Clinical trial NCT03478865
Conditions: AMD
Keywords: Eye Examinations Retinal Pigment Epithelium
Sponsor: National Eye Institute (NEI)
Start date: 2018-04-20; Completion date: 2023-06-16
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Age-related macular degeneration (AMD) is an eye disease. It is the leading cause of vision loss in people over 55 in the U.S. Changes in the eye can make it difficult for the eye to adjust to low light. This is known as dark adaptation. Identifying and watching the early to middle stages of AMD and changes in dark adaptation might help researchers develop new treatments to stop the disease before it becomes severe. Taking vitamin A might help improve vision in people with AMD.

Objectives:

To see if taking 16,000 IU of vitamin A per day improves vision in people with AMD. Also to improve understanding of AMD and associated dark adaptation.

Eligibility:

Adults ages 50 and older with AMD and normal liver function

Design:

Participants will be screened with:

Medical and eye disease history

Eye exam: The pupil will be dilated with eye drops. Pictures will be taken of the retina and the inside of the eye.

Including the screening visit, participants will have at least 5 visits. They will be about once a month over 6 months. Visits include:

Questions about eye problems in certain light

Eye exam

Blood and urine tests

Dark adaptation protocol: Participants will sit at a machine in a dark room. They will look into the machine and push a button when they see a light. This lasts 20-30 minutes.

Participants will take a vitamin A supplement by mouth once a day for 2 months. They will record when they take the pills in a diary.

Detailed description:
Objective:

The objective of this study is to investigate the potential efficacy and safety of vitamin A palmitate dosing in improving dark adaptation in participants with age-related macular degeneration (AMD) and abnormal dark adaptation.

Study Population:

The first cohort consists of five participants with AMD who meet the eligibility criteria. The second cohort will consist of five participants with AMD who meet the eligibility criteria. Up to five additional participants may be accrued in the second cohort to account for participants who withdraw from the study prior to receiving one month of study supplementation for a reason unrelated to an adverse reaction. Up to 18 participants may be enrolled in this study.

Design:

This is a prospective, uncontrolled, single center, pilot study to investigate the potential efficacy and safety of vitamin A palmitate dosing in improving dark adaptation in participants with AMD and abnormal dark adaptation. Participants in the first cohort were instructed to take 16,000 IU of vitamin A palmitate daily for two months. Enrollment for Cohort 1 ended on May 24, 2019. Participants in the second cohort will be instructed to take 48,000 IU of vitamin A palmitate daily for one month. Participants in both cohorts will continue in the study for one month after ending Vitamin A supplementation. Participants in Cohort 1 may enroll into Cohort 2 as long as their last intake of vitamin A palmitate was greater than two months prior to their enrollment into Cohort 2.

Outcome Measures:

For each cohort, the primary outcome is the measurement of dark adaptation parameters (thresholds and kinetics) by the following: dark adaptation times as measured by the AdaptDx comparing before and after vitamin A palmitate supplementation and dark adaptation parameters as measured by the Medmont comparing before and after vitamin A palmitate supplementation. The primary outcome will be assessed at Month 2 in the first cohort and Month 1 in the second cohort. For both cohorts, the secondary outcomes include changes in low luminance visual acuity (LLVA) and changes in patient reported outcomes as measured by the low luminance questionnaire (LLQ). The secondary outcomes also include measurement of dark adaptation parameters (thresholds and kinetics) comparing baseline and one month after completing supplementation (Month 3 in Cohort 1 and Month 2 in Cohort 2).

Arms: arm 1: Participants with age-related macular degeneration
Interventions: intervention 1: Vitamin A palmitate
Intervention descriptions: intervention 1: Provide vitamin A to participants with pre/post assessments of vision.

Protocol documents:
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entitled. However, to be seen at the NIH, you must be taking part in a study or are 
being considered for a study. If you do choose to leave the study, please inform your 
study team to ensure a safe withdrawal from the research.
WHY IS THIS STUDY BEING DONE?
PURPOSE OF THIS STUDY
Macular degeneration is a condition that can cause permanent loss of central vision, 
which is important for seeing fine details and tasks such as reading, driving or 
sewing. Age-related macular degeneration (AMD) is the leading cause of vision loss 
in people over 55 in the United States. Changes in the eye can lead to difficulty with 
adjustment of the eye to low light, known as dark adaptation.
Identifying and watching the early to intermediate stages of AMD and changes in 
dark adaptation may help us develop new treatments to stop the disease before it 
becomes severe. The purpose of this study is to see if taking 16,000 IU of vitamin A 
per day could improve vision in people with AMD in Cohort 1 and if an increased 
dosage of 48,000 IU of vitamin A per day could improve vision in people with AMD 
in Cohort 2. A procedure that measures how your eyes adjust to the dark (dark 
adaptation protocol) can be used to identify and monitor AMD. We are also doing 
this study to improve our understanding of AMD and associated dark adaptation.
BACKGROUND 
A first step in understanding the disease would be to watch people who have been 
taking vitamin A. Previous researchers have shown that taking vitamin A could help 
improve vision. However, further research is needed to fully understand these 
changes. 
STUDY POPULATION
You have been asked to participate in this study because you have been diagnosed 
with AMD. Up to 18 people with AMD may participate in this study. 
Eight participants were enrolled in Cohort 1 and up to 10 participants will be 
enrolled in Cohort 2. 
PROCEDURES 
This study will last twelve (12) months, with approximately six (6) months for each 
cohort. The participants in Cohort 2 need at least four visits to NIH. After your first 
visit, study visits will happen every month and as needed. The visits will last between 
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four to six hours. The tests scheduled at each visit may be split and completed within 
seven days (including the seventh day) from the visit date. 
While you are enrolled in this study, you may receive standard-of-care therapy at the 
NIH or your own doctors under this protocol. If you receive this therapy at NIH, you 
will sign separate consent forms for risks associated with any standard-of-care 
procedures, drugs or other treatments that are not described in this consent. You will 
stay under the care of your own doctors for your general medical care while you are 
in this study.
At your first visit, we will also ask you about your medical and eye disease history 
and perform an eye exam. The eye exam may be done through your participation in 
another NEI study. If your exam results indicate that you are able to be in this study, 
you will be given this consent so that you can decide if you want to participate. 
If you are able to be in this study and agree to participate, we will perform initial 
examinations which will include a questionnaire. This questionnaire will ask you 
about problems that affect your eyes under different lighting conditions. You will be 
asked to complete this questionnaire at each visit.
If you want to participate and you are enrolled in Cohort 2, you will be given 
instructions on how to take three vitamin A pills by mouth twice a day for one month. 
You will need to record the time when you take your pills every day in a diary that 
we will give you. You will need to bring the diary and your pill bottle with any 
unused study pills to each visit.
At every visit, we will ask you about your health and what medications including 
any vitamins or supplements you are taking.
At each study visit, you will have some or all of the following tests.
Eye Examination: The eye examination includes testing how well you see, 
measuring your eye pressure, and checking your eye movements. For examination 
of the inside of the eye, your pupil will be dilated with eye drops. While your eyes 
are dilated, we will take pictures of the retina and the inside of your eye and will 
measure the thickness of your retina.
Blood Draw: Blood will be drawn through a needle in your arm. We will draw no 
more than 5 mL (one teaspoon) of blood at any one time. In most cases, blood will 
be drawn only once. The blood will be drawn to check your blood chemistry and 
how well your kidneys are functioning. If we are unable to use the first sample we 
collect, we will draw the blood again. 
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Dark Adaptation Protocol: This 20-40 minute procedure measures how fast your 
eyes recover when exposed to decreasing levels of light and how sensitive your eyes 
are to these conditions. This procedure will be performed on your study eye while 
your pupil is dilated with eye drops.
The dark adaptometer is a metal box with a camera inside. You will be given a 
handheld device to push a button when you see a light in the machine. In this study, 
you will be seated at the machine in a dark room with your forehead and chin aligned 
in front of the box. To begin, we will give you a few practice runs for training 
(approximately two minutes). The real study begins with a bright flash of light. 
After the bright flash of light, you will press the button as soon as you see the dim 
lights inside the box.
If you complete the dark adaptation protocol within 40 minutes, we would also like 
to perform the shortened procedure to compare with your first dark adaptation 
procedure. However, you do not have to have this test repeated if you do not want 
to. If you agree, we will ask you to wait 20 minutes before performing the shortened 
procedure.
Urine Tests: If you are able to get pregnant you will have a urine pregnancy test.
STORAGE AND SHARING OF SAMPLES AND DATA
Your data will be stored securely on the NIH campus. Your name and identifying 
information will not be on the data. The data will either have a code that links to 
your identifying information or will be stored without a code linking them to you. 
If they are coded, the key to the code will be kept at NIH in a separate, secure area 
and will not be shared.
Your data may be shared with others, including those not at NIH. Your data may be 
sent to a repository for storage. Your data may be used for other research projects, 
including those not related to AMD if you agree. Some repositories restrict access 
to the data they contain to researchers and projects they approve. Some repositories 
permit unrestricted access. 
Research using data from this study may lead to new tests, drugs, or devices with 
commercial value. You will not receive any payment for any product developed 
from research using your data.
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Please initial on the line below that reflects your choice:
______YES My data may be used for other research projects including those 
not related to AMD. 
______NO I do not want my data used for other research projects. 
If you withdraw from this research study before it is done, we will keep and continue 
to use samples and data that have already been collected. Your privacy will be 
protected as much as possible.
RISKS, INCONVENIENCES AND DISCOMFORTS
Risks of Eye Examination: There is minimal medical risk from the tests of vision, 
measuring eye pressure or retinal thickness or eye photography. The eye drops used 
to dilate your eyes may sting. You may have glare and blurry vision for several hours 
while your eyes are dilated. Some people are allergic to eye drops, while others 
experience a temporary increase in eye pressure. Your eye could become red or 
painful. A brief flash from eye photography equipment may cause temporary 
discomfort. There is a rare instance in which the cornea may be scratched during 
measurement, causing a painful scratch, but it heals quickly with no lasting effects. 
These problems will be treated if they occur.
Risks of Dark Adaptation Protocol: There is minimal medical risk from this 
procedure. They are the same as the risks of the eye examination. However, due to 
the need to focus during the entire testing period (20-40 minutes), there may be some 
discomfort or fatigue and you may be unable to complete the test due to loss of 
motivation or attention. If you are unable to complete the test, you will be withdrawn 
from the study.
If the dark adaptometer device times out during the testing period or the test cannot 
be completed correctly, returning to the clinic a week later to complete another dark 
adaptation procedure may be inconvenient.
Risks of Medical/Ophthalmic History: There is minimal medical risk associated with 
asking you about your medical and eye disease history.
Risks of Blood Drawing: You may have some discomfort and bruising from the 
needle insertion. Some people feel light-headed or faint.
Risks of Vitamin A Use: Vitamin A should be used with caution when combined 
with blood thinning medication, tetracycline antibiotics, and retinoid medications. 
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It may decrease the effectiveness of a drug or supplement and may impair drug or 
supplement absorption. 
Taking a high dose of vitamin, A may cause toxicity (harm or danger). The potential 
toxic effects are different depending on the dose and length of time of 
supplementation. Acute (short term) may rarely include increased pressure in the 
head leading to vomiting or vision changes, or liver damage. Chronic (long 
term/several years of supplementation) can have adverse effects including 
osteoporosis (pain in the joints or bones), anemia (tiredness or weakness), dry skin, 
dryness of mucous membranes (lining on surface of organs or body cavities), or hair 
loss. 
If you are on Coumadin® (Warfarin) at enrollment, you must visit your prescribing 
physician to check your Coumadin® status within two-four weeks after initiating 
vitamin A to have your Coumadin® regimen adjusted if necessary (as taking vitamin 
A may require a decrease of your medication dose.)
Risks of Storage and Sharing of Samples and Data: Even though we will remove 
information that could identify you from samples and data that are sent to 
repositories or shared, there is a very small chance that the samples and data could 
be identified as yours.
CAUTION: PARTICIPANTS WITH CHILDBEARING POTENTIAL OR 
WHO ARE ABLE TO FATHER A CHILD
There is a possible risk of deformity to a fetus if a participant of childbearing 
potential consumes high doses (i.e., greater than 25,000 IU/day) of vitamin A during 
pregnancy. No one should enter this study that plans on fathering a child or getting 
pregnant for the duration of the study. Participants must use at least one effective 
form of contraception while in this study and for one week after the last dose of 
vitamin A.
If you become pregnant (or get someone pregnant) while in this study, you must 
report the pregnancy immediately to a study doctor. We will arrange for a 
consultation with the NIH OB/Gyn service for evaluation and counseling and we 
will continue to follow the pregnancy even after you stop taking Vitamin A.
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ANTICIPATED BENEFITS
You may benefit from participating in this study, if the vitamin A supplementation 
improves your vision. Your participation will help us learn more about AMD, dark 
adaptation and vitamin A that might help you or others in the future.
RIGHT 
OF 
WITHDRAWAL 
AND 
CONDITIONS 
FOR 
EARLY 
WITHDRAWAL
You may withdraw from the study at any time and for any reason without loss of 
benefits or privileges to which you are otherwise entitled. We can remove you from 
the study at any time if we believe that continuation is not in your best medical 
interest or if you are unable to comply with the requirements of the study.
DISCUSSION OF NEW FINDINGS WITH YOU
We will give you the results of all of your eye examinations. With your written 
request, we will send reports to your own doctors.
We will share with you in a timely manner any information we learn that may affect 
your willingness to continue to participate in the study. Data from the eye 
examinations and dark adaptometer including your status at baseline and any 
changes that have occurred will be shared with you at each visit.
Once all participants have completed the study, we will analyze the results and share 
them with you. Please let us know if you change your address or telephone number 
so that we can provide you this information.
ALTERNATIVES TO PARTICIPATION OR TREATMENT
You may choose not to participate in this study but to continue to receive standard 
care for AMD from your own physicians.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your 
participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, 
lodging or meals while participating in the research. The amount, if any, is guided 
by NIH policies and guidelines.
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This study will cover the costs of travel to and from the Clinical Center, lodging and 
meals. You will be reimbursed for these costs. If you require additional financial 
assistance, you may be able to receive supplemental reimbursement. Requests for 
supplemental reimbursement will be evaluated on a case-by-case basis for valid 
financial and/or medical need.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or 
related clinical care that you receive at the NIH Clinical Center. 
CONFLICT OF INTEREST (COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly 
for conflicts of interest. This process is detailed in a COI Guide. You may ask your 
research team for a copy of the COI Guide or for more information. Members of the 
research team who do not work for NIH are expected to follow these guidelines or 
the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH.
No NIH investigator involved in this study receives payments or other benefits from 
any company whose drug, product or device is being tested.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY
When we store your data, we take precautions to protect your information from 
others that should not have access to it. When we share your data, we will do 
everything we can to protect your identity, for example, when appropriate, we 
remove information that can identify you. Even with the safeguards we put in place, 
we cannot guarantee that your identity will never become known or someone may 
gain unauthorized access to your information. New methods may be created in the 
future that could make it possible to re-identify your data. 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical 
record will be kept private. However, we cannot guarantee total privacy. 
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Organizations that may look at and/or copy your medical records for research, 
quality assurance, and data analysis include:

The National Eye and other government agencies, like the Food and Drug 
Administration (FDA), which are involved in keeping research safe for 
people.

