based on the principles of neuroplasticity is to activate neuronal residual 
capabilities in the areas of residual vision. Activating surviving cells leads to increased synaptic activity 
and repeated activation elevates cell activity, which strengthens synaptic efficacy. One therapeutic 
method of influencing neuroplasticity is electrical stimulation therapy (EST). And, repetitive sessions of 
EST are necessary to produce cumulative effects as shown in neurophysiology studies and clinical trials 
in rehabilitation. In this study we will evaluate the effect of one method of electric current stimulation, 
rtACS, as an intervention to treat visual impairment in people with glaucoma. 
1.1.2 Brain Electrical Connectivity 
The brain is comprised of billions of neurons connected to each other via synapses. Neural processing 
involves communication within local ensembles of neurons and between long-range networks of neurons 
via the synapses. Ensembles of neurons in the brain connect to form functionally specialized networks 
and communicate with each other via the generation and transmission of electrical impulses carried along 
their axons. Neuronal network activity occurs through rhythmic firing patterns of synaptic interactions, in 
which the rhythmic changes in electric potential result in synchronized input to other brain regions, thus 
evoking oscillatory brain activity (i.e., rhythmic activity pattern).46 When groups of neurons spike in 
synchrony (i.e., nearby neurons firing very close to or at the same time), they give rise to oscillations that 
reflect neuronal activity which can be measured (i.e., changes in the electric field). As a result, 
synchronized activity generates a more pronounced electric field (Figure 3). This electrical signal activity 
of neuronal networks is measured by electrophysiological methods, such as electroencephalography 
(EEG), which provide information about the temporal relationships between synchronous responses.  

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While there are open questions about the functional role of 
cortical oscillators, there is a growing consensus that 
oscillations are an organizing factor by which neurons and 
neuronal networks communicate and thereby enable 
cognition and behavior.47,48 The point in time within a 
waveform cycle (i.e., phase) influences neuronal firing rates 
over a wide range of frequency bands: delta (<4 Hz), theta 
(4-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), and gamma 
(>30 Hz). Studies found frequency-specific coherence 
between cortical areas as a function of behavioral demands 
(e.g., sleep, wake, solving a mathematical calculation);49 
which gives evidence for the possible role of oscillations 
and functional connectivity in a specific frequency band.50 
The functional role of brain oscillations in a variety of 
cognitive functions is important to understanding brain 
processing.47 Cognitive processes rely on synchronous 
activity of large ensembles of functionally linked neurons 
that occur at distinct frequency bands according to the 
extension of the network configuration.51-54 Evidence 
supports that brain oscillations play a key role in motor, 
perceptual, and cognitive processes.47,49,55-58 In the healthy 
brain, neuronal networks operate in synchrony. In 
neurological disease, alterations of neuronal networks and 
loss of cells and their connections result in disturbances in 
synchronous neuronal firing. 
1.1.3 Alternating Current Stimulation 
EST to the brain uses an electric current to exert an external modifying influence (i.e., modulation) to 
activate or to inhibit brain processes. Initial studies have found EST to be effective in a range of clinical 
conditions to treat functional deficits (i.e., behavioral performance) related to dyslexia,59 stroke,60-62 spinal 
cord injury,63 cognition,64 and depression.65 Recent studies evaluated the use of EST for the treatment of 
ophthalmic disease;66,67 evidence supported the use of EST to prolong retinal survival, preserve visual 
function, and modulate cortical excitability.66,68 This study will use one method of non-invasive EST called 
alternating current stimulation (ACS).69  
 
The application of ACS is a relatively recent therapeutic 
development. ACS influences brain physiology on a 
network level through synchronization of neuronal 
network 
firing 
using 
a 
low-intensity 
sinusoidal 
waveform electric current (Figure 4) to induce 
neuroplastic 
changes.69 
The 
current 
intensities 
produced are lower in magnitude than other stimulation 
techniques, such as transcranial magnetic stimulation 
or electroconvulsive therapy, that are approved by the 
Food and Drug Administration (FDA) for certain 
conditions. 
Francis 
and 
colleagues 
(2003) 
demonstrated that neurons are sensitive to low-
intensity electrical fields and that neuronal networks are more sensitive to field modulation than the average 
single neuron.70 The theory behind ACS is that neuronal network activity can be entrained over time (i.e., 
endogenous oscillating element starts to cycle with the same period as the exogenous stimulus) in a 
frequency band-specific manner when the exogenous stimulus is similar to that of the endogenous electrical 
field of that network.71-77 Neurons acting in synchrony with the stimulation frequency can potentially induce 
restoration of function following disease or injury. Consequently, the brain activity in the range of the 
electrical stimulation frequency is then enhanced.72,78-80 
Figure 3. Illustration of how synchronized activity 
generates a more pronounced electric field 
(EF).46 
Figure 4. Sinusoidal waveform. 

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Entrainment using ACS seems to alter aspects of perception dependent on the frequency of the 
stimulation. Only physiologically meaningful brain rhythms can be entrained.71,81 In this study, ACS is 
used to modulate brain oscillations at the alpha frequency. The alpha rhythm is modulated by visual 
stimuli, likely relies on interaction dynamics between the thalamus and cortex (including occipito-parietal 
areas of the brain), and is thought to reflect the spontaneous rhythms of visual areas.82,83 Studies 
reported decreased alpha band activity in people who were congenitally blind84,85 or had ON 
impairment.80,86-88 Occipital alpha oscillation is synchronized to cyclic activity in visual thalamic relay 
neurons in the lateral geniculate nucleus; therefore, likely involved in signal transmission involved in 
visual perception89 particularly in the early (retinotopic) stages of visual information processing.90 
Therapeutically, brain oscillations are used to modulate function (i.e., behavioral performance). Studies 
demonstrated that transcranial ACS induced frequency-specific effects on brain dynamics as measured 
by EEG.72,77,91,92 This specific stimulation paradigm has been applied to modulate vision, motor function, 
somatosensation, and cognitive and mood disorders.77,81,93,94 
 
The intervention delivered in this proposed study is rtACS. 
Transorbital refers to the site of electrode placement and 
stimulation delivery; electrodes are placed on the skin 
near the eye. While transcranial ACS likely modulates 
neural oscillation focally in several brain regions (based 
on electrode montage95), rtACS may be effective in more 
directly modulating the neural oscillation of visual 
networks because the plasticity induced by ACS is more 
effective when it starts in the early stages of visual 
processing (e.g., retina).96,97 By placing the electrode 
montage transorbitally, the current flow targets a 
physiological trajectory toward the retina and ON. rtACS 
is a non-invasive application of electric current to stimulate 
the retina to induce synaptic efficacy, in particular those 
cells that have some measure of dysfunction but are not 
dead, and oscillations of nearby neuronal ensembles. 
While there is emerging study on the mechanisms of ACS, 
what is established is that sustained ACS (minutes) can 
produce changes in brain oscillations and that these 
changes are plastic and cumulative with repeated 
sessions (Figure 5). rtACS requires further study to fully 
leverage this treatment modality for maximal clinical 
benefit in people with glaucoma. 
 
With innovative imaging technologies, human studies 
research of the neuroplasticity of visual pathway 
structures has advanced. The theory of neuroplasticity is 
that after damage, structures with residual visual 
capabilities can be reactivated through repetitive stimulation leading to improved visual function and brain 
network connectivity.43 rtACS is a non-invasive application of weak electric current used to exert an external 
modifying influence on brain processes through synchronization of neuronal network firing. The mechanism 
of rtACS is to stimulate the retina to influence RGCs, in particular those cells that have some measure of 
dysfunction but are not dead, and oscillations of nearby neuronal ensembles. rtACS has successfully been 
used in the rehabilitation of visual impairments in people with optic neuropathies;80,86-88,98 however, we do 
not know the clinical value of rtACS specifically for people with glaucoma, including the effect of rtACS on 
people’s functional ability and QoL.  
 
 
Figure 5. Illustration of the proposed underlying 
neuronal mechanism of the power increase by 
synchronization. Upper row: Single neuronal 
oscillators, depicted as vectors on a unit circle, with 
a specific intrinsic frequency synchronized to an 
external sinusoidal force with the same frequency. 
Middle row: The mean resultant vector of the single 
oscillating elements represents the amplitude of the 
oscillation. Due to phase alignment of each single 
oscillator to the external oscillation, the length of this 
mean vector increases and likewise the amplitude. 
Lower row: Schematic illustration of the amplitude 
recorded via EEG.73   

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1.1.4 Clinical Data to Date: Repetitive, Transorbital Alternating Current Stimulation 
The following clinical data is summarized from the published literature for rtACS in people with ophthalmic 
diseases. All of the studies reviewed involved administration of rtACS in people with ON impairment. 
Attachment 2 summarizes the studies’ published rtACS protocols. 
 
In a retrospective data analysis of 446 people, Fedorov and colleagues (2011) reported that following 
rtACS participants’ VFs significantly increased (p < .001) by 7.1% and 9.3% in the right and left eyes, 
respectively, as measured by kinetic perimetry.98 Significant improvements (p < .01) in distance visual 
acuity (VA) were also reported for each eye. A sample of 62 people received an additional course of 
rtACS 6 to 9 months following the first treatment. During the stimulation-free interim following the first 
course of treatment, VFs decreased by 4.6% (p = .11) and 5.6% (p = .08) in the right and left eyes, 
respectively. After the second course of rtACS, participants’ VFs remained significantly improved (p < .05) 
in each eye compared to their baseline status (VFs increased 3.9% and 4.9% from the first course of 
treatment to following the second course of treatment in the right and left eyes, respectively).  
 
In a masked, randomized controlled trial,86 participants who received rtACS (n = 12, 19/24 eyes) 
demonstrated significant improvement post-intervention in their detection accuracy (high resolution 
perimetry) in the defective VF areas (p = .03) and VA (p < .05), both near and far, compared to a sham 
stimulation group (n = 10, 14/20 eyes). Effect sizes, comparing rtACS to sham, were moderate (.51 to 
.67) for changes in detection accuracy measured in both the defective and the entire VF and reaction time 
(high resolution perimetry). Alpha frequency significantly increased (p < .001) in EEG recordings following 
rtACS. At 2-month follow-up, all participants who received rtACS (including those in the sham group who 
were offered rtACS once allocation was revealed, n = 29/40 eyes) demonstrated a significant 
improvement in their detection accuracy measured in both the defective and entire VF and reaction time 
(p ≤ .05), mean threshold (static perimetry, p < .01), and near VA (p < .01). 
 
In a multi-center, masked, randomized controlled trial,88 participants who received rtACS (n = 45) 
demonstrated significant improvement post-intervention in detection accuracy (high resolution perimetry) 
in both the defective and entire VF (p < .001), decreased reaction time (high resolution perimetry, p = 
.02), improved mean threshold (static perimetry, p < .01), and mean eccentricity (kinetic perimetry, p = 
.04) compared to the sham stimulation group (n = 37). Detection accuracy in the entire VF was 
significantly different between groups in favor of rtACS (p = .01). Additionally, alpha frequency 
significantly increased (p = .01) following rtACS. At 2-month follow-up, the rtACS group continued to 
demonstrate significantly better detection accuracy in the entire VF (p = .03) and mean threshold (p = .01) 
compared to the sham stimulation group. 
 
