Spectral Domain-Optical Coherence Tomography Angiography of Retinal Diseases
Phase: NA
Conditions: Neovascular Age-related Macular Degeneration, Age-related Macular Degeneration, Diabetic Retinopathy, Retinal Vein Occlusion, Diabetic Macular Edema
Sponsor: Duke University

 
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PROJECT TITLE: 
Spectral Domain-Optical Coherence Tomography 
Angiography of Posterior Segment Diseases 
IDENTIFYING WORDS:  
 
spectral domain optical coherence tomography, optical 
coherence tomography angiography, noninvasive imaging, 
retinal disease, age-related macular degeneration, diabetic 
macular edema, diabetic retinopathy, retinal vascular 
occlusion, macular telangiectasia, glaucoma, optic 
neuropathies, choroidal diseases, uveitis, ocular 
inflammatory diseases 
PRINCIPAL INVESTIGATOR: 
Priyatham S. Mettu, M.D. 
MEDICALLY RESPONSIBLE: 
Priyatham S. Mettu, M.D. 
PROJECT USES IONIZING RADIATION: No 
PROJECT INVOLVES USE OF DURABLE POWER OF ATTORNEY: No 
MULTI-INSTITUTIONAL PROJECT:  No 
 
 
 
 
 
 
Ver. Date:  5/18/2018 

 
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Table of Contents 
Summary ........................................................................................................................................ 3 
1.0 
Background ........................................................................................................................ 4 
2.0 
Objective of the Study  .....................................................................................................  5 
3.0 
Study Design and Methods  .............................................................................................  5 
 
 
3.1 Experimental Design  .............................................................................................  5 
3.2  Participant Selection ................................................................................................ 6 
3.3  Sample Size .............................................................................................................. 6 
3.4  Baseline Evaluation ................................................................................................. 6 
3.5  Study Evaluation ...................................................................................................... 6 
4.0 
Inclusion/Exclusion Criteria ............................................................................................  6 
4.1 Inclusion Criteria  ...................................................................................................  6 
4.2 Exclusion Criteria  ..................................................................................................  7 
4.3 Inclusion of Women and Minorities  ......................................................................  7 
5.0 
Participant Monitoring and Data Collection Plan  .......................................................  8 
 
 
5.1 Statistical Considerations ........................................................................................ 8 
6.0 
Human Participant Protection  .......................................................................................  8 
 
 
6.1  Safety and Confidentiality ....................................................................................... 8 
   
 
6.2  Participant Consent .................................................................................................. 9 
 
 
6.3  Risks and Benefits ................................................................................................. 10 
 
 
6.4  Discomforts and Inconveniences ........................................................................... 10 
7.0 
Ethics  ............................................................................................................................... 10 
8.0 
Changes to the Protocol  ................................................................................................. 10 
 
 

 
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SUMMARY 
 
Optical coherence tomography (OCT) is an optical ranging and imaging technique that provides high-
resolution, micrometer-scale depth imaging in clinical ophthalmology. For the posterior segment of the eye, it allows 
rapid acquisition of cross-sectional posterior segment images that approximate tissue histology. While OCT has 
revolutionized diagnostic capability and advanced the development of therapeutics in the clinic for posterior segment 
diseases (defined as diseases of the retina, choroid, uveal tract, and optic nerve, including glaucoma), current 
commercially available OCT imaging units cannot provide information on retinal vasculature and physiologic 
perfusion. Angiography is the current gold-standard imaging modality for assessment of the retinal blood vessels. 
Angiography utilizes injection of an intravenous dye, a light source emitting light at the specific excitation wavelength 
of the dye, and a specially equipped camera that images at the specific emission wavelength of the dye. While 
generally well tolerated by most patients, angiography does have a few drawbacks: it requires several minutes for 
image acquisition typically on a separate imaging system, and patients can occasionally experience side effects of the 
intravenous dye, including nausea, discomfort, and rarely, anaphylaxis. 
 