National Institutes of Health Intramural Institutional Review Board
The researchers conducting this study and the NIH follow applicable laws and 
policies to keep your identifying information private to the extent possible. 
However, there is always a chance that, despite our best efforts, your identity and/or 
information about your participation in this research may be inadvertently released 
or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about 
you without your written permission. However, your information may be shared as 
described in the section of this document on sharing of specimens and data, and as 
further outlined in the following sections.
Further, the information collected for this study is protected by NIH under a 
Certificate of Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a 
Certificate of Confidentiality (Certificate). With this certificate, researchers may not 
release or use data or information about you except in certain circumstances.
NIH researchers must not share information that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if requested by a court.
The Certificate does not protect your information when it:
1. is disclosed to people connected with the research, for example, information 
may be used for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when 
information must be disclosed to meet the legal requirements of the federal 
Food and Drug Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
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CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
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Prot_000.pdf: 




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Table of Contents 
LIST OF ABBREVIATIONS .................................................................................................................. V 
PRÉCIS  .......................................................................................................................................... 1 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE .............................................................................. 2 
2.0 
STUDY OBJECTIVES ............................................................................................................. 3 
3.0 
PARTICIPANTS ...................................................................................................................... 3 
3.1 
Participant Eligibility Criteria ......................................................................................... 4 
3.1.1 
Inclusion Criteria .............................................................................................. 4 
3.1.2 
Exclusion Criteria ............................................................................................. 5 
3.2 
Study Eye Eligibility Criteria.......................................................................................... 5 
3.2.1 
Study Eye Inclusion Criteria ............................................................................. 5 
3.2.2 
Study Eye Exclusion Criteria ............................................................................ 5 
3.3 
Choice of Study Eye in Cases of Bilateral Disease ........................................................ 6 
4.0 
STUDY DESIGN AND METHODS ............................................................................................ 6 
4.1 
Recruitment ..................................................................................................................... 6 
4.2 
Screening Visit ................................................................................................................ 7 
4.3 
Study Design and Procedures ......................................................................................... 7 
4.3.1 
Ocular and Systemic Evaluations ..................................................................... 8 
4.4 
Study and Concomitant Therapies .................................................................................. 9 
4.4.1 
Study Supplement Formulation ........................................................................ 9 
4.4.2 
Dosage, Administration, and Storage ............................................................... 9 
4.4.3 
Concomitant Therapy........................................................................................ 9 
4.4.4 
Study Supplement Accountability .................................................................. 10 
4.5 
End of Participation ...................................................................................................... 10 
4.6 
Storage of Samples and Data ........................................................................................ 11 
5.0 
RISKS/DISCOMFORTS ......................................................................................................... 11 
5.1 
AdaptDxTM Risks .......................................................................................................... 12 
5.2 
Medmont Dark Adapted Perimetry ............................................................................... 12 
5.2.1 
Kinetics of Dark Adaptation ........................................................................... 12 
5.2.2 
Dark Adapted Retinal Sensitivity ................................................................... 13 
5.3 
Study Supplement-Related............................................................................................ 13 
5.3.1 
Drug Interaction-Related ................................................................................ 14 
6.0 
ADDITIONAL CONSIDERATIONS ......................................................................................... 14 
6.1 
Research with Investigational Drugs ............................................................................ 14 
6.2 
AdaptDx and Medmont Dark Adaptation Devices ....................................................... 14 
7.0 
PARTICIPANT SAFETY MONITORING .................................................................................. 15 
7.1 
Participant Withdrawal Criteria .................................................................................... 15 
7.2 
Pregnancy Monitoring .................................................................................................. 15 
8.0 
OUTCOME MEASURES ........................................................................................................ 16 
8.1 
Primary Outcome .......................................................................................................... 16 
8.2 
Secondary Outcomes .................................................................................................... 16 
9.0 
STATISTICAL ANALYSIS ..................................................................................................... 17 
9.1 
Primary Outcome Analysis ........................................................................................... 17


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9.2 
Secondary Outcome Analysis ....................................................................................... 17 
10.0 
HUMAN SUBJECTS PROTECTION ......................................................................................... 18 
10.1 
Equitability .................................................................................................................... 18 
10.1.1 
Justification for Exclusion of Children ........................................................... 18 
11.0 
BENEFITS ........................................................................................................................... 18 
12.0 
CONSENT DOCUMENTS AND PROCESS ................................................................................ 18 
13.0 
DATA AND SAFETY MONITORING ...................................................................................... 20 
13.1 
Coordinating Center ...................................................................................................... 20 
13.2 
NEI Adverse Event Review Committee ....................................................................... 20 
13.3 
Criteria for Stopping the Study ..................................................................................... 21 
14.0 
QUALITY ASSURANCE ........................................................................................................ 21 
15.0 
REPORTABLE EVENTS ........................................................................................................ 22 
16.0 
ALTERNATIVE THERAPIES .................................................................................................. 22 
17.0 
PRIVACY ............................................................................................................................ 22 
18.0 
CONFIDENTIALITY ............................................................................................................. 22 
19.0 
CONFLICT OF INTEREST ...................................................................................................... 22 
20.0 
TECHNOLOGY TRANSFER ................................................................................................... 23 
21.0 
COMPENSATION ................................................................................................................. 23 
22.0 
REFERENCES ...................................................................................................................... 24 
APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL ............................................................... 27 
APPENDIX 2: STUDY FLOWSHEET .................................................................................................. 28 
APPENDIX 3: DARK ADAPTATION PROTOCOL ................................................................................ 30 
APPENDIX 4: EVALUATION OF LIGHT ............................................................................................. 31 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
BCVA 
Best-corrected visual acuity 
CC 
Clinical Center 
CD 
Clinical Director 
CFP 
Color Fundus Photography 
CFR 
Code of Federal Regulations 
CRIS 
Clinical Research Information System 
CTCAE 
Common Terminology Criteria for Adverse Events 
Emmes 
The Emmes Company, LLC 
EMR 
Electronic Medical Record 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
Fundus Autoflourescence Imaging 
FDA 
Food and Drug Administration 
HRPP 
Human Research Protection Program 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IU 
International Unit 
LLQ 
Low luminance questionnaire 
LLVA 
Low luminance visual acuity 
LORD 
Late-onset retinal disease 
NEI 
National Eye Institute 
NEI QA 
National Eye Institute Quality Assurance 
NEIS 
National Eye Institute Support 
NIH 
National Institutes of Health 
OCT 
Optical Coherence Tomography 
PI 
Principal Investigator 
RIT 
Rod Intercept Time 
RPD 
Reticular Pseudodrusen 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedures 
USP 
United States Pharmacopeia 
YAG 
Yttrium-Aluminum Garnet 


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PRÉCIS 
Objective: The objective of this study is to investigate the potential efficacy and safety of vitamin 
A palmitate dosing in improving dark adaptation in participants with age-related macular 
degeneration (AMD) and abnormal dark adaptation. 
Study Population: The first cohort consists of five participants with AMD who meet the eligibility 
criteria. The second cohort will consist of five participants with AMD who meet the eligibility 
criteria. Up to five additional participants may be accrued in the second cohort to account for 
participants who withdraw from the study prior to receiving one month of study supplementation 
for a reason unrelated to an adverse reaction. Up to 18 participants may be enrolled in this study.  
Design: This is a prospective, uncontrolled, single center, pilot study to investigate the potential 
efficacy and safety of vitamin A palmitate dosing in improving dark adaptation in participants with 
AMD and abnormal dark adaptation. Participants in the first cohort were instructed to take 
16,000 IU of vitamin A palmitate daily for two months. Enrollment for Cohort 1 ended on 
May 24, 2019. Participants in the second cohort will be instructed to take 48,000 IU of vitamin A 
palmitate daily for one month. Participants in both cohorts will continue in the study for one month 
after ending Vitamin A supplementation. Participants in Cohort 1 may enroll into Cohort 2 as long 
as their last intake of vitamin A palmitate was greater than two months prior to their enrollment 
into Cohort 2.  
Outcome Measures: For each cohort, the primary outcome is the measurement of dark adaptation 
parameters (thresholds and kinetics) by the following: dark adaptation times as measured by the 
AdaptDx comparing before and after vitamin A palmitate supplementation and dark adaptation 
parameters as measured by the Medmont comparing before and after vitamin A palmitate 
supplementation. The primary outcome will be assessed at Month 2 in the first cohort and Month 
1 in the second cohort. For both cohorts, the secondary outcomes include changes in low luminance 
visual acuity (LLVA) and changes in patient reported outcomes as measured by the low luminance 
questionnaire (LLQ). The secondary outcomes also include measurement of dark adaptation 
parameters (thresholds and kinetics) comparing baseline and one month after completing 
supplementation (Month 3 in Cohort 1 and Month 2 in Cohort 2). 


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1.0 
INTRODUCTION/SCIENTIFIC RATIONALE 
Age-related macular degeneration (AMD) has been the leading cause of central vision loss in 
people age 65 or older in developed countries1,2. Decreases in central vision from late AMD is 
well-established, and even intermediate AMD can display small but statistically significant 
reductions in central acuity compared with those without AMD3-5. However, earlier cell changes 
accompanying AMD have direct links to additional measures of retinal function. 
Histopathological examination of eyes from patients with AMD has demonstrated preferential loss 
of rods in the photoreceptor layer of the retina with cones persisting as the last surviving 
photoreceptors6-8. Studies employing multiple approaches to measure rod and cone function have 
documented preferential reduced rod function in eyes with AMD9-14. A focal dark adaptometer 
able to focus on areas 0.5 to 3 mm from the fovea, areas thought to have earliest rod loss, has 
demonstrated impairments in eyes with non-advanced AMD compared to older eyes without 
AMD, even when visual acuity varied little between severity groups11. Increasing AMD severity 
was associated with increased rod intercept time (RIT), an outcome of dark adaptation, with eyes 
having reticular pseudodrusen (RPD) demonstrating the most significant delays11.    
Interpreting the data on dark adaptation across different phenotypes of macula, there are several 
possible hypotheses that have been proposed in the literature. A testable hypothesis proposed in 
the literature is that the sub-RPE (retinal pigment epithelium) deposits act as diffusion barriers for 
entry of sufficient vitamin A into the photoreceptors. This would lead to a local deficiency or a 
form of nutritional deprivation at the level of the photoreceptor. Vitamin A deficiency has 
long been known to cause night blindness with rod dysfunction and while these patients are 
not deficient based on serum levels, there still could be a local deficiency at the level of 
photoreceptors. Without available vitamin A (due to a serum deficiency or local deficiency) 
to combine with opsin, photoreceptors cannot regenerate functional visual pigment at the 
normal rate after light exposure leading to a slowing of dark adaptation.  
A first step in understanding the pathophysiology identified by abnormal dark adaptation would 
be to supplement eyes with abnormal dark adaptation with vitamin A palmitate. Restoration or 
improvement of visual function while on supplemental vitamin A palmitate would provide 
data to support this hypothesis in the setting of AMD. Jacobson et al15 tested this hypothesis 
in patients with Sorsby’s fundus dystrophy and demonstrated that vitamin A palmitate 


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supplementation could restore dark adaptation in these patients using 50,000 IU vitamin A 
palmitate for one month, but was also able to show maintenance of some (but not all) aspects 
of dark adaptation with 5,000 IU vitamin A palmitate15. Ayyagari and Sieving et al16 
demonstrated that the dark adaptation of patients with late-onset retinal disease (LORD) with 
mutations in CTRP5 could be shifted with 15,000 IU vitamin A palmitate within two months 
of supplementation. Owsley et al17 initiated investigation into this question in older adults 
with early AMD and the results demonstrated that a short-term, high-dose course of preformed 
vitamin A increased the rate of rod-mediated dark adaptation. However, this hypothesis could 
be investigated with greater depth using more refined fundus phenotyping and psychophysical 
testing.  
The preliminary analysis of the data from Cohort 1 in the DA VitA study shows that 16,000 
IU of vitamin A palmitate per day was well tolerated with no adverse events requiring 
discontinuation of the study product. Given the previously demonstrated efficacy of vitamin 
A palmitate supplementation in the treatment of Sorsby’s fundus dystrophy15 and eyes with 
early AMD17, the introduction of a second cohort that will take an increased dose of vitamin 
A palmitate (48,000 IU per day) in the DA VitA study is necessary since the data show that 
Cohort 1 did not present significant improvement in dark adaptation after taking 16,000 IU 
per day. The knowledge gained would provide further insights into pathogenesis of 
age-related macular degeneration.  
2.0 
STUDY OBJECTIVES 
The study objective is to investigate the potential efficacy and safety of vitamin A palmitate dosing 
in improving dark adaptation in participants with AMD and abnormal dark adaptation. 
3.0 
PARTICIPANTS 
Five participants with AMD who met the eligibility criteria were enrolled into the first cohort. 
Enrollment for Cohort 1 was halted on May 24, 2019 to focus on enrollment for Cohort 2. For the 
second cohort, up to five participants with AMD who meet the eligibility criteria may be enrolled 
in this protocol. Up to five additional participants may be accrued in the second cohort to account 
for participants who withdraw from the study prior to receiving one month of study 
supplementation for a reason unrelated to an adverse reaction. Participants in Cohort 1 may enroll 


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into Cohort 2 as long as their last intake of vitamin A palmitate was greater than two months prior 
to their enrollment into Cohort 2. 
3.1 
Participant Eligibility Criteria 
3.1.1 Inclusion Criteria 
To be eligible, the following inclusion criteria must be met, where applicable. 
1. Participant must be 50 years of age or older. 
2. Participant must understand and sign the protocol’s informed consent document. 
3. Any participant of childbearing potential (see Appendix 1 for definition) must be willing 
to undergo urine pregnancy tests throughout the study. 
4. Any participant of childbearing potential (see Appendix 1 for definition) and any 
participant able to father children must have (or have a partner who has) had a hysterectomy 
or vasectomy, be completely abstinent from intercourse, or must agree to practice at least 
one acceptable method of contraception throughout the course of the study and for one 
week after study supplement discontinuation. Acceptable methods of contraception 
include: 
• 
Hormonal contraception (i.e. birth control pills, injected hormones, dermal patch or 
vaginal ring),  
• 
Intrauterine device,  
• 
Barrier methods (diaphragm, condom) with spermicide, or  
• 
Surgical sterilization (tubal ligation). 
5. Participants must agree to notify the study investigator or coordinator if any of their doctors 
initiate a new prescription medication during the course of this study. 
6. Participant must agree to not take ≥8,000 IU vitamin A palmitate outside the study 
supplementation. 
7. For supplementation eligibility, participant must have normal liver function as 
demonstrated by the Chemistry 20 panel or have mild abnormalities not above grade 1 as 
defined by the Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 
8. Participant must not be pregnant or breast-feeding and must have a negative urine 
pregnancy test within 24 hours prior to initiation of study medication. 
 