Gall and colleagues (2011) reported QoL outcomes, using pooled data from two separate but similarly 
designed studies, for a combined number of 42 participants.99 The effect of rtACS on both vision-related 
and health-related QoL was compared between participants who received rtACS (n = 24) versus a sham 
stimulation (n = 18). Significant differences between groups were reported in regard to vision-related 
quality of life (VRQoL) for general vision (p = .04), distance activities (p = .02), and social functioning (p = 
.03) and for health-related quality of life (HRQoL) in the mental health component score (p = .01) and 
emotion-related role limitations (p = .03). 
 
Schmidt and colleagues (2013) conducted an open-label, prospective study and reported significant 
effects of rtACS on alpha frequency (p = .01) in participants who received rtACS (n = 18) compared to a 
sham stimulation (n = 6).80 The study demonstrated that, with repeated sessions, rtACS induced 
enhancement of alpha oscillations following a progressive amplification over the 10-day course of the 
intervention. Concerning visual perceptual performance (high resolution perimetry), detection accuracy 
improved following rtACS by 17.8% (p < .001). 
 
Bola and colleagues (2014) conducted a case-control, randomized controlled trial for rtACS (n = 7) versus 
sham stimulation (n = 8) with 13 age-matched healthy controls.87 At baseline participants with ON 
impairment exhibited a breakdown in alpha frequency compared to the healthy controls (p < .05), which 
was associated with worse visual perceptual performance measured by high resolution perimetry (VF 

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size, r = .53, p = .04; reaction time, r = -.58, p = .03). Following rtACS the alpha frequency was 
strengthened (p = .03) compared to the sham stimulation group and was associated with better visual 
perceptual performance (detection accuracy, r = .57, p = .04; reaction time, r = -.56, p =.05). The authors 
suggested that alpha frequency in the resting state could be a marker for both loss and restoration of 
visual perceptual capabilities in people with ON impairment; vision loss may not just relate to tissue 
damage but also to breakdown of synchronization in the neuronal network. 
1.2 Investigational Device 
We will use the DC-Stimulator MC (neuroConn GmbH, Ilmenau, Germany) to deliver the rtACS 
intervention per protocol. The device is considered a medical device using the definition by the FDA. Non-
invasive or cutaneously administered electrical stimulation devices are deemed a Category B, Class II 
medical device, for which the DC-Stimulator MC qualifies.100 rtACS is a non-invasive procedure because 
it does not involve penetrating the skin or a body cavity. The DC-Stimulator MC is a non-significant risk 
device based on: (i) it is not an implantable device, (ii) it is not used for supporting or sustaining human 
life, (iii) it is not used for substantial importance to diagnose, cure, mitigate, or treat disease, and (iv) it 
does not present a potential for serious risk to the health, safety, or welfare of a participant. The device 
labeling (in accordance with FDA regulations at 21 CFR §812.5) includes name and place of 
manufacturer, contraindications, hazards, adverse effects, interfering substances or devices, warnings, 
and precautions.101 Additionally, the device displays the label: Caution for United States Owners and 
Operators: Investigational Device. Federal (or U.S.) law limits this device to investigational use. 
 
The DC-Stimulator MC was chosen for this study based on its capacity to deliver the established rtACS 
intervention protocol documented in previous efficacy, safety, and interventional studies.80,86-88,98 The DC-
Stimulator MC is an investigational, multi-channel electrotherapy device consisting of a programmable 
waveform generator that connects to electrodes to deliver a non-invasive weak electric current. Technical 
and safety information related to weak current stimulation protocols have been published.102 Weak 
electric current devices are used in the U.S. for basic and clinical research with Institutional Review Board 
(IRB) approval.100 The DC-Stimulator MC allows for frequency band stimulation in the range of 0-1,000 Hz 
and currents up to 3,000 µA (peak-to-peak) with adjustable phase for ACS. Unique to this device, it can 
be used simultaneously with functional magnetic resonance imaging (fMRI) with minimal artifacts related 
to the electrical interference (though we are not using the MRI function for this study). Additionally, it has 
a computer-controlled sham stimulation function for masking interventionist to study group. The device 
will be used to deliver a weak electric current stimulation protocol to participants via electrodes placed 
transorbitally, with one reference electrode positioned elsewhere.  
1.3 Research Risks & Benefits 
1.3.1 Risk of Investigational Device 
Safety and tolerability of EST in both animal and human studies are published102-107 and to our knowledge 
there have been hundreds of EST studies in the U.S. designated non-significant risk by IRB review. 
Evidence suggests that there is a general lack of observations concerning adverse events or adverse 
effects, only documentation of mild side effects. In experimental protocols following evidence-based dose 
and delivery parameters, the mild side effects of ACS included: local skin reddening, skin tingling, skin 
itching, skin warming sensation, nausea, diffuse or migraine-like headache, blurred vision, forgetfulness, 
difficulty concentrating, dizziness, general fatigue, sleeping difficulties (temporary), spontaneous 
phosphenes (independent of stimulation), blood pressure fluctuation, and difficulty breathing.103,106,108 The 
safety of ACS has been tested80,81,86-88,98 and researchers conclude that ACS, as applied in a dose-
specific manner, is safe and tolerable. 
 
We will assess and document per protocol adverse events (safety) and adverse effects (tolerability, see 
sections 6 and 8). To minimize the risk for adverse events and adverse effects, there are no deviations to 
the established rtACS protocol used in previous studies in this study design. Standard parameters for the 
application of weak current stimulation in general are100: (1) current is less than 2.5 mA, (2) the current is 
applied through electrodes that are known to minimize skin burns at the specific current level 
administered to a participant, (3) the current application duration is less than 20 to 60 minutes per 

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session, and (4) sessions are not more frequent than two times per day. Tolerability of EST is specific to 
(1) dose (session duration, amplitude, electrode size and position, number of sessions) and (2) participant 
exclusion and treatment protocol.46,103,109,110 Additionally, the device will be checked prior to and following 
the delivery of rtACS for each session. 
1.3.2 Other Risks of Study Participation 
The targeted physiological effect of rtACS is to induce neuroplastic changes in the visual system to 
minimize visual impairment. The established rtACS protocol we will use in this study has been safe and 
effective within its stimulation parameters. The current is weak, such that it can hardly be felt. However, if 
parameters are not followed, or changed in any manner that affect the dose, this might lead to 
maladaptive plasticity rather than adaptive or positive effects on neural plasticity. To minimize the risk of 
any deviation from the rtACS protocol, at each contact with a participant, research personnel will examine 
and document that: the rtACS device is functioning properly, the experimental setup is performed per 
protocol, and specific questioning and examination (as appropriate) is performed to the participant.  
 
Infrequent risks that may occur include fatigue, breach of confidentiality of participants’ identifiable 
information (medical record information and questionnaire data), or participants may experience 
frustration in regard to the administration of particular tests (e.g., attention/information processing) and/or 
the time to complete study procedures. To minimize the occurrence of fatigue, participants will be 
informed that they may stop as frequently as needed to rest at time points appropriate to the 
standardization of the test being administered. Research personnel will provide assistance in the 
administration of assessments per standardized protocol as needed. To reduce the likelihood of a breach 
of confidentiality, access to participants’ personal information will be limited to research personnel on a 
need-to-know basis. Additionally, we will secure personal identifiers and clinical information in a separate 
location and limit access to this information by using linking codes assigned to study data and password 
protected electronic files to maximize confidentiality. Screening forms will be placed in a locked file 
cabinet and stored separately from participants’ identification files. We also will provide assurance to the 
participant that the recorded information will not be reused or disclosed to any other person or entity 
(other than members of the research team) except as required by law or for authorized oversight of the 
study. Participants will be advised to inform research personnel if they feel any frustration or discomfort 
about answering questions on the questionnaires. To minimize frustration or discomfort with these 
questions, participants will be educated on their purpose in this study and assisted as per standardized 
protocol in the completion of assessments. Any comments from participants and/or assistance provided 
by research personnel will be documented for tracking purposes. 
1.3.3 Potential Benefits 
rtACS has been associated with improved visual function and QoL in people with visual impairment 
resulting from optic neuropathy.99 In addition to the potential benefits of improved visual function and QoL, 
we will explore the potential benefits of rtACS in regard to participants’ functional ability. We anticipate no 
direct benefit from sham rtACS in regard to visual function, QoL, and functional ability. 
2 Study Objectives 
In this proposed pilot study, we will assess the feasibility of procedures that are key to the conduct of a 
multi-site randomized controlled trial to explore the influence of rtACS versus sham stimulation on 
neuronal morphology and physiology to improve people’s visual function, functional ability, and QoL. The 
expected outcomes (hypotheses) for this project are that (1) rtACS activates viable but poorly or non-
functional RGCs to improve their structural and functional capabilities, (2) measures of retinal, ON, and 
visual brain structures and function will correspond with improvement in visual function, and (3) changes 
in visual function following rtACS will be associated with improvements in participants’ functional ability 
and QoL. 
 

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2.1 Primary Objectives 
2.1.1 
Objective: Assessment of Ophthalmic Structure and Function 
Evaluate procedures to identify changes in vision following rtACS compared to sham stimulation 
at baseline, post-intervention and 4 weeks (follow-up) to inform the design of a multi-site 
collaborative clinical trial for participants with glaucoma  
2.1.1.1 
Aim 1: Evaluate the data collection and data management methods to measure the targeted 
outcomes (structural and functional capabilities) of neuronal physiology and reorganization of 
the visual pathway (from eye to visual brain) 
2.1.1.1.1 
Image structures of the visual pathway with advanced technologies to determine the effect of 
rtACS on structure and function 
2.1.1.1.2 
Assess areas of visual function to determine the effect of rtACS 
2.1.2 
Objective: Assessment of Functional Ability and QoL 
Evaluate procedures to assess participants’ functional ability and QoL following rtACS compared 
to sham stimulation at baseline, post-intervention and 4 weeks (follow-up) to inform the design of 
a multi-site collaborative clinical trial for participants with glaucoma  
2.1.2.1 
Aim 2: Evaluate the data collection and data management methods to measure objective 
ability/disability and subjective well-being 
2.1.2.1.1 
Assess the feasibility of procedures for assessment of functional ability (objective 
ability/disability) to determine the effect of rtACS 
2.1.2.1.2 
Assess the feasibility of procedures for assessment of vision-related and health-related QoL to 
determine the effect of rtACS 
2.2 Secondary Objective 
2.2.1 
Objective: Assessment of Feasibility and Implementation of Procedures 
Evaluate the feasibility and implementation of procedures for a clinical trial protocol (rtACS versus 
sham stimulation) at baseline, post-intervention, and 4 weeks (follow-up) to inform the design of a 
multi-site collaborative clinical trial for participants with glaucoma  
2.2.1.1 
Aim 3: Evaluate the data collection, data management methods, and study procedures for 
targeted outcomes other than the primary objectives 
2.2.1.1.1 
Evaluate recruitment, enrollment procedures and retention, and participants’ adherence to 
procedures between multiple sites 
2.2.1.1.2 
Assess data entry and data management procedures between multiple sites 
2.2.1.1.3 
Assess the feasibility of procedures for assessment methods other than primary objectives 
3 Study Design 
3.1 General Design 
The goal of this prospective, randomized controlled double-masked pilot study is to establish a structured 
protocol for the delivery of rtACS sessions (participants randomized to either active or sham rtACS 
groups) with repeated assessments at baseline, post-intervention, and 4 weeks (follow-up) to inform the 

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design of future clinical trials for people with glaucoma (Table 1). The participants and interventionists will 
be masked to study group. Ten daily sessions will be administered across 2 weeks. The electrode 
montage is per protocol; electrodes will be placed transorbitally (eyes closed) with a reference electrode 
placed elsewhere. Dose will be administered per protocol for session duration (< 60 minutes continuous 
stimulation), amplitude (peak-to-peak), electrode size, electrode position (transorbital), and number of 
sessions (10). 
 