Several retinal imaging companies are developing the next generation of OCT technology: OCT 
angiography (OCT-A). OCT-A allows noninvasive, high-resolution imaging of the microvasculature of the retina 
and choroid (the vascular plexus subjacent to the retina), without the need for intravenous dye administration. OCT-
A platforms currently under development include both spectral domain (SD) and swept-source (SS) based 
technologies. Whereas SS-based OCT-A utilizes a longer wavelength (~1060 nm) light source, SD-based units use 
the same light source used in commercially available and FDA-cleared OCT units on a modified platform. These 
include the AngioVue OCT-A unit (Optovue, Inc., Fremont, CA), the AngioPlex OCT-A unit (Zeiss, Inc., Dublin, 
CA), and the Spectralis SP-X1601 OCT-A (Heidelberg Engineering, Franklin, MA). These units utilize novel 
software algorithms that  allow for detection of motion in the blood vessel lumen by measuring the variation in 
reflected OCT signal amplitude between consecutive cross-sectional scans. Each of these units can generate high-
quality angiograms of both the retina and choroid, with images of the smallest retinal vessels (capillaries) in normal 
healthy control participants. In this proposed prospective interactive clinical study, we will use the AngioVue unit, 
the AngioPlex unit, and the Spectralis SP-X1601 OCT-A unit to image patients and characterize vascular 
abnormalities that are present in the setting of posterior segment diseases.  

 
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BACKGROUND 
1.0 
BACKGROUND 
OCT is an optical ranging and imaging technique first described in 1991 that has since been used 
successfully to provide high-resolution, micrometer-scale depth imaging in clinical ophthalmology (and 
other fields). It can be thought of as the optical analogue of ultrasound imaging. For the ocular posterior 
segment, OCT provides rapid acquisition of high-resolution, cross-sectional images of the posterior segment 
that approximate tissue histology. In vivo imaging of the posterior segment with OCT has thus dramatically 
improved clinicians’ diagnostic capabilities, allowing earlier and more accurate diagnosis of disease and 
more precise assessment of response to therapies over time.  
 
While OCT provides important information on posterior segment anatomy, it is currently limited 
in its ability to provide information on retinal and choroidal vasculature and blood flow. Angiography is the 
current gold-standard imaging modality for retinal and choroidal vascular imaging. Angiography involves 
intravenous injection of a fluorescent dye (typically either fluorescein or indocyanine green for the retinal 
or choroidal vessels, respectively) that circulates through the body. A light source emitting light at the 
specific excitation wavelength of the dye is placed in front of the patient’s eye, and a camera equipped with 
a filter corresponding to the emission wavelength of the dye is then used to image vessel morphology and 
retinal perfusion, either through still images or a short movie. Angiography provides physiologic 
information about the posterior segment that complements the anatomical information provided by OCT. 
While generally well tolerated by most patients, angiography does have drawbacks: it often requires the use 
of a separate imaging system, it requires several minutes for image acquisition, and it involves intravenous 
injection of a dye. Patients occasionally experience side effects of intravenous dye administration, including 
nausea, discomfort, and rarely, anaphylaxis. 
 
Several retinal imaging companies are developing the next generation of OCT technology: OCT 
angiography (OCT-A). OCT-A allows noninvasive, high-resolution imaging of the microvasculature of the 
retina and choroid (the vascular plexus subjacent to the retina), without the need for intravenous dye 

 
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administration. OCT-A platforms currently under development include both spectral domain (SD) and 
swept-source (SS) based technologies. Whereas SS-based OCT-A utilizes a longer wavelength (~1060 nm) 
light source, SD-based units use the same light source used in commercially available and FDA-cleared 
OCT units on a modified platform. These include the AngioVue OCT-A unit (Optovue, Inc., Fremont, CA), 
the AngioPlex OCT-A unit (Zeiss, Inc., Dublin, CA), and the Spectralis SP-X1601 OCT-A (Heidelberg 
Engineering, Franklin, MA). These units utilize novel software algorithms that allow for detection of motion 
in the blood vessel lumen by measuring the variation in reflected OCT signal amplitude between consecutive 
cross-sectional scans. Each of these units can generate high-quality angiograms of both the retina and 
choroid, with images of the smallest retinal vessels (capillaries) in normal healthy control participants. In 
this proposed prospective interactive clinical study, we will use the AngioVue unit, the AngioPlex unit, and 
the Spectralis SP-X1601 OCT-A unit to image patients and characterize vascular abnormalities that are 
present in the setting of posterior segment diseases, as defined as diseases of the retina, choroid, uveal tract, 
and optic nerve, including glaucoma.  
2.0  
OBJECTIVE OF THE STUDY  
The objective of this study is to image posterior segment vascular alterations in patients with posterior 
segment diseases using the AngioVue OCT-A system, the AngioPlex OCT-A system, and the Spectralis 
SP-X1601 OCT-A system and understand the information images captured on all three systems provide. 
3.0  
STUDY DESIGN AND METHODS 
3.1 
Experimental Design:  This project is being conducted under abbreviated IDE, since this study 
was initially approved in 2015 for use of the AngioVue prior to the FDA clearance of the AngioVue unit, 
and because the Spectralis SP-X1601 remains investigational. Following acquisition of consent, study 
participants will undergo imaging of both eyes with the AngioVue unit (approximately 60 seconds/eye), the 
AngioPlex unit (approximately 60 seconds/eye), and the Heidelberg Spectralis unit (approximately 60 
seconds/eye), per standard operating protocol for each unit. Imaging is noncontact, and pharmacologic 
dilation will not be used for the purposes of this study. In most instances, study participants will undergo 