 


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3.1.2 Exclusion Criteria 
A participant is not eligible if any of the following exclusion criteria are present. 
1. Participant is in another investigational study and actively receiving study therapy. 
2. Participant is unable to comply with study procedures or follow-up visits. 
3. Participant is already taking vitamin A palmitate supplements ≥ 8,000 IU. 
4. Participant has a history of vitamin A deficiency. 
5. Participant has a condition that, in the opinion of the investigator, would preclude 
participation in the study (e.g., unstable medical status including blood pressure and 
glycemic control). 
6. Participant has a history of hepatitis or liver failure. 
7. Participant has chronic gastrointestinal disease. 
8. Participant will be excluded if the participant has serologic evidence of an active hepatitis 
infection. 
9.  Participant was in Cohort 1 and took his/her last dose of vitamin A palmitate less than two 
months prior to enrolling in Cohort 2.  
3.2 
Study Eye Eligibility Criteria 
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.2.1 Study Eye Inclusion Criteria 
1. The eye must have a best-corrected ETDRS visual acuity score better than or equal to 20/80 
(i.e., equal to or better than 54 letters). 
2. Participant must have at least one large druse. 
3. Abnormal dark adaptation, which is defined as having an AdaptDx test with a RIT of 
16 minutes or more at the screening visit. This is at least one standard deviation greater 
than the average normal RIT and includes room to account for variability in testing. If at 
any point during current testing or under a previous NEI protocol, a participant has 
exceeded the 40 minute test ceiling, they will have satisfied the inclusion criteria.  
3.2.2 Study Eye Exclusion Criteria 
1. Presence of advanced macular degeneration with central geographic atrophy or choroidal 
neovascularization. 


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2. Presence of definite reticular pseudodrusen. 
3. An ocular condition is present (other than AMD) that, in the opinion of the investigator, 
might alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other 
ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.). 
4. Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual 
acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if 
eye was otherwise normal). 
5. History of major ocular surgery (e.g. cataract extraction, scleral buckle, any intraocular 
surgery, etc.) within three months prior to study entry. 
6. History of YAG (Yttrium-Aluminum Garnet) capsulotomy performed within two months 
prior to study entry.  
3.3 
Choice of Study Eye in Cases of Bilateral Disease 
If both eyes meet the study eye eligibility criteria described above, the following criteria will be 
used to select the study eye for the purposes of this investigation: 
1. The eye with the better visual acuity will be chosen. 
2. If both eyes are equal acuity, the right eye will be arbitrarily chosen as the study eye. 
4.0 
STUDY DESIGN AND METHODS 
This is a prospective, uncontrolled, single center, pilot study to investigate the potential efficacy 
and safety of taking 16,000 IU (Cohort 1) or 48,000 IU (Cohort 2) of vitamin A palmitate in 
improving dark adaptation in participants with AMD and abnormal dark adaptation. 
4.1 
Recruitment 
Participants will be recruited from the NEI clinic. Participants will be initially recruited from the 
following protocols: the NEI screening protocol (08-EI-0102), the Ocular Natural History protocol 
(16-EI-0134), DA Extension (17-EI-0112), Rod Function (16-EI-0024), or DA_AMD 
(11-EI-0147). Eligibility will be determined by the investigator. The participants must have the 
presence of one large druse. Self-referral and referral from outside physicians will be permitted. 
If any recruitment materials are utilized, IRB-approval will be obtained prior to distribution. 
The projected recruitment time for five participants in the second cohort is approximately 
12 months. 


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4.2 
Screening Visit 
After the consent form is signed, all potential participants will undergo a screening evaluation in 
the NEI ophthalmology clinic to determine whether they meet the full eligibility criteria for 
vitamin A supplementation. A screening visit will be used to understand the level of dark 
adaptation impairment and to assess the appropriateness of the participant for inclusion. 
The screening and baseline examinations are outlined in Appendix 2 and listed in section 4.3.1. 
The investigator will review the assessments and serologic testing conducted at the screening visit 
prior to inviting the participant to return for continuation and vitamin A supplementation. 
4.3 
Study Design and Procedures 
The study duration will be three months for the first cohort during which participants will be 
instructed to take vitamin A palmitate 16,000 IU daily by mouth for two months. In the second 
cohort, the study duration will be two months and the participants will be instructed to take vitamin 
A palmitate 48,000 IU daily by mouth for one month. In addition, there will be a screening visit 
between 60 days and one day prior to the baseline visit. For the first cohort, the primary outcome 
will be assessed at baseline versus Month 2 and the secondary outcomes will be assessed at 
baseline versus Month 2 and baseline versus Month 3. For the second cohort, the primary outcomes 
will be assessed at baseline versus Month 1 and the secondary outcomes will be assessed at 
baseline versus Month 1 and baseline versus Month 2. For both cohorts, visits will occur at 
baseline, and then monthly and as clinically indicated. The study will require five visits for the 
first cohort and four visits for the second cohort. All visits must be conducted within a window of 
± 14 days from the target day. At each visit, the participant will undergo a review of systems, such 
as an assessment of headache frequency and severity, as well as an assessment of safety variables. 
The tests scheduled at each visit may be split and completed within seven days (including the 
7th day) from the visit date. A complete ophthalmologic examination will be performed at each 
visit to measure outcome variables. Participants will be screened with serum for hepatitis or hepatic 
dysfunction. However, for caution, we will monitor liver function tests. If participants in either 
cohort cannot tolerate the prescribed dose of vitamin A palmitate, they will be instructed to stop 
taking the supplement and they will be removed from the study.  
If participants are on Coumadin® (Warfarin) at enrollment, they must visit their prescribing 
physician to check their Coumadin® status within two to four weeks after initiating IP to have their 


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Coumadin® regimen adjusted if necessary (as taking vitamin A and Coumadin® can increase the 
chances of bruising and bleeding.) 
4.3.1 Ocular and Systemic Evaluations 
The following examinations will be performed at the study visits as indicated in the study 
flowsheet (Appendix 2):  
1. Medical/Ophthalmic History 
2. Supplement Accountability 
3. Review of Systems 
4. Concomitant Medication Assessment 
5. Adverse Event Assessment 
6. Best-Corrected Visual Acuity (BCVA) (ETDRS) (Short and full testing) 
7. Manifest Refraction 
8. Slit Lamp Examination 
9. Dilated Fundus Examination 
10. Intraocular Pressure (IOP) 
11. Color Fundus Photography on both eyes* 
12. Dark Adaptation using the AdaptDx in the study eye 
13. Dark Adaptation using the Medmont in the study eye 
14. Fundus Autofluorescence Imaging (FAF) on both eyes* 
15. Optical Coherence Tomography (OCT) on both eyes 
16.  Low Luminance Visual Acuity (LLVA) in both eyes 
17. Low Luminance Questionnaire (LLQ) 
18.  Hepatitis Screening (Hepatitis C antibody (HCV Ab) test and Hepatitis B surface antigen 
(HBsAg) test) 
19. Hepatic Panel (Checks liver function testing) 
20. Serum Vitamin A Levels 
21. Pregnancy Test for Participants of Childbearing Potential (See Appendix 1 for definition) 
*Imaging may be done under this or another protocol if done within six months of baseline. 


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4.4 
Study and Concomitant Therapies 
4.4.1 Study Supplement Formulation 
The vitamin A palmitate supplement will be supplied as 8,000 IU pills verified by United States 
Pharmacopeia (USP).   
4.4.2 Dosage, Administration, and Storage 
For both cohorts, participants are considered to have complied with the protocol if they have 
consumed at least 80% of the total doses over the treatment period. The first cohort was instructed 
to take two 8,000 IU pills by mouth once per day (16,000 IU) with a meal. The preliminary 
analysis of the data from the first cohort shows that 16,000 IU of vitamin A palmitate per day 
was well tolerated with no adverse events requiring discontinuation of the study product. 
The data also show that the first cohort did not present significant improvement in dark 
adaptation after taking 16,000 IU of vitamin A palmitate per day. A higher dose (50,000 IU) 
has been previously used in other studies of monogenic (inherited) retinal degeneration with 
good effect and good tolerance.26 It has even been explored in the context of individuals 
≥ 50 years old with AMD, albeit a different study design, but the higher dose of vitamin A 
was well-tolerated.16 Therefore, for the second cohort, administration of three 8,000 IU pills will 
occur by mouth twice per day (48,000 IU) and should be taken with a meal. The vitamin A 
palmitate supplement should be stored at room temperature (15-30°C).  
4.4.3 Concomitant Therapy 
Participants in both cohorts may continue to receive all medications and standard treatments 
administered for their conditions at the discretion of their treating physician, except for high-dose 
vitamin A palmitate supplementation (≥ 8,000 IU per day). A participant will be withdrawn from 
the study if placed on a daily dose of ≥8,000 IU of vitamin A palmitate.  
There are no pharmacologic interactions known to occur between vitamin A palmitate and 
tetracyclines, but there is the potential for additive side effects as each drug has the potential to 
cause intracranial hypertension. One case report in a patient receiving high doses of vitamin A 
palmitate combined with minocycline reported the development of benign intracranial 
hypertension.24 For this reason, regular ophthalmic examinations during study visits is the 


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recommended care for participants receiving the drug combination. Specific questions regarding 
headaches and attention to optic nerve for presence of papilledema will be noted at each visit.  
If participants are on Coumadin® at enrollment, they must visit their prescribing physician to check 
their Coumadin® status within 2-4 weeks after initiating study supplementation to have their 
Coumadin® regimen adjusted if necessary (as taking vitamin A palmitate and Coumadin® can 
increase the chances of bruising and bleeding.) 
All participants are eligible to receive standard-of-care treatment for AMD while enrolled in this 
study. However, if a participant develops neovascular AMD in the study eye during the course of 
the study, the participant may receive standard-of-care treatment for neovascular AMD according 
to the recommendations of the participant’s treating retina specialist. The participant will be 
withdrawn from this study and the last observation will be carried forward for data analyses. 
4.4.4 Study Supplement Accountability 
The NIH pharmacy is responsible for the accountability of all undispensed study supplement. 
Adequate supplement accountability records include documentation of all study supplement and 
supplies shipped, received, dispensed and returned to the NIH pharmacy. The NIH pharmacy will 
destroy returned study supplement and supplies following reconciliation by the Coordinating 
Center. The investigator is responsible for the accountability of all dispensed study supplement. 
Adequate supplement accountability records include documentation of all study supplement 
administered and disposed of by the investigator.  
4.5 
End of Participation 
At the conclusion of the study, the participants will no longer be able to receive the study 
supplement under this protocol. Follow-up care will be arranged with an outside ophthalmologist 
or the participant will continue to be seen at the NIH under another protocol, if available and the 
participant is eligible. The participants and their physicians, with written consent, will be informed 
of their disease status during this study. Clinical data obtained during participation may be shared 
with the participants and with written permission from the participants, their private physicians. 
Results from the overall study may be shared once the study team has analyzed the data from all 
participants. 


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4.6 
Storage of Samples and Data 
No samples will be stored for this study. The clinical data will be stored in the NEI’s electronic 
medical record, the Clinical Research Information System (CRIS) and Emmes’ database. 
All individual data will remain confidential. 
Data may also be shared with collaborating laboratories at NIH or outside of NIH and/or submitted 
to NIH-designated repositories and databases if consent for sharing was obtained. 
Repositories receiving data from this protocol may be open-access or restricted access.  
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked from an 
identifying code (“anonymized”). When coded data is shared, the key to the code will not be 
provided to collaborators, but will remain at NIH. Data may be shared with investigators and 
institutions with an FWA or operating under the Declaration of Helsinki (DoH) and reported at the 
time of continuing review. Sharing with investigators without an FWA or not operating under the 
DoH will be submitted for prospective IRB approval. Submissions to NIH-sponsored or supported 
databases and repositories will be reported at the time of continuing review. Submissions to 
non-NIH sponsored or supported databases and repositories will be submitted for prospective IRB 
approval. 
Required approvals from the collaborating institutions will be obtained and materials will be 
shipped in accordance with NIH and federal regulations. 
5.0 
RISKS/DISCOMFORTS 
There are risks associated with the procedures required for participants in this study. 
However, these are all standard procedures that are performed as part of a normal eye and medical 
examination.  
Some of the discomforts associated with the ocular examination include the following: 
1. Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or if 
contaminated, can cause an infection, but neither of these problems is very likely to occur. 
Dilating drops can also cause a sudden increase of pressure (acute glaucoma) in eyes that 
are already predisposed to develop this condition. There is little risk of glaucoma being 
triggered in this way, but if it is, treatment is available. The participant’s intraocular 


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pressure will be obtained at each ophthalmic examination to determine whether there is an 
increased risk of developing glaucoma. 
2. Color fundus photographs involve a bright flash to take pictures of the retina. This brief 
flash may cause temporary discomfort, but does not damage the eye. 
3. In rare instances, the cornea may be scratched during measurement of intraocular pressure 
or use of a funduscopic contact lens. A corneal abrasion of this sort may be painful, but it 
heals quickly with no lasting effects. 
4. OCT, color fundus photography and fundus Autofluorescence (FAF) imaging are 
non-invasive tests used to document and analyze retinal pathology and have no known 
medical risks. 
Possible risks and discomforts associated with non-ocular examinations include: 
1. Blood draws can cause discomfort and bleeding/bruising at the site of venous puncture. 
There is a remote risk of fainting or local infection. If any of these conditions arise, they 
will be treated. 
2. The medical/ophthalmic history, questionnaires, and pregnancy tests entail no medical risk. 
No additional risks or discomforts are expected for the other clinical procedures. 
3. There may be a risk to confidentiality. All precautions will be employed at the clinical sites 
and Coordinating Center. 
5.1 
AdaptDxTM Risks 
The dark adaptation protocol as outlined in Appendix 3 entails no medical risk. Other than the 
discomforts noted above regarding the dilating eye drops and bright flash of light, there may be 
fatigue and loss of motivation or attention due to the length of the procedure. There is no risk of 
photosensitivity associated with the AdaptDxTM. 
5.2 
Medmont Dark Adapted Perimetry 
5.2.1 Kinetics of Dark Adaptation 
Eye drops will be used to dilate the pupil. Participants will view a background light in a Ganzfeld 
dome for five minutes. The intensity of the background light will vary and calculated to bleach 
between 20 to 90% of rhodopsin. The background light will then be turned off and recovery of 
retinal sensitivity to Medmont blue and red stimuli will be measured. Sensitivity at each time point 
will be measured by the participant pressing a button when a blue or red light is observed. 