Table 1. Anticipated study timeline 
 
2017 
2018-2020 
2021 
Major tasks 
Feb-Oct 
Nov 
Dec 
Jan-Dec 
 
Recruit and train research personnel 
 
 
 
 
 
Screening and assessment protocols 
finalized 
 
 
 
 
 
Develop protocol manual, codebook, 
and data entry procedures 
 
 
 
 
 
Recruitment  
 
 
 
 
 
Data collection 
 
 
 
 
 
Data processing 
 
 
 
 
 
Data analysis 
 
 
 
 
 
Summative data analysis and 
dissemination of findings 
 
 
 
 
 
Presentation / publication of initial and 
ongoing findings 
 
 
 
 
 
Recruitment goal: 16 participants 
Anticipated date of starting recruitment: April 2017 
Anticipated date of completing recruitment: December 2020 
Anticipated date of completing statistical analysis: December 2021 
 
Participants will be randomized in 1:1 ratio to the rtACS and sham stimulation groups using block 
randomization stratified by centers. Random varying block sizes will be used to balance group allocation 
and minimize the risk of unmasking group assignment, and a randomization table will be computer 
generated accordingly. A research staff member not directly involved in the conduct of the study will 
conduct allocation concealment. Participants will complete screening, baseline, pre- and post-session, 
post-intervention, and follow-up assessments (Figure 6). The Pre-/Post-session Questionnaire includes 
brief measures to monitor any stimulation- and research-related effects. 
 

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Figure 6. Study Flow Chart 
 
The timeline for assessment procedures involves 1-2 visits for baseline testing, 10 daily visits for rtACS or 
sham stimulation sessions (across 2 weeks), 1-2 visits for post-intervention testing, and 1-2 visits for 
follow-up testing (4 weeks following intervention); a total of 13-16 visits. The variability in the number of 
sessions is based on the circumstance that an imaging assessment may need to be scheduled on a 
separate day due to device availability. Participants may be contacted, following data collection of the 
study assessments, to request information pertinent to this research study. 
3.2 Primary Study Endpoints 
3.2.1 Assessment of Ophthalmic Structure and Function 
3.2.1.1 
Assess neuronal structure and function (see section 2.1.1.1.1) 
Optical coherence tomography (OCT): Spectral domain OCT is a commonly used imaging technology 
to evaluate glaucomatous structural damage and to detect glaucomatous progression.111,112 It is a non-
invasive technique that allows for in vivo cross-sectional imaging of the ON head and RNFL. The clinical 
utility of OCT is that it enables a comprehensive assessment of the thickness of the RGC and ganglion 
cell nerve fiber (i.e., RNFL) layers as they approach the ON head.113 Studies demonstrated that OCT is a 
reliable and reproducible method to measure RNFL and macular thickness and demonstrated sensitivity 
and specificity in discriminating glaucomatous eyes from healthy eyes.114-119 
 
We will measure (1) peripapillary RNFL thickness (µm), (2) macular ganglion cell-inner plexiform layer 
thickness (µm), and (3) ON head cup-to-disc ratio (%); all three measures are determined from the device 
software automatically. Testing will be performed using an FDA approved device for its approved 
indication and will require 10 minutes to perform. Testing results will be printed and included with 
participants’ source documents. 
 
OCT angiography (OCT-A): There is a growing body of evidence suggesting that glaucoma 
pathogenesis is related to vascular dysfunction.120-122 OCT-A is a new, non-invasive imaging technique 
that employs motion contrast imaging to high-resolution volumetric blood flow information to generate a 
three-dimensional map of the retinal and choroidal vasculature. In people with glaucoma, OCT-A may be 
Pre-screening
• Medical record review of patients' scheduled clinical appointments 
to identify patients diagnosed with glaucoma
Screening for 
eligibility
• Medical record review
• Interview
Enrollment
• (1) Written informed consent
• (2) Randomization and allocation to group
• (3) Baseline testing
Assessment and 
intervention
• (1) Daily sessions 1-10 (Pre-/Post-session Questionnaire)
• (2) Post-intervention testing (2 weeks)
• (3) Follow-up testing (4 weeks)
Data analysis
• Allocation revealed

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a useful tool for evaluating vasculature using density mapping and flow index (0-1), which measures the 
area of large vessels and both the area (vessel density) and velocity of capillaries.123,124 Testing will be 
performed using an FDA approved device for its approved indication and will require 10 minutes to 
perform. Testing results will be printed and included with participants’ source documents. 
 
Multi-modal magnetic resonance imaging (MRI): 
Functional magnetic resonance imaging (fMRI) is a neuroimaging procedure that measures brain activity 
by detecting changes in hemodynamics. fMRI typically uses the blood-oxygen-level dependent (BOLD) 
contrast to map activity in the brain and has been studied to assess how glaucoma affects brain 
function.125,126 We will use an established protocol for assessment of visual function,125,126 using MRI-
compatible visual occlusion spectacles, to measure functional activity and connectivity in different brain 
regions with and without visual stimulation to each eye.  
 
Diffusion MRI is a neuroimaging procedure that uses the diffusion of water molecules to generate contrast 
in magnetic resonance images to map white matter integrity in the brain. Studies reported compromised 
structural integrity of the optic radiations and frontal lobe in people with glaucoma.126 We will use diffusion 
MRI to measure structural connectivity (e.g., tract-based spatial statistics of fractional anisotropy maps) of 
vision-related structures. 
 
MRI scans have long been held to be a safe way to non-invasively visualize tissue in adults. This study 
will be performed in an FDA approved scanner. Testing will be administered per standardized protocol 
and will require up to 90 minutes to perform. MRI testing may be scheduled on a separate day than other 
testing due to timing, location of MRI facility, and patient scheduling. Testing results will be included with 
participants’ source documents. 
 
Electrophysiology: 
Visual evoked potential (VEP) non-invasively assesses the function of visual pathway structures (from 
retina to visual cortex) by measuring the electrical activity of the occipital cortex (amplitude [µA], latency 
[ms]). VEP is used clinically to detect glaucomatous changes and discriminates glaucomatous eyes from 
health eyes.127,128 
 
Pattern electroretinography (PERG) non-invasively assesses the function of RGCs by measuring 
electrical activity of the cells (magnitude [µV]). PERG is used clinically to diagnose and manage 
glaucoma.129-131 
 
Testing will be performed using an FDA approved device for its approved indication and will require 15 
minutes to perform. Testing results will be printed and included with participants’ source documents. 
3.2.1.2 
Assess areas of visual function (see section 2.1.1.1.2) 
Visual field: A VF test is a method to measure the full extent of the areas visible to an eye (i.e., objects 
seen centrally and in the periphery) when the eye is fixated straight ahead. VF loss is one of the leading 
visual function deficits resulting from glaucoma. Hence, VF testing is a benchmark assessment in 
ophthalmic standard of practice to quantify severity of glaucoma. We will use the Humphrey Visual Field 
Analyzer (Carl Zeiss Meditec, Dublin, CA, USA), using the Swedish Interactive Thresholding Algorithm, to 
measure VF. Specifically, we will use the mean deviation (dB), a measure of VF sensitivity through 
threshold testing. The mean deviation is the deviation from the expected threshold value for a person of 
the same age and ethnicity. The Humphrey Visual Field Analyzer is a reliable and valid testing method for 
VF integrity and is considered a gold standard for the diagnosis and measurement of glaucoma.132,133 
Testing will be administered per standardized protocol and will require 20 minutes to perform. Testing 
results will be printed and included with participants’ source documents. 
 
Visual acuity: A VA test is a method to measure people’s ability to distinguish detail clearly. We will use 
the Early Treatment Diabetic Retinopathy Study (ETDRS) VA tests, as they are the worldwide standard 
for VA testing in ophthalmic disease, to measure both near and far acuity (logMAR). Testing will be 

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administered per standardized protocol and will require 5 minutes to perform. Testing results will be 
documented and included with participants’ source documents. 
 
Contrast sensitivity: CS is the ability to detect detail having subtle gradations in color or luminance 
between a target and its background. It is measured over a range of spatial frequencies and contrast 
levels. In people with glaucoma, CS had a strong correlation with and was a significant predictor of 
people’s performance of daily tasks.134 We will use the Pelli-Robson Contrast Sensitivity Chart, 
considered the gold standard, to measure CS (log units). Testing will be administered per standardized 
protocol and will require 5 minutes to perform. Testing results will be documented and included with 
participants’ source documents. 
3.2.2 Assessment of Functional Ability and QoL 
Per standardized assessment guidelines and in order to accommodate and minimize the amount of time 
subjects may be willing and/or able to participate in research procedures at the Eye Center, assessments 
of functional ability and QoL may be coordinated with subjects for virtual administration (e.g., via phone, 
Webex, etc.). 
3.2.2.1 
Assess the feasibility of procedures for assessment of functional ability (see section 
2.1.2.1.1) 
Assessment of Life Habits (LIFE-H), short form 3.1: The LIFE-H is a 77-item questionnaire developed 
to measure: (1) how a respondent accomplishes regular activities and social roles and (2) respondent’s 
satisfaction with how regular activities and social roles are accomplished.135-138 Regular activities and 
social roles are daily tasks that are valued by people and ensure their survival and well-being in society 
throughout their lifespan. Regular activities include nutrition, fitness, personal care, communication, 
housing, and mobility and social roles include responsibilities, interpersonal relationships, community life, 
education, employment, and recreation. Testing will be interviewer-administered per standardized 
protocol and will require 30 minutes to complete. The questionnaire will be included with participants’ 
source documents. 
 