 
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only a single imaging session on all three units on a single day, though participants will receive a break of 
approximately five minutes between imaging sessions. The cumulative time imaged on all three units will 
result in a total light source exposure that will remain well below the ANSI standards for safe maximal 
permissible exposure limits. However, potential participants will be asked to consent for additional imaging 
sessions (up to 12) that may occur over the course of subsequent future visits to the clinic. Additionally, 
study participants will be asked to consent to prospective collection of clinical and demographic data, to 
correlate findings of OCT-A imaging to subsequent clinical course. 
3.2   Participant Selection: Participants will be identified from patients presenting for ophthalmologic 
consultation at the Duke Eye Center and/or one of its satellite clinical locations. All adults (age 18 or older) 
meeting study criteria (as detailed in Section 4.0) will be asked to participate. A care provider known to the 
patient will introduce the study and his/her ophthalmologist will be asked for prior approval before the study 
is discussed with the patient. Following this, members of the study staff will approach potential study 
participants.   
3.3 Sample Size:  The total planned enrollment for this pilot study is approximately 100 participants, to 
allow for the inclusion of a sufficient number of participants with several different posterior segment 
diseases. 
3.4  Baseline Evaluation: Prior to study enrollment, potential participants must have had a previous 
examination that documents the presence of posterior segment diseases (including but not limited to age-
related macular degeneration, diabetic retinopathy, diabetic macular edema, glaucoma, retinal vein 
occlusion, idiopathic macular telangiectasias, uveitis, and optic neuropathies). 
3.5  
Study Evaluation:  If the participant meets the criteria for study inclusion and consent is obtained 
following full explanation of the research, study participants will undergo OCT-A imaging of both eyes, per 
standard operating protocol for imaging. 
4.0    
INCLUSION / EXCLUSION CRITERIA 
4.1 Inclusion Criteria:  

 
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a) Capable and willing to provide consent 
b) History of clinically diagnosed posterior segment diseases, including but not limited to age-related 
macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, macular telangiectasias, 
and diabetic macular edema, uveitis, and optic neuropathies. 
 
c) At least 18 years of age 
4.2     Exclusion Criteria: 
 
a) Unable or unwilling to give consent 
 
b) Under 18 years of age 
4.3   Inclusion of Women and Minorities:  Posterior segment diseases encompass a broad array of 
demographics, though they tend to be slightly more common in older individuals. No specific gender 
predominance is expected for such a diverse group. Study participants will be actively recruited from each 
gender. The target enrollment will be approximately 100 participants. Every effort will be made to include 
individuals of African-American and Hispanic racial/ethnic backgrounds, particularly given the high 
incidence of diabetic retinopathy in these individuals. Participants will not be compensated for participation. 
TARGETED/PLANNED ENROLLMENT: Approximately 100 participants 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
4%
4%
8%
Not Hispanic or Latino 
46%
46%
92%
Ethnic Category Total of All Participants* 
50%
50%
100%
Racial Categories 
  
Native American/Alaska Native 
0
0
0
Asian 
0
0
0
Native Hawaiian or Other Pacific Islander  
0
0
0

 
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Black or African American  
10%
10%
20%
White 
40%
40%
80%
Racial Categories: Total of All Participants* 
50%
50%
100%
 