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Testing time will typically be up to one hour. The procedures for testing with the Medmont dark 
adapted perimeter are described further in Appendix 4. 
5.2.2 Dark Adapted Retinal Sensitivity 
Eye drops will be used to dilate the pupil and the participant will be dark adapted for 30 minutes. 
Dark adapted sensitivity will be measured across the visual field by the participant pressing a 
button when a blue or red light is observed within the field being tested. Testing time will typically 
take 10-15 minutes. 
5.3 
Study Supplement-Related 
While long-term vitamin A supplementation has been associated with hip fractures, short term 
vitamin A supplementation appears to have no effect on bone turnover. 18, 19, 25  
Vitamin A and other retinoids as well as beta carotene, a carotenoid, have been candidate therapies 
in several chemoprevention studies for tobacco-related cancers. Several clinical trials have now 
demonstrated a surprising increase in cancer risk in participants taking beta carotene 
supplements.20,21 Vitamin A supplementation has not been associated with a higher risk of lung 
cancer in tobacco based trials, and additional prevention trials are ongoing.   
A study of pharmacokinetic metabolites over 20 days in adult men who received vitamin A at 
doses equivalent to 50,000 IU found these doses consumed over this length of time did not lead to 
hypervitaminosis A.29 Similar doses of 50,000 IU vitamin A have been explored previously in a 
similar population of patients with AMD with no significant side effects.17 
High doses of vitamin A supplementation has also been administered in accordance with the World 
Health Organization (WHO) guidelines to decrease childhood mortality.30 Some countries, such 
as South Africa, implemented a “routine periodic high -dose Vitamin A supplementation” program 
which provided six monthly high dose (100,000 IU to 200, 000 IU) vitamin A retinyl palmitate 
capsules to children without significant side effects.30  
There are small risks associated with chronic high-dose vitamin A toxicity.28 The effects of toxicity 
may include hepatomegaly, elevated blood lipid levels, bone changes, and increased intracranial 
pressure.28  


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A study investigating high dose vitamin A in molar pregnancy used 200,000 IU vitamin A in adult 
women for up to 60 days and found no significant toxic effects.31 Other studies show there may be 
a possible risk of teratogenicity in a fetus when a participant of childbearing potential consumes 
high doses (i.e., > 10,000 IU/day) of preformed vitamin A palmitate.27 There have been reports of 
malformations in children when their mothers consumed high doses (>25,000 IU/day) of 
preformed vitamin A during pregnancy.27  
5.3.1 Drug Interaction-Related 
Vitamin A palmitate should be used in caution when combined with blood thinning medication. 
If participants are on Coumadin® at enrollment, they must visit their prescribing physician to check 
their Coumadin® status within two to four weeks after initiating the study supplement to have their 
Coumadin® regimen adjusted if necessary (as taking vitamin A palmitate and Coumadin® can 
increase the chances of bruising and bleeding.) 
Additional information can be found in Section 4.4.3. 
6.0 
ADDITIONAL CONSIDERATIONS 
6.1 
Research with Investigational Drugs 
This study is being conducted under an IND 138,192.  
6.2 
AdaptDx and Medmont Dark Adaptation Devices 
On May 1, 2017, the IRB determined that the use of the AdaptDx and the Medmont dark adaptation 
perimeter devices meet the criteria for non-significant risk (NSR) devices under FDA guidelines 
(21 CFR 812.3(m)). These devices are/do not: 
1. Intended as an implant and presents a potential for serious risk to the health, safety or 
welfare of a subject; 
2. Purported or represented to be for use supporting or sustaining human life and presents a 
potential for serious risk to the health, safety or welfare of a subject; 
3. For a use of substantial importance in diagnosing, curing, mitigating or treating disease, or 
otherwise preventing impairment of human health and presents a potential for serious risk 
to the health, safety or welfare of a subject; or 
4. Otherwise presents a potential for serious risk to the health, safety or welfare of a subject. 


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Per this determination, no investigational device exemption (IDE) is needed. The AdaptDx dark 
adaptation device is commercially available. 
7.0 
PARTICIPANT SAFETY MONITORING 
Participants will be monitored for adverse events by the study investigators after IP initiation.  
7.1 
Participant Withdrawal Criteria 
Participation in the study is strictly voluntary. Participants may choose to withdraw from this study 
for any reason at any time without penalty, without loss of benefits or prohibition from enrolling in 
other clinical protocols. All participants will be included in the analyses at the end of the study.  
The investigator may withdraw a participant at his/her discretion for the following reasons: 
• Investigator determination that study continuation is not in the best medical interest of the 
participant; 
• Findings in the course of the trial that may affect willingness to participate; 
• Participant requiring additional medicines that will interfere with the study supplement; 
• Serious suspected adverse reaction; 
• Visual acuity loss of  15 letters from baseline; 
• Any other safety concerns; 
• Participant unable to meet the criteria required for continued participation;  
• Participant stops taking the IP before the primary outcome is assessed; 
• Participant is taking daily dose of ≥ 8,000 IU of vitamin A palmitate in addition to study 
supplement; 
• Participant receives standard-of-care treatment for neovascular AMD in the study eye; 
• Participant is unable to complete the AdaptDx™ test; 
• Participant was in the first cohort and had his/her last intake of vitamin A palmitate less 
than two months prior to enrolling in the second cohort. 
7.2 
Pregnancy Monitoring 
If an investigator becomes aware that a study participant has become pregnant while taking any 
study supplement and for one week after their last dose of study supplement, the investigator will 
advise the participant to stop taking the study supplement immediately.  


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If an investigator becomes aware that a study participant has impregnated their partner while taking 
any study supplement and for one week after their last dose of study supplement, the investigator 
will remind the participant of the potential risks to the unborn fetus.  
In either case of reported pregnancy, the participant (and/or partner) will be referred to the NIH 
OB/GYN consultation service for evaluation and counseling. The investigator must follow the 
participant (or partner) through the pregnancy outcome. 
8.0 
OUTCOME MEASURES 
8.1 
Primary Outcome 
The primary outcome for the first cohort is the measurement of dark adaptation parameters 
(thresholds and kinetics) by the following: 
• Dark adaptation times as measured by the AdaptDx comparing baseline and two months 
after vitamin A palmitate supplementation. 
• Dark adaptation parameters as measured by the Medmont comparing baseline and two 
months after vitamin A palmitate supplementation. 
The primary outcome for the second cohort is the measurement of dark adaptation parameters 
(thresholds and kinetics) by the following: 
• Dark adaptation times as measured by the AdaptDx comparing baseline and one month 
after vitamin A palmitate supplementation. 
• Dark adaptation parameters as measured by the Medmont comparing baseline and one 
month after vitamin A palmitate supplementation. 
8.2 
Secondary Outcomes 
The secondary outcomes include changes in LLVA and patient reported outcomes as measured by 
the LLQ comparing baseline to the following timepoints:  
• Completion of supplementation (Month 2 in Cohort 1 and Month 1 in Cohort 2)  
• One month after completing supplementation (Month 3 in Cohort 1 and Month 2 in 
Cohort 2)  


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The secondary outcomes also include the measurement of dark adaptation parameters (thresholds 
and kinetics) by the following: 
• Dark adaptation times as measured by the AdaptDx comparing baseline and one month 
after completing supplementation (Month 3 in Cohort 1 and Month 2 in Cohort 2). 
• Dark adaptation parameters as measured by the Medmont comparing baseline and  
one month after completing supplementation (Month 3 in Cohort 1 and Month 2 in 
Cohort 2). 
9.0 
STATISTICAL ANALYSIS 
9.1 
Primary Outcome Analysis 
In this prospective, pilot study, analyses will be primarily descriptive and by participant. The study 
does not lend itself to a formal sample size calculation. This is a pilot investigation targeted as 
understanding changes in dark adaptation within a given participant before and after vitamin A 
palmitate supplementation. The number of participants with changes in dark adaptation parameters 
will be summarized. Changes in rod-intercept time on the AdaptDx will be calculated for each 
participant. Similarly, pre-bleach thresholds and kinetic parameters will be compared before 
initiating supplementation to after completing supplementation for Cohort 1 (Month 2) and Cohort 
2 (Month 1).  
9.2 
Secondary Outcome Analysis 
Changes in LLVA and LLQ responses will be presented by the participant and summarized from 
before initiating supplementation to after completing supplementation in Cohort 1 (Month 2) and 
Cohort 2 (Month 1). In addition, LLVA and LLQ will be summarized from before initiating 
supplementation to one month after completing supplementation in Cohort 1 (Month 3) and Cohort 
2 (Month 2).  
The number of participants in the second cohort with changes in dark adaptation parameters one 
month after completing supplementation (Month 3 in Cohort 1 and Month 2 in Cohort 2) will be 
summarized and changes in rod-intercept time will be calculated for each participant. Pre-bleach 
thresholds and kinetic parameters will be compared before initiating supplementation to one month 


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after completing supplementation (Month 3 in Cohort 1 and Month 2 in Cohort 2). The outcomes 
will be monitored throughout the study period.  
Safety outcomes, including the number and severity of systemic and ocular toxicities, adverse 
events and infections will be summarized by severity, type and assessed relatedness to the study 
therapy throughout the study period. 
10.0 
HUMAN SUBJECTS PROTECTION 
10.1 
Equitability 
Accrual for this study will be equitable among participants meeting the enrollment criteria. 
Participants less than 50 years of age are excluded because persons younger than 50 rarely present 
with AMD. Pregnant and lactating individuals are also excluded from the study based on the 
teratogenicity of vitamin A. 
10.1.1 Justification for Exclusion of Children 
Children are not eligible for this study as children rarely present with AMD. 
11.0 
BENEFITS 
While enrolled in this study, all participants are eligible to receive standard-of-care treatment for 
AMD. Some benefit may occur if the vitamin A supplementation improves vision. The study will 
lead to generalizable knowledge about AMD. 
12.0 
CONSENT DOCUMENTS AND PROCESS 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee as applicable for review prior to consenting. A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomfort and benefits. In order to minimize potential coercion, as much time as 
is needed to review the document will be given, including an opportunity to discuss it with friends, 
family members and/or other advisors, and to ask questions of any designated study investigator. 
A signed informed consent document will be obtained prior to any research activities taking place. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 


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policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s). The remote consent option will allow the 
consent designee and participant to engage in the informed consent process in a way that is similar 
to what it would be if it were conducted in-person when a participant is unable to be present at the 
study site. Whether in person or remote, the privacy of the subject will be maintained. 
Consenting investigators (and participant/consent designee, when in person) will be in a private 
area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent 
designee will be informed of the private nature of the discussion and will be encouraged to relocate 
to a more private setting if needed. If the consent process is occurring remotely, participants and 
investigators will view individual copies of the approved consent document on screens at their 
respective locations; the same screen may be used when both the investigator and the participant 
are co-located but this is not required. 
Note: When required, the witness signature will be obtained similarly as described for the 
investigator and participant below. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to the participant) or on the electronic document. 
The process for documenting signatures on an electronic document is described below. 
When a hand signature on an electronic document is used for the documentation of consent, this 
study will use the following electronic platform to obtain the required signatures:  
• iMedConsent platform (which is 21 CFR Part 11 compliant) 
Both the investigator and the participant will sign the electronic document using a finger, stylus or 
mouse. Electronic signatures (i.e., the “signature” and a timestamp are digitally generated) will not 
be used.  
Study investigators with consenting privileges will obtain informed consent. All participants will 
receive a verbal explanation in terms suited to their comprehension of the purposes, procedures 
and potential risks of the study. The participants must have the ability to understand and sign an 
informed consent form, which must be signed prior to enrollment. The participants will have an 
opportunity to carefully review the consent and ask questions regarding this study prior to signing, 


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and they will be informed that they may withdraw from the study at any time without prejudice to 
themselves or benefits lost. If the participant requires the consent to be in larger font in order to 
read it well, this will be provided. If participants are visually impaired to the point of being unable 
to read the consent, they can take the consent back with them to read it over with a family member 
or with the use of magnifying devices. If the participant chooses, the investigator can also read the 
consent verbatim to the participant and answer any questions that may arise. 
An investigator present during the consent process will document the consent process in the 
participant’s medical record. A signed copy of the informed consent form will be provided for the 
participant to keep. 
13.0 
DATA AND SAFETY MONITORING 
The NEI Serious Adverse Event (SAE) Review Committee is responsible for monitoring data and 
safety and will exercise oversight of the clinical investigation independently from the study 
investigators. 
13.1 
Coordinating Center 
The Emmes Company, LLC has been assigned as the coordinating center for this trial to conduct 
data collection, protocol monitoring, data analysis and reporting. The coordinating center provides 
routine monitoring of study participants’ data. Monitoring visits will occur on a schedule depending 
on the status of the study. More frequent monitoring visits will be performed at the beginning of the 
study when enrollment is open. Monitoring will decrease as enrollment closes and as participant 
follow-up continues.  
Although Emmes advises the NEI Clinical Director and Principal Investigator on data and 
statistical activities, the coordinating center staff does not have direct access to or interaction with 
participants. 
13.2 
NEI Adverse Event Review Committee 
The NEI SAE Review Committee, which consists of the NEI Clinical Director and three other NEI 
physicians, will be responsible for reviewing any reported serious safety events, if they occur under 
this protocol. The Committee will review accumulating data on a semiannual basis to determine 
whether the study should continue. The study PI will recuse herself from discussions of this 


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protocol. If changes to the protocol are indicated, recommendations will be made to the NEI 
Director and Institutional Review Board (IRB) who will consider and act on such 
recommendations in a timely manner. Should any suspected serious adverse reactions occur, the 
NEI Clinical Director may, at his discretion, assemble the Review Committee before the scheduled 
date to consider if the study should go forward. In addition, if three or more participants experience 
non-serious suspected adverse reactions that require temporary or permanent cessation of the IP, 
the PI shall report this to the NEI Clinical Director. The NEI Clinical Director may convene the 
Review Committee before the scheduled time to consider the cessation of the study as a whole. 
13.3 
Criteria for Stopping the Study 
The NEI SAE Review Committee may recommend temporarily suspending or closing enrollment 
or stopping the study at any time due to safety concerns, demonstration of efficacy or lack of 
efficacy or slow recruitment. 
14.0 
QUALITY ASSURANCE 
The NEI and Emmes maintain quality control by adhering to standard operating procedures 
(NEI QA program and NEIS standard operating procedures). These procedures cover the full 
protocol cycle beginning with staff credentialing and training, and protocol development and 
approval, through database development, data collection, monitoring and analysis, and finally 
manuscript preparation at the conclusion of the study. Data quality assurance is of the utmost 
importance to the NEI and Emmes. The two groups use a quality assurance system that relies on 
real-time data checks and reports throughout the course of a study to ensure the accuracy of 
information. This system is a secure and confidential data management system that stores data and 
provides quality assurance and reporting. Emmes has developed a number of routine reports 
specifically designed for monitors (e.g., listings of serious adverse events, etc.). Data will be 
reviewed for quality at least annually. 
Additionally, Emmes has developed summary reports of discrepancies, as well as reports of the 
exceptions databases, which include requests and reasons for exceptions. The results of the reports 
are communicated back to site staff, and, along with protocol compliance issues, to the NEI SAE 
Review Committee (if applicable).  