Minnesota Low Vision Reading Test (MNRead): The MNRead is a standardized assessment designed 
to measure reading performance in three ways: (1) reading acuity (the smallest print that can just be 
read), (2) maximum reading speed (reading speed when performance is not limited by print size), and (3) 
critical print size (the smallest print read that supports maximum reading speed).139 Evidence suggests 
that reading speed is slower among people with glaucoma compared to normal-sighted controls140 and 
reading performance had a significant influence on people’s reading engagement (e.g., reading 
avoidance or restriction of tasks that required sustained reading).141 Testing will be administered per 
standardized protocol and will require 10 minutes to perform. The MNRead score sheet will be included 
with participants’ source documents. 
3.2.2.2 
Assess the feasibility of procedures for assessment of vision-related and health-related 
QoL (see section 2.1.2.1.2) 
National Eye Institute Visual Functioning Questionnaire (VFQ-39): The 39-item VFQ is designed to 
measure VRQoL. It is a frequently used measure of VRQoL in vision science research. The VFQ-39 is 
divided into 12 subscales: general health, general vision, ocular pain, near vision, distant vision, vision-
specific social functioning, vision-specific role difficulties, vision-specific mental health, vision-specific 
dependency, driving, peripheral vision, and color vision. Responses are rated on either Likert or 
dichotomous (yes/no) scales. Testing will be self-administered per standardized protocol and will require 
25 minutes to complete. The questionnaire will be included with participants’ source documents. 
 
36-Item Short Form Survey (SF-36): The SF-36 is a 36-item questionnaire developed to measure 
HRQoL. It is divided into eight subscales: physical functioning, bodily pain, role limitations due to physical 
health problems, role limitations due to personal or emotional problems, emotional well-being, social 
functioning, energy/fatigue, and general health. The SF-36 also includes a single item that probes a 
respondent’s perceived change in health. Testing will be self-administered per standardized protocol and 

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will require 25 minutes to complete. The questionnaire will be included with participants’ source 
documents. 
3.3 Secondary Study Endpoints 
3.3.1.1 
Evaluate recruitment, enrollment, and adherence procedures (see section 2.2.1.1.1) 
The following feasibility information, at minimum but not limited to, that pertains to recruitment and 
enrollment will be tracked: number of scheduled clinical appointments reviewed, number of patients 
considered potentially eligible as determined during review of the clinical appointment schedule, number 
of patients who are potentially eligible but express no interest in participating in the study, number of 
patients who are determined ineligible following screening procedures, and etc. Additionally, data will be 
collected in regard to participants’ adherence to the study protocol regimen. All information obtained 
during pre-screening activities of those patients who do not enroll in the study will be de-identified and 
destroyed after feasibility information is documented. 
3.3.1.2 
Assess data entry and data management procedures (see section 2.2.1.1.2) 
Data will be entered and managed using an NYU and Health Insurance Portability and Accountability Act 
(HIPAA) compliant data collection system. Feasibility of this system between sites and timing of data 
entry/management will be assessed. 
3.3.1.3 
Assess evaluation methods: Other (see section 2.2.1.1.3) 
Demographic Questionnaire: Data will include gender, ethnicity, race, education, living situation, marital 
status, caregiver assistance, socioeconomic status, date of glaucoma diagnosis, medical and eye 
histories, glaucoma treatment regimen, glaucoma symptoms measured with the Glaucoma Symptom 
Scale,142 and depression risk measured with the Patient Health Questionnaire-9.143,144 The demographic 
questionnaire will be self-administered and require 15 minutes to complete; research personnel will be 
present to answer questions or assist as needed. The questionnaire will be included with participants’ 
source documents. 
 
Delis-Kaplan Executive Function System (D-KEFS): The D-KEFS is a neuropsychological test used to 
measure executive function, normed for ages 8-89 years.145 The test consists of nine sub-tests designed 
to stand alone. To address the potential that improved performance following intervention is an artifact of 
attention versus effect of the intervention, we will administer the Verbal Fluency Test that is comprised of 
three testing conditions: Letter Fluency, Category Fluency, and Category Switching. The test has an 
alternate form that can be used at post-intervention and/or follow-up. We chose this sub-test to eliminate 
any visual component and the test was shown to be sensitive to the effect of EST. The Verbal Fluency 
Test will require 5 minutes to perform. The Verbal Fluency Test score sheet will be included with 
participants’ source documents. 
 
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV): The WAIS-IV is designed to measure 
intelligence and cognition, normed for ages 16-90 years.146 The test consists of 10 sub-tests and 5 
supplemental sub-tests designed to stand alone. To address the potential that improved performance 
following intervention is an artifact of attention versus effect of the intervention, we will administer the Digit 
Span sub-test, for which respondents must recall a series of numbers as presented in order. We chose 
this sub-test to eliminate any visual component and the test was shown to be sensitive to the effects of 
EST.146 The Digit Span test will require 5 minutes to perform. The Digit Span score sheet will be included 
with participants’ source documents. 
 
Pre-/Post-session Questionnaire: A data collection form and questionnaire designed specifically for this 
study will track basic health-related and intervention-related information including the following data: heart 
rate, blood pressure, visual skin observation at electrode sites, any changes in participant’s typical 
glaucoma therapy regimen prescribed by their physician, and symptoms. It will be completed at baseline, 
each study intervention visit (1-10), and post-intervention. The form will require 5 minutes to complete. 
The questionnaire will be included with participants’ source documents. 
 

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Post-intervention Interview: A subjective, open-ended visual function interview, used clinically by 
collaborators of this study for patients who received rtACS, will be conducted for participants to report 
their subjective functional and related experiences in association with the rtACS intervention.  
4 Subject Selection and Withdrawal 
We will enroll 16 participants with confirmed glaucoma (moderate stage or worse but not total blindness). 
Participation will be open to those with all types of glaucoma who meet the eligibility criteria (described 
below). Patients will be recruited until the estimated sample size is achieved, the metric for which is when 
the total number of enrolled participants projected to be randomized to the intervention group complete 
the rtACS protocol through the follow-up time point. 
4.1 Inclusion Criteria 
Participants must meet the following inclusion criteria 
in order to participate in the pilot study. 
1. Aged 50-70 years 
2. Live in a community, residential setting (i.e., non-
institutionalized, not homeless) 
3. Diagnosis of glaucoma (not type-specific, 
excluding traumatic glaucoma) 
a. Glaucoma severity (Hodapp-Parrish-
Anderson147): Moderate defect or worse in 
both eyes but not total blindness (must be 
able to perform VF testing, Table 2) 
b. Because of the inherent variability in subject’s 
       performance of the visual field test (the test 
       being a subjective, behavioral test  
       influenced by factors such as alertness and 
       wakefulness), one eye must test at MD ≤ -6.0 
       dB and the other eye may test at MD ≤ -3.0 dB. 
       This criterion will allow for qualification of subjects for whom their disease is considered moderate  
       but their visual field testing demonstrates variability. 
4. VF defects present for at least 6 months 
5. Clear optical apparatus 
6. Best-corrected VA of 20/200 (1.0 logMAR) or better in at least one eye 
7. Commitment to comply with study procedures (2 week period of intervention sessions) with baseline, 
post-intervention, and follow-up visits 
a. Scheduling 
b. Testing 
 
Modification 05.24.2017 
Original inclusion criteria number 1 is changed from aged 50-70 years to aged 50-80 years. 
4.2 Exclusion Criteria 
Participants that meet any of the following criteria will be excluded from the pilot study. 
1. Diagnosed optic neuropathy/pathology other than glaucoma 
2. End-stage organ disease or medical condition with subsequent vision loss (e.g., diabetes, stroke) 
3. Other diseases of the retina or cataracts responsible for worse than 20/70 best-corrected VA 
4. Pathological nystagmus 
5. Acute conjunctivitis  
6. Photosensitivity to flickering lights 
7. IOP > 27 mmHg at baseline 
8. Non-ocular/ocular surgery within the previous 2 months to enrollment date 
9. Medically diagnosed memory disorder or Telephone Interview for Cognitive Status-modified (TICS-m) 
score ≤ 27 
Table 2. Hodapp-Parrish-Anderson 
Classification 
Classification of defect: 
• 
MD ≤ -6.0 dB 
• 
≥ 25% of the points (18) are depressed below 
the 5% level and ≥ 10 points are depressed 
below the 1% level on the pattern standard 
deviation plot 
• 
≤ 1 point in the central 5° can have a sensitivity 
of 0 dB 
• 
Only one hemifield may have a point with 
sensitivity of < 15 dB within 5° of fixation OR 
points within the central 5° with sensitivity < 15 
dB in both hemifields 
MD=mean deviation. 

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10. Electric or electronic implants (e.g., cardiac pacemaker) 
11. Metallic artifacts/implants in head and/or torso (titanium screw and dental implants are allowed) 
12. Diagnosed epilepsy 
13. Epileptic seizure within the past 3 years of enrollment date 
14. Auto-immune disease, acute stage (e.g., rheumatoid arthritis) 
15. Metastatic disease 
16. Certain mental diseases/psychiatric conditions (e.g., schizophrenia) that would preclude reliable 
testing and participation 
17. Certain unstable medical conditions (e.g., diabetes, diabetes causing diabetic retinopathy) 
18. Addiction (e.g., drug/alcohol dependence) 
19. Systemic hypertension (> 160/100 mmHg) 
20. Pregnant or breast-feeding women 
21. Any severe skin condition (e.g., blisters, open wounds, cuts or irritation) or other skin defect which 
compromise the integrity of the skin at or near stimulation locations 
22. 10-item Geriatric Anxiety Scale (GAS-10) score ≥ 12 
23. Claustrophobia (to limit functional neuroimaging) 
24. Obesity (MRI weight limit: <300 pounds) 
25. Received rtACS in the past 
4.3 Subject Recruitment and Screening 
4.3.1 Recruitment [NYU Langone Eye Center and New York Eye and Ear Infirmary of 
Mount Sinai] 
Recruitment procedures include pre-screening activities and an introduction of the research study to 
potentially eligible patients by ophthalmologists (including the clinical staff under their supervision) and/or 
members of the research team. Patients will be recruited in New York, New York, from the following 
centers: NYU Langone Eye Center and New York Eye and Ear Infirmary of Mount Sinai (referred to as 
Centers from this point forward).  
• 
Recruitment from the Centers will occur simultaneously.  
• 
Patients will be recruited in accordance with the pace the research personnel are able to schedule 
recruitment and screening activities. 
• 
Patients will be recruited until the estimated sample size is achieved, the metric for which is when the 
total number of enrolled participants projected to be randomized to the intervention group complete 
the rtACS intervention through the follow-up time point. 
 
NYU Langone Health will enroll NYU employees, including those working within the Department of 
Ophthalmology. Employees, who are listed on the delegation log as study team member, will not be 
enrolled into the research study. 
IRB approved advertisements are distributed and displayed at approved NYU Langone Health locations. 
Interested employees will approach the study team members to discuss the study. The eligibility 
determination procedures will follow the standard methods listed above. The study team members will 
emphasize that participation is voluntary. The person obtaining consent will also emphasize that the 
candidate’s decision will not affect their employment within NYU Langone Health and/or NYU School of 
Medicine. 
Procedure 
• 
Pre-screening activities: Patients’ clinical appointments scheduled with ophthalmologists involved in 
this study will be reviewed to identify potential participants with a known medical diagnosis of 
glaucoma. Additionally, patients’ relevant medical histories will be reviewed preparatory for research 
only to identify exclusionary medical and/or ophthalmic criteria. Trained research personnel in 
partnership with a clinical research coordinator and/or clinical staff will complete these procedures 
during the week prior to the scheduled appointment. This step will be implemented: 1) to minimize the 
time burden for patients and physicians in regard to research activities associated with determining 
study eligibility and 2) to allow patients time to consider participation in this study to maximize the 
efficiency of the screening process. 