5.0 
PARTICIPANT MONITORING AND DATA COLLECTION PLAN: 
Clinically indicated care will be provided to all participants as required. All imaging will be obtained 
according to established imaging protocols, by study personnel who have received necessary training in the 
safe and appropriate use of the OCT-A imaging devices. Data analysis will occur at the conclusion of the 
study using descriptive methods.  
5.1 Statistical Considerations: We have planned on an enrollment of 100 participants to allow for the 
inclusion of a sufficient number of individuals with several different posterior segment vascular diseases 
at varying stages in the disease course. No prior clinical studies exist to guide our study sample size. We 
will use descriptive statistics to analyze data derived from the OCT-A images.  
6.0 
HUMAN PARTICIPANT PROTECTION 
6.1 Safety and Confidentiality: No long-term safety concerns are anticipated as a result of study 
interventions. Imaging will not require contact with the eye. As prolonged intense light exposure can be 
harmful, this device will not be used for ocular examination under prolonged circumstances. The brightness 
settings will not exceed what is needed to provide clear visualization of the target structures. Additionally, 
the intensity of light directed into the patient’s eye will be limited to the minimum level which is necessary 
for diagnosis. Dr. Mettu and his study staff will monitor for any safety events on a regular basis. After hours 
contact information will be provided to all study participants in case of an adverse event.   
 
The AngioVue unit (Optovue) is comprised of the commercially available and FDA-cleared 
RTVue conventional SD-OCT imaging platform that has been modified to incorporate a novel imaging 
algorithm. Both the hardware and the imaging algorithm software of the AngioVue unit have been FDA 

 
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cleared, and the AngioVue unit is now commercially available (as of early 2016). This study was initially 
IRB approved in late 2015 under an abbreviated IDE, with non-significant risk (NSR) designation. 
 
The AngioPlex unit (Zeiss) incorporates optical micro angiography algorithms that utilize 
amplitude and phase OCT signal data to deliver the high quality angiography images of the retina and 
choroidal vascular beds. The AngioPlex unit has received FDA clearance for use in clinical practice.  
 
The Spectralis SP-X1601 OCT-A system uses the same light source used in commercially 
available and FDA approved OCT unit. Heidelberg has developed the SP-X1601 software which utilizes a 
novel algorithm to produce high quality angiography images on the Spectralis platform. While the Spectralis 
hardware of the platform is FDA cleared for use in clinical practice, the SP-X1601 software is 
investigational. 
 
Each OCT system stores its scans locally within an internal hard drive, and all units will be stored 
securely with the Clinical Research Unit of the Duke Eye Center. However, confidentiality of the scans/files 
on the OCT device will be maintained by use of a unique study identifier (without medical record number, 
date of birth, or other PHI), effectively rendering the data de-identified on the local drive. The internal hard 
drive associated with the system will only be accessible by study personnel. Password-protected portable 
hard drives used to transfer and store de-identified OCT images for offline analysis; these hard drives will 
be “wiped” upon completion of this study. 
 
Collected clinical data, including a single master list to relink the study ID to the participant, 
will be stored on password-protected, hard drive-encrypted computers in the Department of 
Ophthalmology.  Only the investigators and approved study personnel will have access to these files. Once 
all data analyses are complete, the master list of study IDs will be deleted and overwritten to permanently 
de-identify all collected data for that study. 
6.2    Participant Consent: A consent form has been developed that describes the nature of the research, 
the risk/benefit ratio, and the voluntary nature of participant involvement. Consent will be obtained directly 
from the participant in a private location within the clinic by the study PI, study coordinator, or other study 

 
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staff. Participants will be given a verbal explanation of the research and then will be granted ample time to 
read the consent form or have the consent read to them if necessary, and they will be permitted to ask 
questions. The consent and imaging will occur on the same day as the participant’s visit to the clinic in order 
to limit transportation and logistical hardships, unless otherwise requested by the participant. Individuals 
unwilling to provide signed consent will not be enrolled. 
6.3 
Risks and Benefits:  The risks of the study are as outlined above, for all study participants. 
Participants will not receive compensation and may not directly benefit from the study; however, this study 
will test a novel imaging modality that may improve the experience of future patients and could serve as the 
basis for future studies of OCT-A, with the overall goal of optimizing efficiency of care delivery for patients 
with posterior segment diseases. 
6.4 
Discomforts and Inconveniences:  Expected discomforts and inconveniences of this study are 
related to the time required of the study participants for imaging. Dr. Mettu and study staff will monitor for 
any unanticipated adverse events arising from participation in this study; however, Duke University, the 
study physicians, and study staff will make no commitment to provide monetary compensation or free 
medical care to participants in the event of a study-related injury. 
7.0 
ETHICS  
We will perform this trial in accordance with the protocol, International Conference on Harmonization Good 
Clinical Practice guidelines, and applicable local regulatory requirements and laws. Additionally, we will 
conduct the trial in accordance with the Declaration of Helsinki. 
8.0 CHANGES TO THE PROTOCOL 
Any change or addition to this protocol will only be completed with a written protocol amendment submitted 
to the IRB.