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Following the monitoring plan for this study, Emmes will perform monitoring activities, including 
on-site audits, review of database entries and the resolution of study issues. In addition to 
monitoring, Emmes performs various detailed automated and manual data quality checks. 
The results from these checks and any protocol compliance issues are communicated back to site 
staff and to the NEI Project Officer, NEI Clinical Director and applicable regulatory bodies. 
15.0 
REPORTABLE EVENTS 
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801. 
16.0 
ALTERNATIVE THERAPIES 
There are currently no alternative therapies for treating AMD or dark adaptation deficits associated 
with them. 
17.0 
PRIVACY 
All research activities will be conducted in as private a setting as possible. 
18.0 
CONFIDENTIALITY 
No blood, tissue or other samples will be stored in this study. All medical records will be kept 
confidential and will only be reviewed by the participating investigators. Data will be kept in 
password-protected computers held at the NEI and the coordinating center. Only study 
investigators and authorized coordinating center staff will have access to the study data. 
The participants’ names will not appear on any of the data forms reported to the coordinating 
center. A unique identifier will identify the participant if their information is shared with the 
coordinating center for research purposes. The participants’ names will not appear in any 
publication of the study results. Participants’ personal information will be kept as private as 
possible. However, records can be inspected by organizations for quality assurance and data 
analysis. These include the members of the IRB and NEI SAE review committee. 
19.0 
CONFLICT OF INTEREST 
The NIH guidelines were distributed to all the investigators and none of the investigators had any 
conflicts of interest.  


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20.0 
TECHNOLOGY TRANSFER 
There are no technology transfer agreements in place for this protocol. The AdaptDx dark 
adaptometer was provided to the NEI as a gift from Genentech, Inc. 
21.0 
COMPENSATION 
For this study, there is no compensation for participation. This protocol includes reimbursement 
for travel and subsistence. Participants needing financial assistance will be able to receive 
supplemental reimbursement based upon need. Requests for supplemental reimbursement will be 
evaluated on a case-by-case basis for valid financial and/or medical need through a standardized 
process. 


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22.0 
REFERENCES 
1. 
Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study monograph: 
An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, 
macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. 
Surv Ophthalmol 1980;24:335-610. 
2. 
Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye 
Study. Ophthalmology 1992;99:933-43. 
3. 
Chew EY, Clemons TE, Agron E, et al. Ten-year follow-up of age-related macular 
degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmol 
2014;132:272-7. 
4. 
Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related 
maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 
1995;36:182-91. 
5. 
Wu Z, Ayton LN, Guymer RH, Luu CD. Low-luminance visual acuity and microperimetry 
in age-related macular degeneration. Ophthalmology 2014;121:1612-9. 
6. 
Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in age-related macular 
degeneration. Invest Ophthalmol Vis Sci 1996;37:1236-49. 
7. 
Jackson GR, Owsley C, Curcio CA. Photoreceptor degeneration and dysfunction in aging 
and age-related maculopathy. Ageing Res Rev 2002;1:381-96. 
8. 
Medeiros NE, Curcio CA. Preservation of ganglion cell layer neurons in age-related macular 
degeneration. Invest Ophthalmol Vis Sci 2001;42:795-803. 
9. 
Curcio CA, Owsley C, Jackson GR. Spare the rods, save the cones in aging and age-related 
maculopathy. Invest Ophthalmol Vis Sci 2000;41:2015-8. 
10. Owsley C, Huisingh C, Jackson GR, et al. Associations between abnormal rod-mediated dark 
adaptation and health and functioning in older adults with normal macular health. Invest 
Ophthalmol Vis Sci 2014;55:4776-89. 
11. Flamendorf J, Agron E, Wong WT, et al. Impairments in Dark Adaptation Are Associated 
with Age-Related Macular Degeneration Severity and Reticular Pseudodrusen. 
Ophthalmology 2015;122:2053-62. 
12. Owsley C, McGwin G, Jr., Clark ME, et al. Delayed Rod-Mediated Dark Adaptation Is a 
Functional 
Biomarker 
for 
Incident 
Early 
Age-Related 
Macular 
Degeneration. 
Ophthalmology 2015. 
13. Owsley C, Huisingh C, Clark ME, Jackson GR, McGwin G, Jr. Comparison of Visual 
Function in Older Eyes in the Earliest Stages of Age-related Macular Degeneration to Those 
in Normal Macular Health. Curr Eye Res 2015:1-7. 


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14. Jackson GR, Scott IU, Kim IK, Quillen DA, Iannaccone A, Edwards JG. Diagnostic 
sensitivity and specificity of dark adaptometry for detection of age-related macular 
degeneration. Invest Ophthalmol Vis Sci 2014;55:1427-31. 
15. Jacobson SG, Cideciyan AV, Regunath G, et al. Night blindness in Sorsby's fundus 
dystrophy reversed by vitamin A. Nature genetics 1995;11:27-32. 
16. Ayyagari R, Mandal MN, Karoukis AJ, et al. Late-onset macular degeneration and long 
anterior lens zonules result from a CTRP5 gene mutation. Invest Ophthalmol Vis Sci 
2005;46:3363-71. 
17. Owsley C, McGwin G, Jackson GR, et al. Effect of short-term, high-dose retinol on dark 
adaptation in aging and early age-related maculopathy. Invest Ophthalmol Vis Sci 
2006;47:1310-8. 
18. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among 
postmenopausal women. JAMA. 2002;287(1):47-54.  
19. 
J Nutr. 2002 Jun;132(6):1169-72. Short-term vitamin A supplementation does not affect 
bone turnover in men. Kawahara TN1, Krueger DC, Engelke JA, Harke JM, Binkley NC. 
20. Omenn G, Goodman G, Thornquist M, et al. Risk factors for lung cancer and for intervention 
effects in CARET, the beta-carotene and retinol efficacy trial. JNatl Cancer Inst 
1996;88:1550 – 9. [78] 
21. Albanes D, Heinonen, OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements 
and lung cancer incidence in the alpha-topcopherol, beta-carotene cancer prevention study: 
effects of base-line characteristics and study compliance. JNatl Cancer Inst 1996;88:1560 – 
70. 
22. Rayapudi S, Schwartz SG, Wang X, Chavis P. Vitamin A and fish oils for retinitis 
pigmentosa. Cochrane Database Syst Rev 2013:CD008428. 
23. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. The 
American journal of clinical nutrition 2006;83:191-201. 
24. Ophthalmol, A. Pseudotumor cerebri induced by vitamin A combined with minocycline 1993 
Aug; 25(8): 306-8. 
25. Michaëlsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of 
fracture. N Engl J Med. 2003;348(4):287-294. 
26. Jacobson SG, Cideciyan AV, Wright E, Wright AF. Phenotypic marker for early disease 
detection in dominant late-onset retinal degeneration. Invest Ophthalmol Vis Sci. 2001 
Jul;42(8):1882-90. 
27. Bastos Maia S, Rolland Souza AS, Costa Caminha MF, et al. Vitamin A and Pregnancy: 
A 
Narrative 
Review. Nutrients. 
2019;11(3):681. 
Published 
2019 
Mar 
22. 
doi:10.3390/nu11030681 


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28. Garg, S., MD, PhD. (n.d.). Retinitis pigmentosa: Treatment. Retrieved June 22, 2020, 
from 
https://www.uptodate.com/contents/retinitis-pigmentosa-treatment?search= 
vitamin+A+palmitate+side+effects 
29. Eckhoff C, Nau H. Vitamin A supplementation increases levels of retinoic acid compounds 
in human plasma: possible implications for teratogenesis. Arch Toxicol 1990;64:502–3 
30. Coutsoudis, A., Sanders, D., Dhansay, M., Stuijvenberg, M., & Benn, C. (2019). Is it time 
for South Africa to end the routine high-dose vitamin A supplementation programme? 
Retrieved 
June 
23, 
2020, 
from 
http://www.samj.org.za/index.php/samj/article/ 
view/12785/9053. 
31. Maria Hartmann Uberti, E., Karina Escobar Diaz, R., O Bernardes Cardoso, R., & Braga, A. 
(2020). Evaluation of High-Dose Vitamin A Treatment in Postmolar Patients with Low and 
Plateauing Serum Human Chorionic Gonadotropin Levels. Revista Brasileira De 
Ginecologia E Obstetrícia / RBGO Gynecology and Obstetrics, 42(05). doi:10.1055/s-010-
48652 
 
 
 
 


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APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL 
A participant who is considered non-childbearing due to a medical condition (i.e., participant has 
previously undergone a hysterectomy) does not need a pregnancy test, Follicle-stimulating 
Hormone (FSH) test or contraception. 
If a participant is considered non-childbearing due to menopause, it must be in accordance with 
the IRB/NIH OB-GYN guidance on the definition of menopause. This guidance defines 
menopause as: 
• Participants over age 55 who have not had a period for one year will be considered 
menopausal and do not need a pregnancy test, FSH test or contraception. 
• Participants between 50 and 55, who have not had a period for one year, should have an 
FSH test. If their FSH level is ≥ 20 mIU/mL, they will be considered menopausal and do 
not need pregnancy testing or contraception. If their FSH level is < 20 mIU/mL, they will 
need pregnancy testing and contraception as required by the protocol. 
• Participants between 45 and 50 who have not had a period for one year will need both an 
FSH test and a pregnancy test. If they are not pregnant and their FSH level is ≥ 20 mIU/mL, 
they will be considered menopausal and will not require contraception or additional 
pregnancy testing. If their FSH test is < 20 mIU/mL, they will need pregnancy testing and 
contraception as required by the protocol. 
 




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† The color fundus photography and fundus autofluorescence results may be utilized from any NEI protocol if performed 
within six months of baseline. 
1  The option to use the BCVA (ETDRS) short testing can only occur during the screening visit. The BCVA (ETDRS) 
full testing will occur at the baseline and subsequent visits  
2 
BCVA with manifest refraction must also be performed when scheduled and when there is a change in visual acuity 
of ≥10 ETDRS letters (≥ 0.20 logMAR) from the last study visit.  
3 
Fundus Autofluorescence may include multi-spectral imaging. 
4 If AdaptDx and/or Medmont have been performed within 6 months under any other protocol, they do not have to be 
done at the screening visit. For participants who have exceeded the AdaptDx test ceiling during any NEI protocol, 
their data will be accepted regardless of their test date. 
5 Screening labs can be performed under this protocol or another NEI protocol (08-EI-0102, 11-EI-0147, 16-EI-0134, 
17-EI-0112, or 16-EI-0024) within 60 days of projected baseline visit. 
6 For participants of childbearing potential only, participants must have a negative pregnancy test within 24 hours prior 
to dispensation of study supplement. Pregnancy tests will only be conducted at each visit if the participant is 
determined to be of childbearing potential. See Appendix 1 for guidance on determining whether a participant is 
considered to be of childbearing potential. 
7 The tests scheduled at each visit may be split and completed within seven days (including the 7th day) from the visit 
date. 
8 The study visit, treatment, and assessments at Month 3 are to be completed for Cohort 1 only. 
9 This assessment will be completed for any participants who return the study supplement at Month 2. 
 
 


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APPENDIX 3: DARK ADAPTATION PROTOCOL 
Dark adaptation is the primary exposure of interest. Rod-mediated dark adaptation will be 
measured with an AdaptDxTM dark adaptometer manufactured by MacuLogix. Participants will 
view the test target with their best optical correction for the test distance. To control for pupil size 
prior to dark adaptation testing, pupils of the study eye will be dilated to ≥ 6 mm with 
1% tropicamide and 2.5% phenylephrine hydrochloride. Pupil size will be measured before each 
dark adaptation measurement to confirm adequate dilation. Based on prior studies of dark 
adaptation, it is expected that up to 5% of participants will be unable to adequately complete the 
test due to poor motivation or poor attention. Participants who are unable to complete the test will 
be considered withdrawals and additional participants may be accrued.  
 
The AdaptDxTM provide the rod intercept time as a characterization of dark adaptation speed. 
The protocol for testing with a computer–automated dark adaptometer is described in detail in the 
User Manuals. Briefly, the dilated test eye is exposed to a standard photographic flash and the 
speed of visual sensitivity recovery in the dark is measured. Sensitivity recovery is measured by 
repeatedly estimating absolute threshold (least amount of light detected) about once per minute 
until recovery reaches a criterion sensitivity, typically in 40 minutes or less. Sensitivity recovery 
is measured at 5˚ in the inferior visual field on the vertical meridian. The test target is a 500 nm, 
2˚ diameter circular spot. Participants are given a 15-second rest break between each measurement. 
The resulting recovery function is characterized by a measure of visual sensitivity recovery called 
the rod intercept. The rod intercept is the time in minutes at which the visual sensitivity recovery 
crosses the criterion sensitivity. 
 
 


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APPENDIX 4: EVALUATION OF LIGHT 
Medmont Dark Adapted Chromatic (DAC) Perimeter 
The DAC perimeter uses blue and red LEDs and has been specifically designed to measure dark 
adapted retinal sensitivity. Sensitivity is calculated from the inverse of light thresholds. Due to the 
sensitivity of dark adapted photoreceptors, light thresholds are extremely low (ca. 10-5 cd/m2). 
Therefore, maximum light intensity of the blue and red LEDs is quite low (ca. 10 cd/m2) so that 
photoreceptor thresholds can be achieved at maximum attenuation of the LEDs. By comparison a 
typical perimeter (e.g. Humphrey or Octopus) used in the eye clinic has a maximum intensity of 
3200 cd/m2. As such, the light intensities used by the Medmont DAC at more than 100 times lower 
than used in commercially available conventional perimeters and as such do not represent a light 
hazard to the patient.  
 
Light Intensity for Rhodopsin Bleaching 
We are proposing to bleach 20% to 90% of retinal rhodopsin by having the participant view a 
background light from 210 to 4250 cd/m2 respectively for five minutes. These background levels 
are at least 40% lower than the 7000 cd/m2 used by the only currently commercially available 
full--field dark adaptometer (Roland Consult, Germany) which the patient also views for five 
minutes. In addition, the maximum background light level we are proposing is only 14% of the 
light level (30 000 cd/m2) used by other dark adaptation studies.15 The background intensities we 
are proposing are 40%-85% lower than used previously and as such do not represent a light hazard 
to the patient. 
Procedures: 
1. The participant is placed in the dark for 30 minutes. 
2. Sensitivities on the Medmont perimeter are tested to obtain level of “pre-bleach” 
sensitivities. 
3. Participant is asked to view a background light from 210 to 4250 cd/m2 respectively for 
five minutes. 
4. Sensitivities at various locations in the macula are tested using the Medmont perimeter 
over a time frame not to exceed 60 minutes. 
 