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o 
Patients’ medical records will be reviewed only to identify whether they generally meet 
the research study eligibility criteria (see Attachment 3, Pre-screening Form). 
o 
For those patients identified as potentially eligible for the study, a research notification 
alert will be provided to the clinical team the day of the patient’s clinical appointment (see 
Attachment 3, Physician Form). 
o 
In addition to the eligibility criteria identified during the medical record review and only 
when all criteria are met, the patient’s age and phone number(s) listed as the means of 
contact will be documented in order to verify the correct response on the TICS-m. 
o 
Following pre-screening activities, de-identified information will be entered into a 
password protected electronic research file for tracking purposes (see Attachment 3, 
Tracking Form: Clinical Appointments Review). Recruitment forms for non-enrolled 
patients will be disposed of, following PHI procedures, once the data is entered into the 
research file. 
 
• 
An ophthalmologist, using conventional techniques, will examine patients during their clinical 
appointment (routine standard of care). Physicians will complete the appropriate Physician Form (see 
Attachment 3) to indicate there was no change in patient’s medical history (as it relates in general to 
the eligibility criteria for this study) identified during the pre-screening review of patient’s medical 
record. For those patients who generally meet the eligibility criteria, the physicians will introduce the 
research study. If a patient expresses interest in learning more about the study, research personnel 
will discuss the study with the patient (no research activities conducted other than exchange of 
general information about the study and answering any questions; see Attachment 4, Recruitment 
Script [recruitment section only]).  
 
o 
Research personnel will be present as often possible at the Centers on those days when 
the physicians involved in this study are scheduled with clinical appointments. 
o 
When research personnel are not physically available to discuss the study, the patient 
will provide his/her contact (phone) information for the research team and the process will 
be documented on the Physician Form. The patient will be informed that a trained 
research team member will contact him/her to discuss the research study. The research 
personnel’s contact information will be provided to the patient so he/she is aware of 
whom to expect will be contacting him/her. Once the patient has been contacted by 
research personnel, his/her contact information will be immediately destroyed. If the 
patient decides to engage in screening activities, procedures as outlined for screening 
will be followed. 
4.3.2 Recruitment [Other] 
In the case when NYU Langone Eye Center/a member of the research team is contacted by an entity 
other than an NYU Langone Health patient in regard to rtACS research, general information in regard to 
the purpose of the protocol and the eligibility requirements to participate will be provided. In said case, 
said entity may send a copy of both the (1) ophthalmic health record and (2) medical health record of the 
potential candidate to Dr. Joseph Panarelli at NYU Langone Eye Center, attention toDr. Maria De Los 
Angeles Ramos Cadena, for review in regard to eligibility. It is the responsibility of the interested entity to 
request from their eye care and primary medical providers the release of their ophthalmic and medical 
health records, respectively, to be sent to NYU Langone Eye Center. Said records sent to NYU Langone 
Eye Center will be scanned to EPIC by ophthalmology clinical staff; the records are reviewed by research 
personnel and a glaucoma specialist involved in this study as part of the pre-screening research 
procedures. In the case when clarification of ophthalmic and/or medical health histories is required, the 
record’s provider will be contacted to clarify details that pertain to eligibility for this protocol.  
After review of the ophthalmic and medical health records, screening procedures for the screening 
interview (the same as those already established, see section 4.3.3) will be conducted (see Attachment 4, 
Recruitment Script, Verbal Consent, and Screening Interview) which further queries/verifies potential 
participants’ ophthalmic and medical health histories. If eligible to participate in the protocol, said entity 

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will follow the same protocol and procedures as established for subjects recruited from New York Eye and 
Ear Infirmary of Mount Sinai. 
4.3.3 Recruitment: Flyer 
An IRB approved recruitment flyer will be displayed at NYU Langone Eye Center and may be used in 
conjunction with discussions with interested persons in regard to rtACS. When a potential subject 
contacts a study team member, information regarding the next steps for eligibility determination will be 
conducted. 
4.3.4 Screening 
Screening procedures will be performed to identify patients’ eligibility to participate in this study. All 
participants will be screened to determine that they meet all eligibility criteria. Screening procedures to 
determine eligibility will be performed by trained research personnel. The screening procedures were 
designed such that the screening tools that require patient interaction can be administered either face-to-
face or via the telephone. This screen is minimal risk to the patient and collected information will be 
maintained in secured, locked files. De-identified information (assigned a study screening code [screen 
pass or screen fail]) will be entered into a secure, NYU and HIPAA compliant database. When a patient is 
not eligible, they will be considered a screen fail. No additional information will be collected. Only study 
personnel will have access to said records. Clinic recruitment tracking data will be collected (see 
Attachment 4, Tracking Form: Clinic Recruitment). For any patient who is determined not to be eligible or 
declines to participate, any identifiable health information that was collected will be disposed of, following 
PHI procedures, once the de-identified tracking data is entered into the research file. 
 
There are two components to the screening process (see Attachment 4): 1) interview and 2) medical 
record review. Screening procedures will require less than 30 minutes of patient’s time.  
4.3.4.1 
Screening Interview 
The screening interview (see Attachment 4, Recruitment Script) involves educating patients about the 
study and obtaining their verbal permission to conduct screening activities (under waiver of 
documentation of consent). Interview questions pertain to eligibility criteria, anxiety and cognitive screens. 
 
Anxiety: The GAS-10 is a 10-item instrument that measures anxiety symptoms in adults/older adults; 
items were derived from the range of anxiety disorder symptoms in the DSM-IV-TR.148,149 The GAS-10 will 
be administered to patients to minimize variance for the purposes of a pilot study. Per the expert 
recommendation of collaborators who administer the rtACS intervention, the basis for including this test 
as part of the screening process is that said collaborators have found that people with greater anxiety 
have a poorer response to rtACS. The GAS-10 will be administered per protocol. Patients who score ≥12 
are excluded from the study based on receiver operating characteristic analyses. Eligibility for enrollment 
in the study based on the GAS-10 score will be indicated on the Recruitment Script form. 
 
Cognition: The TICS-m is a 13-item instrument that will be administered as part of the screening process 
to identify potential patients with a cognitive impairment who are likely unable to accurately complete self-
report questionnaires.150,151 The TICS-m can be administered either face-to-face or via the telephone, 
which is why it is the tool chosen for the screening process. The TICS-m will be administered per 
protocol. Patients who score ≤ 27 are excluded from the study; based on score interpretation that these 
people have greater than mild cognitive impairment.152 Eligibility for enrollment in the study based on the 
TICS-m score will be indicated on the Recruitment Script form. 
 
• 
Setup: The GAS-10 and TICS-m will be administered in a distraction free room. When administered 
via the telephone, patients will be prompted that they should be in a distraction free area and should 
not be interrupted during the interview. 

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4.3.4.2 
Medical Record Review 
A review of patients’ ophthalmic medical records will be conducted as part of the screening process to 
ensure there were no significant changes identified during their ophthalmic examination to determine 
patients’ eligibility for this pilot study (see Attachment 4, Screening Form). Eligibility for enrollment in the 
study based on the medical record review will be indicated on the Screening Form. Patient identifiable 
information will only be recorded from the medical record after patients enroll in the study. 
 
Procedure: Screening  
• 
When trained research personnel are present at the Centers, screening procedures will be conducted 
the same day as the clinical appointment per patient’s availability. 
 
o 
Research personnel will be present as often possible at the Centers on those days when 
the physicians involved in this study are scheduled with clinical appointments. 
o 
Screening procedures will be conducted in a private room, distraction free, to safeguard 
privacy. 
 
• 
When trained research personnel are not available to conduct screening activities, the patient’s verbal 
permission that his/her information can be shared with the research team will be obtained and 
documented and the patient will be informed that a trained research team member will contact 
him/her to discuss the research study and screening procedures. The research personnel’s contact 
information will be provided to the patient so he/she is aware of whom to expect will be contacting 
him/her. 
 
o 
Patients will be contacted via phone unless otherwise specified by the patient at the time 
when verbal permission was obtained and documented. 
o 
Research personnel will contact patients within two business days of being informed of 
the patient’s permission that his/her information can be shared with the research team. 
Three attempts will be made within 7 days. After three attempts, research personnel will 
initiate no further phone contact. 
 
• 
When patients are not able or available to participate in screening activities the same day as their 
clinical visit, screening procedures will follow those described for when trained research personnel 
are not available. 
• 
Once all screening procedures are completed and the information analyzed, patients will be informed 
of their eligibility to participate in this study.  
 
o 
Patients will be informed of their eligibility to participate in the study as soon as possible, 
no more than two business days following completion of screening procedures. This 
timeframe is established to account for potential variability in the timing of the screening 
procedures, patients’ availability, and documentation of medical record review. 
 
• 
For those patients who meet the eligibility criteria and agree to participate in the study, trained 
research personnel will schedule a date and time to meet with the patient to review and obtain written 
informed consent prior to initiating administration of study assessments (see Attachment 4, 
Participant Visit Schedule). 
 
In the case when NYU Langone Eye Center/a member of the research team is contacted by an entity 
other than an NYU Langone Health patient in regard to rtACS research, the screening interview will be 
conducted via phone. A health records review will be conducted again to confirm no conflicting reports 
between information gathered during the screening interview with what is documented in the entity’s 
health records. All other screening procedures are the same as conducted for the Centers. 

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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Research personnel will monitor participants throughout the course of the study. Participants may be 
withdrawn from the study as decided by trained research personnel prior to the expected completion of 
that participant’s role in the study. Reasons for withdrawal may include, but not be limited to: 
• 
Adverse event  
• 
Change in status relevant for inclusion or exclusion eligibility 
• 
Change in medical diagnosis or treatment 
• 
Non-compliance with study protocol 
• 
Atypical skin condition* 
• 
Atypical headache** 
• 
Atypical discomfort*** 
*Erythema (skin reddening) is not a criterion for withdrawal. It is an anticipated effect (monitored) that may occur following the 
intervention as a result of increased blood flow at the site of the electrodes due to vasodilation as a secondary effect of current 
application across the skin and tissue barriers. 
**Headaches naturally occur in the normal population. Atypical headache is an unusual headache either in occurrence or in 
intensity. 
***Atypical discomfort entails an event when a participant expresses a desire to terminate a session, i.e., electrical stimulation would 
be aborted. In this case, when a participant requests to terminate a session, they will be withdrawn from the study. 
 