SAP_001.pdf: 
 
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Statistical Analysis Plan 
For 
An Investigation of Vitamin A Palmitate Supplementation in Patients with Age-Related 
Macular Degeneration (and Without Reticular Pseudodrusen) and Delayed Dark 
Adaptation 
 
NCT03478865 
 
Version 2.0 
January 11, 2024 
 
Prepared by 
 
 
 
 
Original Author Signature:         
 
 
 
 
       
 
Reviewer Signature:   
       
 
 
 
 
       
 
Principal Investigator Signature: 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................... V 
1.0 
INTRODUCTION ................................................................................................................. 1 
1.1 
Age-related Macular Degeneration (AMD) and Scientific Rationale for the Study ...................... 1 
2.0 
DATA SOURCE ................................................................................................................... 3 
3.0 
GENERAL REVIEW OF STUDY DESIGN ............................................................................. 3 
3.1 
Study Design .................................................................................................................................. 3 
3.2 
Study Objective .............................................................................................................................. 4 
3.3 
Study Population ............................................................................................................................ 4 
3.3.1 
Participant Eligibility Criteria ................................................................................................. 4 
3.3.1.1 
Inclusion Criteria ............................................................................................................. 4 
3.3.1.2 
Exclusion Criteria ............................................................................................................ 5 
3.3.2 
Study Eye Eligibility Criteria .................................................................................................. 6 
3.3.2.1 
Study Eye Inclusion Criteria ............................................................................................ 6 
3.3.2.2 
Study Eye Exclusion Criteria ........................................................................................... 6 
3.3.2.3 
Choice of Study Eye in Case of Bilateral Disease ........................................................... 6 
3.4 
Outcomes ........................................................................................................................................ 7 
3.4.1 
Primary Study Outcome .......................................................................................................... 7 
3.4.2 
Secondary Study Outcomes .................................................................................................... 7 
4.0 
DEFINITIONS ..................................................................................................................... 8 
5.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 8 
5.1 
Sample Size .................................................................................................................................... 8 
5.2 
Analysis Populations ...................................................................................................................... 8 
5.3 
Descriptive Statistics ...................................................................................................................... 9 
5.4 
Handling Duplicate Assessments ................................................................................................... 9 
5.5 
Handling of Missing Values ........................................................................................................... 9 
5.6 
Statistical Tests and Adjustment for Multiplicity ......................................................................... 10 
5.7 
Software for Analyses .................................................................................................................. 10 
6.0 
PARTICIPANT DISPOSITION ............................................................................................ 10 
7.0 
PARTICIPANT CHARACTERISTICS .................................................................................. 10 
7.1 
Participant Demographics ............................................................................................................ 10 
7.2 
Medical, Medication, Smoking and Ocular History ..................................................................... 10 
8.0 
PARTICIPANT COMPLIANCE ........................................................................................... 11 
8.1 
Protocol Deviations and Unanticipated Problems ........................................................................ 11 
8.1.1 
IP Compliance Deviations ..................................................................................................... 11 
8.1.2 
Study Procedure Deviations .................................................................................................. 12 
8.1.3 
Visit Schedule Deviations ..................................................................................................... 12 
8.2 
Premature Treatment and Study Withdrawals .............................................................................. 13 
9.0 
PRIMARY OUTCOMES ANALYSIS ..................................................................................... 13 
9.1 
Dark Adaptation Times ................................................................................................................ 13 
9.2 
Dark Adaptation Parameters ......................................................................................................... 13 
10.0 
SECONDARY OUTCOMES ANALYSIS ................................................................................ 14 
10.1 Low Luminance Visual Acuity (LLVA) ...................................................................................... 14 
10.2 Low Luminance Questionnaire (LLQ) ......................................................................................... 14 
10.3 Dark Adaptation Times ................................................................................................................ 14 
10.4 Dark Adaptation Parameters ......................................................................................................... 14 


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11.0 
EXPLORATORY ANALYSES.............................................................................................. 15 
11.1 Dark Adaptation Times ................................................................................................................ 15 
11.2 Low Luminance Visual Acuity (LLVA) ...................................................................................... 15 
11.3 Low Luminance Questionnaire (LLQ) ......................................................................................... 16 
12.0 
SAFETY OUTCOMES ........................................................................................................ 16 
12.1 Adverse Events (AEs) .................................................................................................................. 16 
13.0 
OTHER SAFETY OUTCOMES ........................................................................................... 16 
13.1 Natural Progressions of the Disease ............................................................................................. 16 
13.2 Laboratory Assessments ............................................................................................................... 17 
14.0 
OTHER OPHTHALMIC ASSESSMENTS ............................................................................. 17 
14.1 Rod-Intercept Time (RIT) ............................................................................................................ 17 
14.2 Best-Corrected Visual Acuity (BCVA) ........................................................................................ 17 
14.3 Low Luminance Visual Acuity (LLVA) ...................................................................................... 18 
14.4 Low Luminance Questionnaire (LLQ) ......................................................................................... 18 
14.5 Intraocular Pressure (IOP) ............................................................................................................ 18 
14.6 Optic Nerve Papilledema, Headache, and Medication Assessment ............................................. 18 
14.7 Other Ophthalmic Assessments .................................................................................................... 18 
15.0 
RATIONALE FOR ANY DEVIATION FROM PRE-SPECIFIED ANALYSIS PLAN ................. 19 
16.0 
QUALITY ASSURANCE PLANS ......................................................................................... 19 
17.0 
REFERENCES ................................................................................................................... 20 
18.0 
MOCK SHELLS ................................................................................................................ 22 
TABLES ....................................................................................................................................... 22 
 
 
 


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TABLE OF TABLES 
Table 1. Participant Disposition .................................................................................................... 22 
Table 2. Summary of Participant Demographics .......................................................................... 23 
Table 3. Medical, Medication, and Smoking History ................................................................... 24 
Table 4. Ocular History ................................................................................................................. 25 
Table 5. Protocol Deviations and Unanticipated Problems .......................................................... 26 
Table 6. IP Compliance ................................................................................................................. 27 
Table 7. Study Procedure Deviations ............................................................................................ 27 
Table 8. Missed and Out of Window Follow-Up Study Visits ..................................................... 28 
Table 9. Analysis of Primary Outcome of Change in Dark Adaptation Rod Intercept Time (RIT) 
from Baseline in the Study Eye and Corresponding Secondary and Exploratory Analyses ........ 29 
Table 10. Analysis of Secondary Outcome of Change in LLVA Total Letters Read from Baseline 
in the Study Eye and Corresponding Exploratory Analyses ......................................................... 30 
Table 11. Analysis of Secondary Outcome of Change in LLQ Subscale and Composite Scores 
from Baseline and Corresponding Exploratory Analyses ............................................................. 31 
Table 12. Summary of Adverse Events (AEs) .............................................................................. 33 
Table 13. AEs by System Organ Class (SOC) and Preferred Term (PT) ..................................... 34 
Table 14. Summary of Laboratory Assessments Over Time ........................................................ 35 
Table 15. Summary of Dark Adaptation Rod Intercept Time ...................................................... 36 
Table 16. Summary of BCVA Total Letters Read ........................................................................ 37 
Table 17. Summary of LLVA Total Letters Read ........................................................................ 38 
Table 18. Summary of LLQ Subscale and Composite Scores ...................................................... 39 
Table 19. Summary of IOP ........................................................................................................... 40 
Table 20. Summary of Optic Nerve Papilledema, Headache, and Medication Assessment ........ 41 
Table 21. Summary of Additional Ophthalmic Assessments ....................................................... 42 
 
TABLE OF LISTINGS 
 
Listing 1. DA Rod Intercept Time in Study Eye from Baseline to Treatment Completion and 
Post-Treatment Follow-Up ........................................................................................................... 47 
Listing 2. LLVA Total Letters Read in Study Eye from Baseline to Treatment Completion and 
Post-Treatment Follow-Up ........................................................................................................... 47 
Listing 3. LLQ Subscale and Composite Scores from Baseline to Treatment Completion and 
Post-Treatment Follow-Up ........................................................................................................... 48 
 
TABLE OF FIGURES 
Figure 1. Study Disposition .......................................................................................................... 49 
 
 
 


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VERSION HISTORY 
Version/Date 
Changes 
1.0/27JUL2021 
Initial Document 
2.0/18DEC2023 
Title Page: Updated Principal Investigator; 
List of Abbreviations: Updated for currency; 
Section 1.0: Updated protocol version and date; 
Section 2.0: Updated “Advantage EDC” to “Advantage eClinical®”; 
Section 3.3.1.1: Updated inclusion criterion corresponding to the 
number of acceptable methods of contraception; 
Section 5.2: Updated to clarify that exploratory analyses are based on 
the primary analysis population;  
Section 5.7: Removed Graphpad Prism from utilized software; 
Section 11.2: Excluded fellow eye from statistical model results for 
LLVA; 
Section 12.1: Added “outcome” to AE table summary; 
Section 13.2: Updated to clarify that abnormal results from laboratory 
assessments preformed at Screening are reported at Baseline; 
Section 14.6: Added summary of vitamin A palmitate consumption; 
Section 14.7: Updated to clarify that Presence of RPD is assessed at 
Baseline; 
Section 18.0: Made applicable corresponding updates described above 
to mock shells. Additionally, added continuous age summary in Table 
2; added assessment for Coumadin in Table 3; updated placement of 
statistical results and inclusion of covariance structure in Table 9, 
Table 10, and Table 11; and updated reported decimal places for LLQ 
values. 
General updates throughout document to ensure consistency of 
abbreviations. 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
AMD 
Age-related Macular Degeneration 
BCVA 
Best-Corrected Visual Acuity 
CC 
Clinical Center 
CTCAE 
Common Terminology Criteria for Adverse Events 
EMR 
Electronic Medical Record 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IU 
International Unit 
LLQ 
Low luminance questionnaire 
LLVA 
Low luminance visual acuity 
LORD 
Late-onset retinal disease 
NEI 
National Eye Institute 
NIH 
National Institutes of Health 
PSC 
Posterior Subcapsular Cataract 
PT 
Preferred Term 
RIT 
Rod Intercept Time 
RPD 
Reticular Pseudodrusen 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
YAG 
Yttrium-Aluminum Garnet 
 


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1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides the proposed analyses for DA VitA AMD protocol 
titled “An Investigation of Vitamin A Palmitate Supplementation in Patients with Age-Related 
Macular Degeneration (and Without Reticular Pseudodrusen) and Delayed Dark Adaptation”. 
This document contains 18 sections: (1) background of the study, (2) data sources for analyses, 
(3) an overview of the study design, (4) definitions, (5) statistical considerations, (6) participant 
disposition, (7) participant characteristics, (8) participant compliance, (9) statistical analysis for 
the primary outcome, (10) statistical analyses for secondary outcomes, (11) exploratory analyses 
(12) safety outcomes, (13) other safety outcomes, (14) other ophthalmic assessments, 
(15) rationale for deviation from pre-specified analysis plan, (16) quality assurance plan, 
(17) references, and (18) mock shells for proposed tables, listings, and figures. This document is 
based on version 9.0 of the protocol dated September 25, 2023. Any deviation from this SAP, not 
outlined in Section 15.0, will be described and justified in protocol amendments and/or in the final 
study report, as appropriate. 
1.1 
Age-related Macular Degeneration (AMD) and Scientific Rationale for the Study 
Age-related macular degeneration (AMD) has been the leading cause of central vision loss in 
people aged 65 or older in developed countries1,2. Decreases in central vision from late AMD is 
well-established, and even intermediate AMD can display small but statistically significant 
reductions in central acuity compared with those without AMD3-5. However, earlier cell changes 
accompanying AMD have direct links to additional measures of retinal function. 
Histopathological examination of eyes from patients with AMD has demonstrated preferential loss 
of rods in the photoreceptor layer of the retina with cones persisting as the last surviving 
photoreceptors6-8. Studies employing multiple approaches to measure rod and cone function have 
documented preferential reduced rod function in eyes with AMD9-14 A focal dark adaptometer able 
to focus on areas 0.5 to 3 mm from the fovea, areas thought to have earliest rod loss, has 
demonstrated impairments in eyes with non-advanced AMD compared to older eyes without 
AMD, even when visual acuity varied little between severity groups11. Increasing AMD severity 


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was associated with increased rod intercept time (RIT), an outcome of dark adaptation, with eyes 
having reticular pseudodrusen (RPD) demonstrating the most significant delays11.    
Interpreting the data on dark adaptation across different phenotypes of macula, there are several 
possible hypotheses that have been proposed in the literature. A testable hypothesis proposed in 
the literature is that the sub-RPE (retinal pigment epithelium) deposits act as diffusion barriers for 
entry of sufficient vitamin A into the photoreceptors. This would lead to a local deficiency or a 
form of nutritional deprivation at the level of the photoreceptor. Vitamin A deficiency has long 
been known to cause night blindness with rod dysfunction and while these patients are not deficient 
based on serum levels, there still could be a local deficiency at the level of photoreceptors. 
Without available vitamin A (due to a serum deficiency or local deficiency) to combine with opsin, 
photoreceptors cannot regenerate functional visual pigment at the normal rate after light exposure 
leading to a slowing of dark adaptation.  
A first step in understanding the pathophysiology identified by abnormal dark adaptation would 
be to supplement eyes with abnormal dark adaptation with vitamin A palmitate. Restoration or 
improvement of visual function while on supplemental vitamin A palmitate would provide data to 
support this hypothesis in the setting of AMD. Jacobson et al15 tested this hypothesis in patients 
with Sorsby’s fundus dystrophy and demonstrated that vitamin A palmitate supplementation could 
restore dark adaptation in these patients using 50,000 international unit (IU) vitamin A palmitate 
for one month, but was also able to show maintenance of some (but not all) aspects of dark 
adaptation with 5,000 IU vitamin A palmitate15. Ayyagari and Sieving et al16 demonstrated that 
the dark adaptation of patients with late-onset retinal disease (LORD) with mutations in CTRP5 
could be shifted with 15,000 IU vitamin A palmitate within two months of supplementation. 
Owsley et al17 initiated investigation into this question in older adults with early AMD, and the 
results demonstrated that a short-term, high-dose course of preformed vitamin A increased 
the rate of rod-mediated dark adaptation. However, this hypothesis could be investigated with 
greater depth using more refined fundus phenotyping and psychophysical testing.  
The preliminary analysis of the data from Cohort 1 in the DA VitA study showed that 16,000 
IU of vitamin A palmitate per day was well tolerated with no adverse events (AEs) requiring 
discontinuation of the study product. Given the previously demonstrated efficacy of vitamin 