Because the risk profile of ACS is very low, no research-related injury is anticipated. The delivered current 
is weak, such that it can hardly be felt. In the unlikely event that a participant reports clinically-relevant 
harm from the study, this information will be conveyed to the study physician who will evaluate the 
participant. The physician will ensure that the participant has appropriate medical follow-up when 
indicated. If the event is serious and unexpected, the event will be reported to the IRB, per their reporting 
guidelines. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
In the case when a participant is withdrawn from the study, prior to the expected completion of that 
participant’s role in the study as decided by trained research personnel, we will obtain written permission 
to collect relevant follow-up data that directly pertains to the safety of that participant in regard to the 
intervention (e.g., adverse event/adverse effect related to intervention). Participants may withdrawal their 
consent to participate in the study at any time. Any identifiable research or medical information recorded 
for or resulting from the participant’s participation in the study prior to the date that the participant formally 
withdrew consent (written notification of withdrawal) may be used and disclosed by the investigators for 
the purposes of the study described above. 
5 Study Device  
5.1 Description 
The DC-Stimulator MC (neuroConn, GmbH, Ilmenau, Germany) will be used to deliver the rtACS protocol. 
It can be classified a Category B, Class II non-significant risk medical device. It has the capacity to deliver 
the established rtACS protocol documented in previous efficacy, safety, and interventional studies. It is a 
multi-channel electrotherapy device consisting of a programmable waveform generator that connects to 
electrodes to deliver a non-invasive, weak electric current (see section 1.2). 
5.2 Treatment Regimen 
After obtaining written informed consent, participants will be allocated (1:1 ratio) to either rtACS or sham 
stimulation intervention group. The intervention protocol for each group involves 10 daily sessions 
delivered over 2 weeks, 1 session per day, < 60 minutes of continuous/sham stimulation (0-100 Hz) per 
day following the established dose parameters. The rtACS group will receive the stimulation dose per 
protocol. During a sham stimulation session, the DC-Stimulator MC will be programmed accordingly 
which may include brief periods of stimulation at the beginning and/or end of the session, serving to 

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mimic the effects of a true stimulation session. Researchers report this is necessary to designing the 
masking component of this study.  
5.3 Method for Assigning Subjects to Treatment Groups 
For the randomization scheme, participants will be randomized (1:1 ratio) to the rtACS and sham 
stimulation groups using blocked randomization stratified by Centers (to determine any differences 
between the Centers). Random varying block sizes will be used to balance group allocation and minimize 
the risk of unmasking group assignment, and a randomization table will be computer generated 
accordingly. A statistician will generate a randomization table and a research staff member indirectly 
involved in the conduct of this study will conduct the process of allocation. Participants will be assigned in 
the order that they are enrolled. The randomization and allocation concealment will be uploaded to a 
secure database. 
5.4 Subject Compliance Monitoring 
Research personnel will monitor and document participants’ compliance with attendance at scheduled 
baseline assessments, daily intervention sessions, and follow-up assessments. As part of the recruitment 
process, patients will be interviewed in regard to their availability to attend 10 daily sessions over a 2-
week period. Participants’ baseline assessments will be scheduled to accommodate their schedule within 
reason and the timeframe for the conduct of this study. In the event when an enrolled participant is unable 
to adhere to the study protocol, consideration for withdrawal will be discussed and documented by the 
research team.  
5.5 Prior and Concomitant Therapy 
During the study, participants will continue their normal glaucoma treatment regimen prescribed by their 
physician. Any change in said regimen or clinical procedures will be evaluated based on the eligibility 
criteria for this study. 
5.6 Packaging 
N/A. The DC-Stimulator MC device will be owned by NYULMC Department of Ophthalmology and will be 
used for this study for all participants at NYU Langone Eye Center. The device is treated like any patient-
care instrument used within the department. Therefore, there are no individual packaging or kits for each 
participant. Each participant will have their own set of electrodes that will be managed per protocol (i.e., 
setup and cleaning), kept in individually labeled and sealed storage vessels, and will be stored in a 
research-designated space. In the event of device malfunction, a back-up device and extra electrodes will 
be stored onsite to avoid disruption of the study procedures. 
5.7 Masking of Study 
Interventionist will be masked to rtACS versus sham stimulation intervention group. He/she will not be 
involved in the allocation process. The DC-Stimulator MC has a programmable sham feature to maintain 
masking. A trained personnel who is not involved in data collection or analysis will be involved in the 
setup of the DC-Stimulator MC according to group allocation and rtACS protocol for each participant, 
following setup parameters and current standards for masking. Participants will be blind to group 
allocation. Following completion of the 10 daily sessions, interventionist and participants will be asked to 
guess the assigned condition during follow-up assessments.  
5.8 Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Study Device 
The DC-Stimulator MC will be purchased and shipped from neuroCare Group GmbH, Rindermarkt 7, 
80331 München, Germany to NYU Langone Eye Center, 240 East 38th Street, 13th floor, New York, NY 
10016. Upon receipt of the device (including backup device), an inventory will be performed and 
designated staff will verify that the shipment contains all the items noted in the shipment inventory. Any 

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damaged piece in a given shipment will be reported to research personnel and documented. The DC-
Stimulator MC will be used for this study for all participants at NYU Langone Eye Center. 
5.8.2 Storage 
The devices and supplies will be located in a treatment room designated for research purposes at NYU 
Langone Eye Center. The backup device will be appropriately placed for storage in a locked room.  
6 Study Procedures 
Screening procedures will be conducted in a research-designated room at the Centers appropriate for the 
setup and confidentiality for the interview procedures. Baseline assessments, intervention sessions, post-
intervention and follow-up assessments for all participants will be conducted in a research-designated 
room at NYU Langone Eye Center.  
 
Per standardized assessment guidelines and in order to accommodate and minimize the amount of time 
subjects may be willing and/or able to participate in research procedures at the Eye Center, assessments 
of functional ability and QoL may be coordinated with subjects for virtual administration (e.g., via phone, 
Webex, etc.). 
 
The IRB-approved recruitment script used during the screening procedures for this study will be used for 
contacting new patients, in conjunction with the COVID-19 Updates Research Participant Recruitment 
script provided by the OSR/IRB. In addition, the applicable COVID information sheet for potential and 
enrolled subjects will be provided in the appropriate situation and while they are applicable to subjects. 
 
Trained personnel who are not involved in data collection or analysis will be involved in the programming 
of the DC-Stimulator MC according to group allocation for each participant and the masking procedures 
that distinguish the delivery of rtACS versus sham stimulation. All intervention procedures will be 
conducted the same for both groups (rtACS and sham). Adverse events/adverse effects will be assessed 
in either condition. 
 
Refer to Attachment 5 for the study schedule of events and Attachment 6 for documentation forms 
described below. 
6.1 Visit: Baseline 
Within five business days prior to the start of intervention sessions, the informed consent procedures and 
baseline assessments will be administered. 
6.1.1 Process of Consent 
Trained research personnel will review the consent form with the patient and explain the purpose of the 
study, the procedures, as well as risks and benefits.  
• 
Review study requirements 
• 
Allow patient to read consent 
• 
Answer questions 
• 
Patient will sign consent 
A copy of the consent form will be given to the patient. All questions will be addressed before acquiring a 
patient’s signed consent. The signed consent form will be placed in the Regulatory Binder, kept separate 
from participant data. The consent process will be documented on the Case Report Form. Each 
participant will be asked whether they wish to receive documentation linking them to the study. 
6.1.2 Assessments  
Ophthalmic examination: Procedures follow standard practice including examination by an 
ophthalmologist and testing includes: recording medical and family history, VA testing, axial length, IOP 
and central corneal thickness measurements, slit lamp examination, indirect ophthalmoscopy, and 

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stereophotography of the optic nerve head, macula, and nerve fiber layer. The total time requirement for 
the ophthalmic examination is approximately 45 minutes. 
 
The following assessments (approximate minutes to complete) will be administered at baseline: Pre-
/Post-session Questionnaire (5), VF (20), VA (5), CS (5), OCT (10), OCT-A (10), VEP and PERG (15), 
Demographic Questionnaire (15), Verbal Fluency Test (5), Digit Span (5), LIFE-H (30), MNRead (10), 
VFQ-39 (25), SF-36 (25), and PSQI (10).  
 
The total time requirement for participants for baseline testing is approximately 3 hours in addition to the 
ophthalmic examination. 
 
MRI testing will be performed at baseline and will require up to 2 hours. Baseline assessments may be 
scheduled on separate days due to timing, location of MRI facility, and patient scheduling.  
 
The Brief COPE questionnaire (Attachment 10) will be included in the battery of questionnaires. The Brief 
COPE is a 28-item questionnaire designed to measure effective/ineffective coping in response to a 
stressful life event. The time requirement for the questionnaire is less than 5 minutes. The questionnaire 
is included in order to capture effective/ineffective ways subjects cope with the COVID-19 situation and in 
order to determine whether their response to their lived experience with the COVID-19 situation may 
influence other study outcomes. The Brief COPE has been validated.155,156 
 
Pittsburgh Sleep Quality Index (PSQI) will be included in the battery of questionnaires. The PSQI is a 
validated 10-item questionnaire designed to measure sleep quality. Evidence suggests RGCs are 
involved in circadian photoreception to regulate homeostasis; modulating a non-visual response to light 
associated with sleep. Testing will be administered per standardized protocol and will require < 10 
minutes to perform. For subjects who have completed research procedures through follow-up, we will 
contact them to conduct the questionnaire. 
6.2 Visit: Daily intervention sessions 1-10 
Beginning on a Monday, 10 daily intervention sessions will be scheduled to span 2 weeks (excluding the 
weekend). Prior to each daily session on the same date, trained personnel will check the DC-Stimulator 
MC and other necessary equipment that will be used during the session for quality and integrity of 
function (see Research Activity Checklist). The Pre-/Post-session Questionnaire will be completed (5 
minutes). The stimulation protocol (rtACS or sham) will be delivered, requiring approximately 90 minutes 
including all associated procedures including setup. 
 
The total time requirement for participants for daily sessions is approximately 1 hour. 
6.3 Visit: Post-intervention 
Post-intervention assessments will be scheduled for administration within five business days of 
participants’ last intervention sessions.  
 
Ophthalmic examination: Procedures follow standard practice including examination by an 
ophthalmologist and testing includes: recording medical and family history, VA testing, axial length, IOP 
and central corneal thickness measurements, slit lamp examination, indirect ophthalmoscopy, and 
stereophotography of the optic nerve head, macula, and nerve fiber layer. The total time requirement for 
the ophthalmic examination is approximately 45 minutes. 
 
The following assessments (approximate minutes to complete) will be administered: Pre-/Post-session 
Questionnaire (5), VF (20), VA (5), CS (5), OCT (10), OCT-A (10), VEP and PERG (15), Verbal Fluency 
Test (5), Digit Span (5), LIFE-H (30), MNRead (10), VFQ-39 (25), SF-36 (25), and Post-intervention 
Interview (60).  
 
The total time requirement for participants for post-intervention testing is 3 hours in addition to the 
ophthalmic evaluation. 

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MRI testing will be performed at post-intervention and will require up to 2 hours. Post-intervention 
assessments may be scheduled on separate days due to timing, location of MRI facility, and patient 
scheduling. 
 
The Brief COPE questionnaire (Attachment 10) will be included in the battery of questionnaires. The Brief 
COPE is a 28-item questionnaire designed to measure effective/ineffective coping in response to a 
stressful life event. The time requirement for the questionnaire is less than 5 minutes. 
6.4 Visit: Follow-up 
Follow-up assessments will be scheduled for administration 4 weeks following the participants’ last 
intervention sessions.  
 
Ophthalmic examination: Procedures follow standard practice including examination by an 
ophthalmologist and testing includes: recording medical and family history, VA testing, axial length, IOP 
and central corneal thickness measurements, slit lamp examination, indirect ophthalmoscopy, and 
stereophotography of the optic nerve head, macula, and nerve fiber layer. The total time requirement for 
the ophthalmic examination is approximately 45 minutes. 
 
The following assessments (approximate minutes to complete) will be administered: Pre-/Post-session 
Questionnaire (5), VF (20), VA (5), CS (5), OCT (10), OCT-A (10), VEP and PERG (15), Verbal Fluency 
Test (5), Digit Span (5), LIFE-H (30), MNRead (10), VFQ-39 (25), and SF-36 (25).  
 
The total time requirement for participants for follow-up testing is approximately 3 hours in addition to the 
ophthalmic examination. 
 
MRI testing will be performed at follow-up and will require up to 2 hours. Follow-up assessments may be 
scheduled on separate days due to timing, location of MRI facility, and patient scheduling. 
 
The Brief COPE questionnaire (Attachment 10) will be included in the battery of questionnaires. The Brief 
COPE is a 28-item questionnaire designed to measure effective/ineffective coping in response to a 
stressful life event. The time requirement for the questionnaire is less than 5 minutes. 
7 Statistical Plan 
7.1 Sample Size Determination 
Given the objectives of this pilot study (see section 2) and limited data about the effect of rtACS for 
people with glaucoma, we estimate to enroll 16 participants to complete the study protocol. Our rationale 
for this number includes the following considerations: feasibility, quantifying an estimate of effect and 
estimate of variance, and validating methodologies.153 We are using a block randomization scheme with a 
1:1 allocation ratio for rtACS versus sham stimulation groups to collect data to inform the characterization 
of each group. We anticipate finding little to no effects in the sham stimulation group for a control but we 
establish equal allocation to groups to assess potential placebo effect. 
7.2 Statistical Methods 
All study participants will be included in efficacy analyses as randomized (intent to treat population). 
Treatment effects on all outcomes will be estimated with 95% confidence interval. Supportive analyses 
will include estimating effects in study participants who received at least five sessions of their randomized 
assigned treatment as supportive analyses and hypothesis testing with two-sided tests at significance 
level of 0.05. 
 
The primary outcome variables that will be evaluated in this study are structure and function of the retina 
and visual pathway (using imaging and electrophysiological technology), visual function, functional ability, 

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and QoL. Secondary outcome variables include feasibility of procedures and methodologies for 
recruitment, enrollment, data collection and data management. 
 
Subjective demographic and clinical characteristics will be analyzed using descriptive statistics. 
Continuous variables will be described by means and standard deviations (or by median and interquartile 
range for skew distribution) and categorical variables will be described by frequencies (count) and 
percentages. Overall, to analyze our aims and test our hypotheses we will use between and within group 
comparison analyses (e.g., t-tests) to evaluate change scores from baseline to post-intervention and 
follow-up between rtACS and sham stimulation groups. We will use effect size calculations to evaluate 
the magnitude of differences between and within groups. Additionally, we will quantify an estimate of 
variance using 95% confidence interval. Analyses will be conducted using R statistical computing 
software. 
 
Aim 1 (2.1.1.1): Measure structural and functional capabilities of neuronal physiology and reorganization 
of the visual pathway (from eye to visual brain)  
 
We will calculate change scores between baseline and study end scores on primary outcome variables. 
These difference scores will then be described and compared between and within groups for: 1) structure 
and function of the retina and visual pathway measures and 2) visual function. We will perform a 
multivariate analysis to examine the correlation between measures of retinal and visual pathway 
structure/function and measures of visual function. We will quantify estimates of effect and estimates of 
variance. 
 
Aim 2 (2.1.2.1): Measure objective ability/disability and subjective well-being (i.e., QoL) 
 
We will perform a multivariate analysis to examine the correlation among measures of visual function, 
functional ability, and QoL. 
 
Aim 3 (2.2.1.1): Evaluate the data collection, data management methods, and study procedures for 
targeted outcomes other than the primary objectives 
 
We will use descriptive statistics to analyze secondary outcomes to measure feasibility of procedures and 
methodologies for recruitment, enrollment, data collection and data management, etc.  
7.3 Subject Population(s) for Analysis 
Our primary analysis will be an intention to treat analysis. The data for all participants randomized into the 
study, regardless of study group, will be subjected to the study analyses, both for the primary and any 
applicable secondary analyses. 
8 Safety and Adverse Events 
Both the IRB and participants will be notified immediately of any new information in regard to this pilot 
study that affects participants’ participation in the study. Unexpected and serious adverse events that 
occur will be reported to the IRB according to the IRB protocol. The primary investigator (PI) and research 
investigator(s) involved will monitor a review of the outcome, anticipated effects, and adverse event data 
in determining whether the study should continue, change, or terminate. If there is a major unresolved 
dispute between a research investigator and a research participant or between research investigators, a 
letter will be submitted to the IRB describing the dispute and identifying the parties involved.  
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria. 
• Unexpected in nature, severity, or frequency (i.e., not described in study-related documents such 
as the IRB-approved protocol or consent form, etc.) 

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• Related or possibly related to participation in the research (i.e., possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places participants or others at greater risk of harm (including physical, 
psychological, economic, or social harm) 
 
Unanticipated Adverse Device Effect  
An unanticipated device effect is any serious adverse effect on health or safety, or any life-threatening 
problem or death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of participants. 
 
Serious injury 
Any injury or illness that is any one of the following:  
• life-threatening 
• results in permanent impairment of a body function or permanent damage to body structure 
• necessitates medical or surgical intervention to preclude permanent impairment of a body function 
or permanent damage to a body structure 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries will be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered adverse events if the abnormality: 
• results in study withdrawal, 
• is associated with a serious adverse device effect, 
• is associated with clinical signs or symptoms, 
• leads to additional treatment or to further diagnostic tests, or 
• is considered by the investigator to be of clinical significance. 
 
Based on International and U.S. guidelines on serious adverse events from medical devices (including 
the Office of Human Research and Protection of the U.S. Department of Health and Human Services; 
FDA regulations at 21 CFR §312.32[a]; 1996 International Conference on Harmonization E-6 Guidelines 
for Good Clinical Practice; ISO/DIS 14155-Clinical investigations of medical devices in humans, Good 
Clinical Practices, 2008), we classify a severe adverse event related to rtACS as a documented event 
that: 
1) Based on scientific judgment is determined to be caused or aggravated by the application of 
current to the head, such that serious adverse events not linked to stimulation are excluded, even 
if they are subject to reporting requirements, AND 
2) Results in irreversible damage of brain tissue, OR 
3) Results in persistent disability or incapacity that produces an unwanted and substantial disruption 
of a person’s ability to conduct normal life functions (i.e., the adverse effect resulted in an 
unwanted significant, persistent or permanent change, impairment, damage or disruption in the 
participant’s body function/structure, physical activities and/or QoL), OR 
4) Results in unexpected inpatient hospitalization or prolongation of existing hospitalization, where 
emergency room visits that do not result in admission to the hospital should be evaluated for one 
of the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent 
impairment or damage; other serious medically important event), OR 
5) Results in death or is life-threatening where the patient was at substantial risk of dying as a result 
of the adverse event, or use of the device was discontinued based on evidence rtACS might have 
resulted in death, OR 

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6) Medical or surgical interventions were necessary to preclude permanent imminent impairment of 
a body function due to rtACS, or prevent permanent damage to a body structure, due to rtACS. 
8.2 Recording of Adverse Device Effects 
Prior to and at each contact with the participant, the investigator will evaluate adverse device effects by 
examination and, as appropriate, by specific questioning. Information on all adverse device effects will be 
recorded immediately in the source document and in the appropriate adverse effect module of the 
Research Activities Checklist (see Attachment 7) and Case Report Form. All clearly related signs, 
symptoms, and abnormal diagnostic procedure results will be recorded in the source document, grouped 
under one diagnosis. 
 
All adverse device effects 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 treatment 
or participation is not the cause. Serious adverse device effects that are still ongoing at the end of the 
study period will be followed up to determine the final outcome (see section 8.3). 
 
The minimum initial information to be captured in the participant’s source document concerning the 
adverse device effect includes:  
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
Device model and serial number 
• 
A description of the event 
• 
Date of onset 
• 
Investigator assessment of the association 
between the event and study treatment 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
Whether the event is serious and reason for 
classification as serious 
8.3 Reporting of Adverse Device Effects and Unanticipated Problems 
8.3.1 Investigator Reporting: Notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to participants or others. The following describes the NYULMC IRB reporting requirements, 
though investigators at participating sites are responsible for meeting the specific requirements of their 
IRB of record.  
 
Report promptly, but no later than 5 working days: 
Researchers will submit reports of the following problems promptly but no later than 10 working days from 
the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the PI, the event was more likely than not to be caused by the research procedures.  
– Harmful: either caused harm to participants or others, or placed them at increased risk 
 
• Unanticipated adverse device effect: Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application, or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of subjects). 
 

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Other Reportable events: 
The following events will be promptly reported to the IRB, though no later than 10 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency (e.g., analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect, other research finds arm of study has no therapeutic value, 
FDA labeling change or withdrawal from market). 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the Reportable Events Log (see 
Attachment 7) or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form 
and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Regulatory 
Binder. 
8.4 Recording and Reporting of Anticipated Effects 
At each contact with the participant, the investigator will seek information on the occurrence of any known 
(anticipated) effects of the intervention by specific questioning and, as appropriate, by examination (see 
Attachment 7, Adverse Event Reporting). Information on all anticipated effects will be recorded 
immediately in the source document. All clearly related signs, symptoms, and abnormal diagnostic 
procedure results will be recorded in the source document, grouped under one diagnosis. 
 
All anticipated effects occurring during the study period will be reported to the appropriate research 
personnel involved in the participants’ intervention programs. The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause. Any effects that are still ongoing at the end of the study period will be 
followed up to determine the final outcome. Any effects that occur after the study period will be recorded 
and reported promptly. The minimum initial information to be captured in the subject’s source document 
concerning the anticipated effects are listed in section 8.2.  
 
Documented cases of mild side effects related to delivery of ACS which occasionally occurred include: 
erythema (skin reddening), skin tingling, skin itching, skin burning sensation, sensation of warmth at site 
of electrode placement, nausea, diffuse or migraine-like headache, facial muscle twitching, blurred vision, 
short-lived localized head pain or pressure, weak headache, forgetfulness, difficulty concentrating, 
change in mood, dizziness, general fatigue, sleeping difficulties (temporary), spontaneous phosphenes 
(independent of stimulation), blood pressure fluctuation, and difficulty breathing (103, 106). 
 