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A palmitate supplementation in the treatment of Sorsby’s fundus dystrophy15 and eyes with 
early AMD17, the introduction of a second cohort that will take an increased dose of vitamin 
A palmitate (48,000 IU per day) in the DA VitA study is necessary since the data show that 
Cohort 1 did not present significant improvement in dark adaptation after taking 16,000 IU 
per day. The knowledge gained would provide further insights into pathogenesis of 
age-related macular degeneration.  
2.0 
DATA SOURCE 
Data will be received from the National Eye Institute (NEI) via their electronic data capture system 
(Electronic Medical Record, EMR), which will then be uploaded daily to the Coordinating 
Center’s (CC) database, Advantage eClinical®. Medmont and AdaptDx kinetic measures 
(i.e., curve parameters) and Medmont pre-bleach thresholds will be collected and analyzed at the 
NEI and will not be entered into EMR or transferred to the CC. All other analyses described in this 
document will be performed by the CC.  
3.0 
GENERAL REVIEW OF STUDY DESIGN 
3.1 
Study Design 
The DA VitA AMD study is a prospective, uncontrolled, single center, pilot study to investigate 
the potential efficacy and safety of vitamin A palmitate dosing in improving dark adaptation in 
participants with AMD (without RPD) and abnormal dark adaptation. 
The study will require five visits (screening, baseline, Month 1, Month 2, and Month 3) for Cohort 
1 and four visits (screening, baseline, Month 1, and Month 2) for Cohort 2. Participants in Cohort 
1 will be instructed to take vitamin A palmitate 16,000 IU daily by mouth for two months from 
baseline through Month 2 and will continue in the study through Month 3. Participants in Cohort 
2 will be instructed to take 48,000 IU of vitamin A palmitate daily by mouth from baseline through 
Month 1 and will continue in the study through Month 2. The screening visit must occur between 
60 days and one day prior to the baseline visit while Months 1, 2 and 3 visits must be conducted 
within a window of ± 14 days from the target day. The tests scheduled at each visit may be split 
and completed within seven days (including the 7th day) from the visit date. At each visit, the 
participant will undergo a review of systems, such as an assessment of headache frequency and 


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severity, as well as an assessment of safety variables. A complete ophthalmologic examination 
will be performed at each visit to measure outcome variables. If participants in either cohort cannot 
tolerate the prescribed dose of vitamin A palmitate, they will be instructed to stop taking the 
supplement and they will be removed from the study. 
3.2 
Study Objective 
The objective of the study is to investigate the potential efficacy and safety of vitamin A palmitate 
dosing in improving dark adaptation in participants with AMD and abnormal dark adaptation.  
3.3 
Study Population 
Five participants with AMD who met the eligibility criteria were enrolled into Cohort 1. 
Enrollment for Cohort 1 was halted on May 24, 2019 to focus on enrollment for Cohort 2. Up to 
five participants with AMD who meet the eligibility criteria may be enrolled in Cohort 2. Up to 
five additional participants may be accrued in the Cohort 2 to account for participants who 
withdraw from the study prior to receiving one month of study supplementation for a reason 
unrelated to an adverse reaction. Participants in Cohort 1 may enroll into Cohort 2 as long as their 
last intake of vitamin A palmitate was greater than two months prior to their enrollment into 
Cohort 2. 
3.3.1 Participant Eligibility Criteria 
3.3.1.1 Inclusion Criteria 
To be eligible, the following inclusion criteria must be met, where applicable. 
1. Participant must be 50 years of age or older. 
2. Participant must understand and sign the protocol’s informed consent document. 
3. Any participant of childbearing potential must be willing to undergo urine pregnancy tests 
throughout the study. 
4. Any participant of childbearing potential and any participant able to father children must 
have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent 
from intercourse, or must agree to practice at least one acceptable method of contraception 
throughout the course of the study and for one week after study supplement 
discontinuation. Acceptable methods of contraception include: 


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x 
Hormonal contraception (i.e., birth control pills, injected hormones, dermal patch 
or vaginal ring),  
x 
Intrauterine device,  
x 
Barrier methods (diaphragm, condom) with spermicide, or  
x 
Surgical sterilization (tubal ligation). 
5. Participants must agree to notify the study investigator or coordinator if any of their doctors 
initiate a new prescription medication during the course of this study. 
6. Participant must agree to not take ≥8,000 IU vitamin A palmitate outside the study 
supplementation. 
7. For supplementation eligibility, participant must have normal liver function as 
demonstrated by the Chemistry 20 panel or have mild abnormalities not above grade 1 as 
defined by the Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 
8. Participant must not be pregnant or breast-feeding and must have a negative urine 
pregnancy test within 24 hours prior to initiation of study medication. 
3.3.1.2 Exclusion Criteria 
A participant is not eligible if any of the following exclusion criteria are present. 
1. Participant is in another investigational study and actively receiving study therapy. 
2. Participant is unable to comply with study procedures or follow-up visits. 
3. Participant is already taking vitamin A palmitate supplements ≥ 8,000 IU. 
4. Participant has a history of vitamin A deficiency. 
5. Participant has a condition that, in the opinion of the investigator, would preclude 
participation in the study (e.g., unstable medical status including blood pressure and 
glycemic control). 
6. Participant has a history of hepatitis or liver failure. 
7. Participant has chronic gastrointestinal disease. 
8. Participant will be excluded if the participant has serologic evidence of an active hepatitis 
infection. 
9.  Participant was in Cohort 1 and took his/her last dose of vitamin A palmitate less than two 
months prior to enrolling in Cohort 2. 


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3.3.2 Study Eye Eligibility Criteria 
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.3.2.1 
Study Eye Inclusion Criteria 
1. The eye must have a best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) 
visual acuity score better than or equal to 20/80 (i.e., equal to or better than 54 letters). 
2. Participant must have at least one large druse. 
3. Abnormal dark adaptation, which is defined as having an AdaptDx test with a RIT of 
16 minutes or more at the screening visit. This is at least one standard deviation greater 
than the average normal RIT and includes room to account for variability in testing. If at 
any point during current testing or under a previous NEI protocol, a participant has 
exceeded the 40 minute test ceiling, they will have satisfied the inclusion criteria.  
3.3.2.2 
Study Eye Exclusion Criteria 
1. Presence of advanced macular degeneration with central geographic atrophy or choroidal 
neovascularization. 
2. Presence of definite reticular pseudodrusen. 
3. An ocular condition is present (other than AMD) that, in the opinion of the investigator, 
might alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other 
ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.). 
4. Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual 
acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if 
eye was otherwise normal). 
5. History of major ocular surgery (e.g. cataract extraction, scleral buckle, any intraocular 
surgery, etc.) within three months prior to study entry. 
6. History of Yttrium-Aluminum Garnet (YAG) capsulotomy performed within two months 
prior to study entry.  
3.3.2.3 
Choice of Study Eye in Case of Bilateral Disease 
If both eyes meet the study eye eligibility criteria described above, the following criteria will be 
used to select the study eye for the purposes of this investigation: 


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1. The eye with the better visual acuity will be chosen. 
2. If both eyes have equal acuity, the right eye will be arbitrarily chosen as the study eye. 
3.4 
Outcomes 
3.4.1 Primary Study Outcome 
The primary outcome for the first cohort is the measurement of dark adaptation parameters 
(thresholds and kinetics) in the study eye by the following: 
x Dark adaptation times and kinetic parameters (i.e., curve parameters) as measured by the 
AdaptDx comparing baseline and two months after vitamin A palmitate supplementation. 
x Dark adaptation parameters (kinetic/curve parameters and pre-bleach thresholds) as 
measured by the Medmont comparing baseline and two months after vitamin A palmitate 
supplementation. 
The primary outcome for the second cohort is the measurement of dark adaptation parameters 
(thresholds and kinetics) in the study eye by the following: 
x Dark adaptation times and kinetic parameters (i.e., curve parameters) as measured by the 
AdaptDx comparing baseline and one month after vitamin A palmitate supplementation. 
x Dark adaptation parameters (kinetic/curve parameters and pre-bleach thresholds) as 
measured by the Medmont comparing baseline and one month after vitamin A palmitate 
supplementation. 
3.4.2 Secondary Study Outcomes 
The secondary outcomes for both cohorts are changes in low luminance visual acuity (LLVA) and 
patient-reported outcomes as measured by the low luminance questionnaire (LLQ) comparing 
baseline to the following timepoints: 
x Completion of supplementation (Month 2 in Cohort 1 and Month 1 in Cohort 2) 
x One month after completing supplementation (Month 3 in Cohort 1 and Month 2 in  
Cohort 2).  


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The secondary outcomes for both cohorts also include the measurement of dark adaptation 
parameters (thresholds and kinetics) by the following:  
x Dark adaptation times and kinetic parameters (i.e., curve parameters) as measured by the 
AdaptDx comparing baseline and post-treatment follow-up visit 
x Dark adaptation parameters (kinetic/curve parameters and pre-bleach thresholds) as 
measured by the Medmont comparing baseline and post-treatment follow-up visit 
Safety outcomes include the number and severity of systemic and ocular toxicities, AEs and 
infections, occurring throughout the study period. 
4.0 
DEFINITIONS 
Treatment completion visit: The visit corresponding to completion of treatment, occurring at 
Month 2 in Cohort 1 and Month 1 in Cohort 2. The primary outcome is assessed at this visit. 
Post-treatment follow-up visit: The final study visit which occurs one month after completion of 
treatment, corresponding to Month 3 in Cohort 1 and Month 2 in Cohort 2.  
5.0 
STATISTICAL CONSIDERATIONS 
Since this is a proof-of-principle study, all analyses will be exploratory in nature. 
5.1 
Sample Size 
A total of 18 participants, eight in Cohort 1 and up to ten in Cohort 2, may be enrolled in the study 
to obtain five participants for the primary outcome analysis for each cohort. No formal sample size 
calculation was conducted, since this pilot study will not attempt to definitively determine the 
safety or efficacy of this treatment.  
5.2 
Analysis Populations 
The following analysis populations will be considered for this study:  
Screened population: Includes all participants screened, regardless of eligibility determination / 
enrollment status. Participant disposition will be based on this population. 


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Enrolled population: Includes all participants enrolled in the study, regardless of compliance, 
follow-up, or treatment received. Demographic characteristics and compliance will be based on 
this population. Screen failures are not included in the enrolled population. 
Primary analysis population: Includes all enrolled participants who receive investigational product 
(IP) through the treatment completion visit. The primary, secondary, and exploratory outcome 
analyses will be based on this population. 
Safety population: Includes all enrolled participants who receive at least one dose of IP. All safety 
analyses will be based on this population. 
5.3 
Descriptive Statistics 
For continuous parameters, descriptive statistics will include number of observations, mean, 
standard deviation, median, minimum and maximum. For categorical parameters, frequency and 
percentage of participants will be summarized. 
5.4 
Handling Duplicate Assessments  
If participants completed assessments at both scheduled and supplementary visits, the assessments 
from the scheduled visit will be considered in the analysis and tabular summaries. However, if an 
assessment is completed only at supplementary visits, then the assessments from the most recent 
supplementary visit will be included in the analysis and tabular summaries. Results of all 
assessments, including those performed during supplementary visits, will be included in the 
listings.  
5.5 
Handling of Missing Values 
In general, missing observations will be excluded from analyses. If a participant receives 
standard-of-care treatment for neovascular AMD in the study eye during the course of the study, 
the participant will be withdrawn from the study and the last observation will be carried forward 
for data analyses. This would be identified manually by reviewing the AEs and natural progression 
of disease events because it is not included as a termination reason in the case report form.  


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5.6 
Statistical Tests and Adjustment for Multiplicity 
Results of statistical analyses are considered significant if the p-value from the statistical test is 
< 0.05 for two-sided tests and < 0.025 for one-sided tests. 
Since all analyses in this study are considered exploratory, no adjustments for multiple 
comparisons will be made. 
5.7 
Software for Analyses 
Statistical analyses will be performed using SAS version 9.4 or higher, or R v3.6.1 or higher. 
All tables, listings and figures presented in the analysis will be created using SAS version 9.4 or 
higher, or R v3.6.1 or higher. 
6.0 
PARTICIPANT DISPOSITION 
Overall participant disposition including the number of participants screened, failed screening, 
enrolled, received at least one dose of IP, received IP through treatment completion visit, 
discontinued IP early, terminated early from the study and completed study will be summarized 
by cohort and overall. Reasons for early treatment and study discontinuation will also be 
summarized (Table 1). This table will be based on the screened population. A consort diagram 
showing participant flow will also be included as shown in Figure 1. 
7.0 
PARTICIPANT CHARACTERISTICS 
These presentations will be based on the enrolled population. 
7.1 
Participant Demographics 
Demographic data including baseline age, gender, race and ethnicity will be summarized by cohort 
and overall as in Table 2 and presented by participant. The listing will also include study 
registration date and indicate the eye determined to be the study eye.  
7.2 
Medical, Medication, Smoking and Ocular History 
Medical, medication and smoking history and history of ophthalmic procedures will be 
summarized by cohort and overall (Tables 3 and 4, respectively) and presented by participant. 


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8.0 
PARTICIPANT COMPLIANCE 
These presentations will be based on the enrolled population. 
8.1 
Protocol Deviations and Unanticipated Problems 
The total number of protocol deviations and unanticipated problems and the number and 
percentage of participants with deviations and unanticipated problems will be summarized by 
cohort and overall.  
Effective July 1, 2019, with the implementation of National Institutes of Health (NIH) Intramural 
Research Program Policy 801, protocol deviations and unanticipated problems are classified by 
the Investigator as major or minor at the time of data entry (as opposed to serious or not serious), 
and seriousness of major deviations and unanticipated problems is determined after review by the 
NIH Institutional Review Board (IRB). The number of events per participant and the type (minor, 
serious, not serious, or pending determination by IRB) and outcome of events will also be 
summarized (Table 5). Listings of participant-specific and non-participant-specific protocol 
deviations and unanticipated problems will be presented. 
8.1.1 IP Compliance Deviations 
The number of expected doses, number of doses taken, number of doses missed, and the 
compliance rate will be summarized by participant, cohort, and overall as in Table 6.   
For cohort 1, each dose consists of two pills of 8,000 IU of vitamin A palmitate, taken once per 
day, for a total of 16,000 IU per day. For cohort 2, each dose consists of three pills of 8,000 IU of 
vitamin A palmitate, taken twice per day, for a total of 48,000 IU per day. 
For each participant, the number of expected doses will be calculated as follows:  
Ndoses expected   =  (DateMonth x/ early IP withdrawal  – DateIP first taken)*Number of doses per day 
If participants took IP on the date they withdrew from the study or completed the study, the number 
of expected doses overall and between visits will be calculated as follows:  
Ndoses expected   = (DateMonth x/ early IP withdrawal  – DateIP first taken +1) *Number of doses per day 
Where: Month x = Month 2 for Cohort 1 and Month 1 for Cohort 2 
DateIP first taken = date of the visit when IP was first dispensed to the participant 
Number of doses per day = 1 for Cohort 1 and 2 for Cohort 2 