Participants may experience double vision and difficulty in near vision tasks (e.g., reading), which is 
common, as an effect of dilating eye drops used during the clinical vision evaluation. Additionally, dilating 
eye drops may cause: redness of the eye, tearing or stinging of the eye, feeling faint or dizzy, and/or 
sensitivity to light. As it is standard of care, it is recommended that participants arrange for someone to 

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assist them in their transportation after the study visit. It is also recommended participants wear 
sunglasses when they go outside or into a brightly lit room. The effects of these dilating drops will 
disappear within 3-4 hours after they are instilled in the eye. Pupillary dilation may cause an increase in 
eye pressure or the possibility of an angle-closure event, which happens in a rare configuration of the 
eyes. There is a low risk that the instrument used to check participants’ eye pressures (standard of care) 
might cause a scratch on the cornea. All participants will be examined clinically before dilating drops are 
instilled to identify eyes at risk, in which no dilation drops will be used. If either of these risks should 
occur, the participant will be treated immediately at no cost. 
 
There is minimal risk of eye infection to participants from the ophthalmic testing procedures. To reduce 
the risk of eye infection, all exposed surfaces near the eye, as well as chin rest and forehead rest of the 
instruments, will be cleaned with alcohol before participants are examined per standard practice. 
 
Some research subjects have reported mild discomfort with MRI scans. MRI uses a strong magnetic field 
to create images of the body. Because of the strong magnetic field, there are risks. One possible risk is 
burns to the skin. There is an increased risk of burns from devices that conduct electrical energy. These 
devices can include metallic objects or skin tattoos. These devices can be either in or on the patient in 
order for a skin burn to occur. The FDA has found that 70% of all who reported injuries from MRIs were 
burns to the skin. To reduce this risk, all participants who are scanned in this study must complete 
thorough screening to ensure that no conductive materials are present in or on the participant’s body. 
Additionally, the power limits of the magnet will be adjusted as necessary. Another possible risk is that a 
metal object could be pulled into the scanner and hit the participant. To reduce this risk, everyone near 
the magnet will remove all metal from his/her clothing or pockets when in the scanning environment. 
Participants will be carefully screened to ensure no metal objects enter the magnetic field and they will be 
asked to place all metallic and magnetic objects in their possession (e.g., keys, jewelry, credit cards) in a 
secure location outside the magnet room.  
 
The magnetic fields, at the strengths used, are felt to be without harm and the MRI scanning procedures 
fall within the FDA guidelines for radiofrequency electromagnetic field exposure. It is felt these are safe 
levels and less hazardous than a comparable x-ray computed tomography examination. Exceptions 
include if a person has electrically, magnetically, or mechanically activated implants (such as cardiac 
pacemaker), or clips on blood vessels in their brain, or other metallic objects in their body such as 
shrapnel, bullets, buckshot, or metal fragments. Therefore, participants will be carefully screened for 
previous exposure to metallic fragments or to implanted devices.  
 
If participants are prone to claustrophobia, they will be asked to notify the researcher in charge of the 
scan, who will discontinue the scan upon the participant’s request. The MRI scanner makes loud 
knocking or beeping sounds during imaging; earplugs will be provided to help reduce this noise. Due to 
the rapid rate of change of the magnetic gradients during imaging, peripheral nerve stimulation is 
possible. If this happens, participants may feel creeping or tingling sensations, typically along their arms 
or lower back. Dizziness and nausea may occur if the participants move their head in the bore of the 
magnet. Finally, rarely there may be some heating from the radio frequency coils, the cables to the coils, 
response and physiological monitoring devices. If at any time participants feel discomfort, they will be 
instructed to contact the operator immediately. They will also be instructed in how to use an emergency 
handheld device to inform the operator if they wish to immediately stop scanning and be removed from 
the magnet. 
8.5 Unmasking Procedures 
Allocation to group (unmasking) will be revealed once all participants complete the study procedures. In 
the event when the safety of the participant is in question, per protocol participants will be assessed by 
the physicians involved in this study and care directed and/or referred accordingly. Given the consistent 
reports for safety and tolerability of rtACS across several clinical trials, we don’t anticipate the occurrence 
of any adverse events or adverse effects that are the direct consequence of rtACS; therefore, there is 
likely not a justifiable need for unmasking to occur prior to the study’s end.  
 

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At the study’s end, the staff personnel who managed the allocation concealment and randomization 
processes will reveal the allocation (database) to the study research team involved in any subsequent 
communication with participants. Participants will be informed of their group randomization at the 
conclusion of their participation in the study via face-to-face or phone conversation with research 
personnel, documented in the participant’s source document.  
 
In the unlikely event when unmasking is deemed to occur related to managing an adverse event, the 
unmasking will be reported with the adverse event. In the unlikely event when unmasking is not 
associated with an adverse event, unmasking will be reported to the research team in an immediate and 
timely manner. 
8.6 Medical Monitoring 
It is the responsibility of the PI to oversee the safety of the study at his/her site. This safety monitoring will 
include careful assessment and appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan (see section 9). Medical 
monitoring will include a regular assessment of the number and type of adverse events. The PI and lead 
research investigators and personnel will be ultimately responsible for the data safety monitoring of the 
overall study and will meet bimonthly to monitor data, recruitment, retention, confidentiality, and 
adherence to the study protocol.  
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study participants will be kept confidential and managed according to the requirements 
of HIPAA (1996). 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 participant 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.  
 
All medical information collected from participants and documentation related to their participation in the 
study will be kept in a locked cabinet designated for research conducted at NYU Langone Eye Center 
during the conduct of the study. Unique patient identifiers will be used to label all data; a password-
protected linking file will be accessible to/managed by the study PI and Co-PI. Strict standards of 
confidentiality will be upheld at all times. 
9.2 Source Documents 
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 study. Source data will be kept in 
participant files that will be physically located in a locked filing cabinet in a locked office at NYU Langone 
Eye Center during the conduct of the study. Research data will be entered online through the NYU and 
HIPAA compliant database, designed specifically for this study. An anonymous database number will be 
assigned to each participant and will be used for both the data entry sheets and the patient follow-up 
sheets. Data collected using the Linking File Form (see Attachment 6), which includes the participant’s 
name and study ID number, will be stored separately from participants’ data files in a password protected 
electronic file. Access to this data will be restricted to study personnel only. The assigned ID will code 
participant data and identifying information will not be presented or published to maintain participant 
privacy and confidentiality. 

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9.3 Case Report Forms 
The study Case Report Form (see Attachment 6) is the primary data collection instrument for the study. 
All data requested on the Case Report Form will be recorded. All missing data will be explained. If a 
space on the Case Report Form 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 will be 
printed legibly in black ink. If any entry error has been made, to correct such an error, a single straight line 
will be drawn through the incorrect entry and the correct data entered above it. All such changes will be 
initialed and dated. For clarification of illegible or uncertain entries, print the clarification above the item, 
then initial and date it. 
9.4 Records Retention 
A list of all persons authorized to perform study procedures will be maintained in the Regulatory Binder. 
All study related essential documentation will also be kept in the Regulatory Binder. The assigned study 
staff will maintain participants’ study files and source documentation. Study files will be kept locked in the 
research offices. Following completion or termination of the study, all study documents will be kept for a 
minimum of 2 years as required by the IRB. 
9.5 Electronic Medical Record and Release of Study-Related Information 
In compliance with the 21st Century Cures Act, some research-related information in subjects’ Electronic 
Medical Records will not be immediately available in order to protect the randomization integrity of the 
research. The suppressed information will be accessible to subjects once the study is concluded. The 
information to be suppressed includes: visual field results, OCT imaging, and ophthalmic report. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Data and Safety Monitoring Plan 
We will utilize operating procedures for reviewing patient safety data and source data generated from this 
study. This will include routine monitoring according to the Data and Safety Monitoring Plan (see 
Attachment 8), allowing for adequate time and space for such monitoring activities and 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. The following aspects will be specifically monitored: enrollment 
and retention, data collection, confidentiality, multi-centers, breaches from the study protocol, and any 
adverse event.  
 
Data and safety monitoring will include monthly meetings between the PI, research investigators, study 
coordinators, and pertinent study research personnel as necessary. The Data and Safety Monitoring Plan 
encompasses the research-related activities as they apply to recruitment and screening procedures 
conducted at New York Eye and Ear Infirmary of Mount Sinai. At these meetings, the research team will 
review the clinical ratings, assessments, clinical course, and study processes for each active participant 
as they apply to each Center. Specific attention will be given to data quality and timeliness, HIPAA 
compliance, safe storage of data, and data backup of electronic source data. Attention will also be given 
to participant recruitment, accrual and retention, participant risk versus benefit, adverse events, and other 
factors that can affect study outcome, including scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the study.  
 
There are no predetermined stopping rules for this pilot study. As needed, a yearly report will be 
submitted to the IRB during the renewal as to the frequency of monitoring and a summary report 
addressing any recommendations to adjust the risk/benefit ratio, participant privacy, or confidentiality 
procedures. 
 
All data will be shared with previous PI Joel Schuman for study analysis. 

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10.2 Auditing and Inspecting 
The research investigators will permit study-related monitoring, audits, and inspections by the IRB, 
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 investigators will ensure the capability for inspections of applicable study-related facilities. 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to U.S. and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable NYULMC 
and federal regulatory requirements. 
 
This protocol and any amendments will be submitted to a properly constituted IRB, in agreement with 
local legal prescriptions, for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator before commencement of this study. 
 
No deviation from the protocol will be implemented without prior review and approval of the IRB, except 
where it may be necessary to eliminate an immediate risk to a participant. In such case, the deviation will 
be reported to the IRB according to its policies and procedures. 
 
All participants for this study will be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. See 
Attachment 9 for a copy of the Participant Informed Consent Form. This consent form will be submitted 
with the protocol for review and approval by the IRB for the study. The formal consent of a participant, 
using the IRB-approved consent form, will be obtained before that participant undergoes any study 
procedure. The participant and the investigator-designated research professional obtaining the consent 
will sign the consent form.  
 
Research investigators who will obtain consent will be trained in the consent process. The process of 
informed consent will follow the outline as described in section 6. Trained research personnel involved in 
the administration of assessments will review and obtain written informed consent of participants who 
enroll in the study.  
12 Study Finances 
12.1 Funding Source 
This pilot study is funded through the NYULMC Department of Ophthalmology. Charges will be billed only 
for procedures performed as part of participants’ routine clinical care. No study-related procedures will be 
billed to the participant but to the research program within the Department of Ophthalmology. 
12.2 Subject Stipends or Payments 
In an effort to maximize the rate of enrollment in this study, participants will receive a payment of $20.00 
(gift card) after the completion of each study visit. The payment process will follow departmental and NYU 
guidelines. Participants, nor their insurance provider, will be charged for any of the procedures or tests 
performed solely for the purpose of this research study. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol will be 
published or passed on to any third party without the consent of the research investigators. One co-
investigator, Heather Livengood, will be the primary research personnel responsible for coordinating 
publication of the results of this pilot study. 

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This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
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