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The number of pills returned at each study visit will be recorded by the site. Number of doses taken 
and missed will be calculated for each period timeframe as follows:  
Ndoses taken = (Npills dispensed – Npills returned) / Number of pills per dose 
Ndoses missed = Ndoses expected – Ndoses taken  
Where: Number of pills per dose = 2 for Cohort 1 and 3 for Cohort 2. 
Compliance rate will be calculated as follows:  
Compliance Rate = (Ndoses taken / Ndoses expected) * 100 
Participants are considered to have complied with the protocol if they consumed at least 80% of 
the total expected doses of vitamin A palmitate. Compliance rates falling below 80% will be 
highlighted in yellow in Table 6.  
8.1.2 Study Procedure Deviations 
Table 7 will present the expected number of procedures and number and percentage of procedures 
missed by participant, cohort, procedure, and cumulatively across all participants. Number of 
procedures missed is defined when the site reports a missed procedure or when the protocol 
monitors note missed procedures at the site and will be presented as a sum. Expected number of 
procedures is defined based on the study flowsheet and will also be presented as a sum. Percentage 
of procedures missed will be calculated as follows:  
%procedures missed = (Nprocedures missed / Nexpected procedures) * 100 
8.1.3 Visit Schedule Deviations 
The number of expected visits, number and percentage of missed visits, and number and 
percentage of out of window visits will be summarized by participant, cohort and cumulatively 
across all participants as in Table 8. Number of expected, missed and out of window visits will be 
presented as sums. The percentage of missed and out of window study visits will be calculated as 
follows:  
%missed visits = (Nmissed visits / Nexpected visits) * 100 
 
%out of window visits = (Nout of window visits / Nexpected visits) * 100 


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8.2 
Premature Treatment and Study Withdrawals 
Participants who withdrew from treatment and study early will be summarized as outlined in 
Section 6.0 and listed separately along with reason(s) for withdrawal.   
9.0 
PRIMARY OUTCOMES ANALYSIS 
The analysis of primary outcome will be considered exploratory; no adjustment for multiplicity 
will be performed. These analyses will be based on the primary analysis population. 
9.1 
Dark Adaptation Times 
Change in RIT, as measured by the AdaptDx, from baseline in the study eye at treatment 
completion visit will be summarized (Table 9) and listed (Listing 1) for each cohort.  
For each cohort, the mean change in RIT in the study eye at the treatment completion visit from 
baseline will be assessed using a Student’s paired t-test (TTEST procedure in SAS) (Table 9). 
The following hypothesis will be tested at a type I error rate of 5%, where μBaseline RIT is the mean 
RIT at baseline and μtreatment completion RIT is the mean RIT at at the treatment completion visit:  
Ho:  μBaseline RIT  =  μtreatment completion RIT 
HA: μBaseline RIT  ≠  μtreatment completion RIT   
9.2 
Dark Adaptation Parameters 
Changes in AdaptDx curve parameters measured at baseline and at treatment completion will be 
assessed by first fitting a two part (exponential and linear) curve to the data: 
y = ae -bx  + c max (x-d, 0) + e, 
where  y is the threshold, b is the cone adaptation rate, x is time after cessation of bleach, c is the 
rod slope, d is the time of the rod cone break, and a + e is the cone-rod plateau. Changes in 
pre-bleach thresholds and kinetic parameters as measured by the Medmont in the study eye at the 
treatment completion visit will be compared to baseline for each cohort, as described in Flynn et. 
al.18 All dark adaptation parameters will be analyzed by researchers at the NEI. 


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10.0 
SECONDARY OUTCOMES ANALYSIS 
The analysis of secondary outcomes will be considered exploratory; no adjustment for multiplicity 
will be performed. Secondary analyses will be based on the primary analysis population. 
10.1 
Low Luminance Visual Acuity (LLVA) 
Change from baseline in LLVA total letters read in the study eye at the treatment completion visit 
and the post-treatment follow-up visit will be summarized and presented by participant for each 
cohort (Table 10, Listing 2).  
10.2 
Low Luminance Questionnaire (LLQ) 
The LLQ is used to assess self-reported visual problems under low luminance and at night. 
The 32-item LLQ has six subscales: driving, extreme lighting, mobility, emotional distress, 
general dim lighting and peripheral vision. Each subscale score is derived by taking the average of 
a subset of questions from the LLQ, and a composite score is calculated as a weighted average of 
the subscales.19 
Change from baseline in LLQ subscale and composite scores at the treatment completion visit and 
post-treatment follow-up visit will be summarized and presented by participant for each cohort 
(Table 11, Listing 3). 
10.3 
Dark Adaptation Times  
A similar analysis to the primary outcome analysis for dark adaptation times described in 
Section 9.1 will be conducted comparing baseline to post-treatment follow-up visit in each cohort 
(Table 9, Listing 1).  
10.4 
Dark Adaptation Parameters  
A similar analysis to the primary outcome analysis for dark adaptation parameters described in 
Section 9.2 will be conducted comparing baseline to post-treatment follow-up visit in each cohort. 
All dark adaptation parameters will be analyzed by researchers at the NEI. 


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11.0 
EXPLORATORY ANALYSES 
11.1 
Dark Adaptation Times 
To explore the effect of within-subject correlation, a mixed effects model (Model 1) will be fit 
using PROC MIXED in SAS to assess mean change from baseline in RIT in the study eye at the 
treatment completion visit and post-treatment follow-up visit in Cohort 1.  
Model 1: Ŷij= β̂ o + β̂ * Timej + bi + εt 
Where:  
Ŷij = Estimate of mean RIT for participant i at timepoint j  
β̂ o = Estimate of mean RIT at baseline  
β̂  = Estimate of mean rate of change (monthly) in RIT  
Timej = Time in months from baseline  
bi = Random effect for baseline RIT in the ith participant  
εt  = Random variability not explained by the model, which is assumed to be normally distributed 
and independent across participants and time  
Based on this model, the estimated mean difference in RIT between baseline and Month 2 is 2β1, 
and the estimated mean difference between baseline and Month 3 is 3β1. The following hypothesis 
will be tested at a type I error rate of 5%:  
Ho: β1 = 0 
HA: β1 ≠ 0 
The results of this analysis will be summarized as in Table 9. 
11.2 
Low Luminance Visual Acuity (LLVA) 
For each cohort, change from baseline in LLVA total letters read at the treatment completion visit 
and post-treatment follow-up visit will be assessed using Student’s paired t-test similar to the 
analysis of primary outcome as outlined in Section 9.1 for the study eye. Additionally, a model 
similar to Model 1 will be fitted to assess the mean difference in total letters read in the study eye 


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at the treatment completion visit and post-treatment follow-up visit compared to baseline in 
Cohort 1 (Table 10).  
11.3 
Low Luminance Questionnaire (LLQ) 
For each cohort, change from baseline at the treatment completion visit and post-treatment 
follow-up visit for each subscale and the composite score will be assessed using Student’s paired 
t-test similar to the analysis of the primary outcome as outlined in Section 9.1. Additionally, a 
model similar to Model 1 will be fitted to assess the mean difference in the composite score at the 
treatment completion visit and post-treatment follow-up visit compared to baseline in Cohort 1 
(Table 11). 
12.0 
SAFETY OUTCOMES 
These presentations will be based on the safety population. All relevant information will be listed.  
12.1 
Adverse Events (AEs) 
AEs reported throughout the study period will be presented in a listing with details including date 
reported, description, severity, relatedness to IP, outcome and date resolved. Total number and 
percentage of participants with AEs will be summarized by cohort and overall and categorized by 
severity of the AE, ocular specification (ocular vs. systemic), outcome, and relation to IP 
(Table 12).  
AEs will also be summarized by system organ class (SOC) and preferred term (PT) (Table 13). 
If sufficient data are present, summaries similar to Table 12 and Table 13 will be generated for all 
serious adverse events (SAEs).  
13.0 
OTHER SAFETY OUTCOMES 
These presentations will be based on the safety population. All relevant information will be listed. 
13.1 
Natural Progressions of the Disease 
Events corresponding to natural progression of the disease will be listed by participant. If sufficient 
data are present, summaries similar to Tables 12 and 13 will be presented for these events.  


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13.2 
Laboratory Assessments  
Hepatitis screening is performed at the screening visit. Serum vitamin A levels and hepatic panels 
are performed at the screening visit and all follow-up visits. Abnormal results from laboratory 
assessments performed at screening are reported at the baseline visit. 
Frequency and percentage of participants reporting laboratory abnormalities at baseline and shift 
from baseline at each follow-up visit will be summarized by cohort and overall as in Table 14. 
14.0 
OTHER OPHTHALMIC ASSESSMENTS 
These presentations will be based on the safety population. All relevant information will be listed. 
Outcome measurements or relative change in outcome measurements may be plotted against time.  
14.1 
Rod-Intercept Time (RIT) 
RIT, as measured by the AdaptDx™, is assessed at baseline and all follow-up visits in the study 
eye. RIT at all visits and change from baseline at all follow-up visits will be presented by 
participant and summarized by cohort and overall as in Table 15. 
14.2 
Best-Corrected Visual Acuity (BCVA) 
Visual acuity is assessed at baseline and all follow-up visits in both eyes. BCVA with manifest 
refraction is scheduled to be performed at baseline and Month 2 and if a change in BCVA total 
letters read of ≥ 10 (≥ 0.20 logMAR) since previous visit is observed. Values from assessments 
performed with manifest refraction will be used for the analysis if available; otherwise, values 
from assessments performed without manifest refraction will be used. 
Total letters read at each visit and change from baseline at each follow-up visit will be presented 
by participant for both eyes and summarized by cohort and overall as in Table 16. 
Participants experiencing loss of ≥ 15 letters from baseline may be withdrawn from the study at 
investigator’s discretion. Frequency and percentage of participants presenting with a loss of 
≥ 15 letters from baseline at each follow-up visit will be included in Table 16.  


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14.3 
Low Luminance Visual Acuity (LLVA)  
LLVA total letters read is assessed at baseline and all follow-up visits in both eyes. Total letters 
read at each visit and change from baseline at each follow-up visit will be presented by participant 
and summarized by cohort and overall as in Table 17. 
14.4 
Low Luminance Questionnaire (LLQ)  
The low luminance questionnaire is completed at baseline and all follow-up visits. Subscale and 
composite scores at baseline and change from baseline at each follow-up visit will be presented by 
participant and summarized by cohort and overall (Table 18).  
14.5 
Intraocular Pressure (IOP) 
IOP is assessed at baseline and all follow-up visits in both eyes. IOP measurements at each visit 
and change from baseline at each follow-up visit will be presented by participant and summarized 
for each eye by cohort and overall as in Table 19. 
14.6 
Optic Nerve Papilledema, Headache, and Medication Assessment  
Participants are assessed at each visit for headache and presence of optic nerve papilledema. 
Additionally, vitamin A palmitate consumption outside of the study is assessed at each follow-up 
visit. Number and percentage of participants experiencing optic nerve papilledema in each eye, 
headache classified by severity, and vitamin A palmitate consumption outside of the study will be 
summarized by cohort and overall as in Table 20; relevant information will be listed by participant.  
14.7 
Other Ophthalmic Assessments  
The following additional ophthalmic assessments are conducted at each visit and will be presented 
by participant. Number and percentage of participants experiencing these events will be 
summarized as in Table 21.  
x Presence and size of drusen 
x Presence of hypo/hyperpigmentation 
x Presence of RPE detachment 
x Choroidal neovascularization 
x Subretinal / Intraretinal fluid 
x Geographic atrophy 
x Lens aphakia 


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x Pseudophakic lens 
x Nuclear cataract score  
x Posterior Subcapsular Cataract (PSC) cataract score  
x Presence of RPD (at Baseline) 
15.0 
RATIONALE FOR ANY DEVIATION FROM PRE-SPECIFIED ANALYSIS PLAN 
Depending on the nature of the data, certain outcomes may be presented differently than outlined 
in this analysis pan. Tables and figures will be presented only when an adequate amount of data 
are available. Data for some outcomes may not be available to the CC at every visit. Because of 
this, these outcomes may not be presented until after study closure.  
16.0 
QUALITY ASSURANCE PLANS 
To ensure accurate, reliable study results, two statisticians will separately analyze and compare the 
study outcomes. All SAS or R code use to generate primary and secondary outcomes will undergo 
a code validation by an independent statistician or SAS programmer. Documentation related to 
code validation audits will be maintained on file at the CC. 
 


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17.0 
REFERENCES 
1. 
Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study monograph: 
An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, 
macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. 
Surv Ophthalmol 1980;24:335-610. 
2. 
Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye 
Study. Ophthalmology 1992;99:933-43. 
3. 
Chew EY, Clemons TE, Agron E, et al. Ten-year follow-up of age-related macular 
degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmol 
2014;132:272-7. 
4. 
Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related 
maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 
1995;36:182-91. 
5. 
Wu Z, Ayton LN, Guymer RH, Luu CD. Low-luminance visual acuity and microperimetry 
in age-related macular degeneration. Ophthalmology 2014;121:1612-9. 
6. 
Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in age-related macular 
degeneration. Invest Ophthalmol Vis Sci 1996;37:1236-49. 
7. 
Jackson GR, Owsley C, Curcio CA. Photoreceptor degeneration and dysfunction in aging 
and age-related maculopathy. Ageing Res Rev 2002;1:381-96. 
8. 
Medeiros NE, Curcio CA. Preservation of ganglion cell layer neurons in age-related macular 
degeneration. Invest Ophthalmol Vis Sci 2001;42:795-803. 
9. 
Curcio CA, Owsley C, Jackson GR. Spare the rods, save the cones in aging and age-related 
maculopathy. Invest Ophthalmol Vis Sci 2000;41:2015-8. 
10. Owsley C, Huisingh C, Jackson GR, et al. Associations between abnormal rod-mediated dark 
adaptation and health and functioning in older adults with normal macular health. Invest 
Ophthalmol Vis Sci 2014;55:4776-89. 


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11. Flamendorf J, Agron E, Wong WT, et al. Impairments in Dark Adaptation Are Associated 
with Age-Related Macular Degeneration Severity and Reticular Pseudodrusen. 
Ophthalmology 2015;122:2053-62. 
12. Owsley C, McGwin G, Jr., Clark ME, et al. Delayed Rod-Mediated Dark Adaptation Is a 
Functional 
Biomarker 
for 
Incident 
Early 
Age-Related 
Macular 
Degeneration. 
Ophthalmology 2015. 
13. Owsley C, Huisingh C, Clark ME, Jackson GR, McGwin G, Jr. Comparison of Visual 
Function in Older Eyes in the Earliest Stages of Age-related Macular Degeneration to Those 
in Normal Macular Health. Curr Eye Res 2015:1-7. 
14. Jackson GR, Scott IU, Kim IK, Quillen DA, Iannaccone A, Edwards JG. Diagnostic 
sensitivity and specificity of dark adaptometry for detection of age-related macular 
degeneration. Invest Ophthalmol Vis Sci 2014;55:1427-31. 
15. Jacobson SG, Cideciyan AV, Regunath G, et al. Night blindness in Sorsby's fundus 
dystrophy reversed by vitamin A. Nature genetics 1995;11:27-32. 
16. Ayyagari R, Mandal MN, Karoukis AJ, et al. Late-onset macular degeneration and long 
anterior lens zonules result from a CTRP5 gene mutation. Invest Ophthalmol Vis Sci 
2005;46:3363-71. 
17. Owsley C, McGwin G, Jackson GR, et al. Effect of short-term, high-dose retinol on dark 
adaptation in aging and early age-related maculopathy. Invest Ophthalmol Vis Sci 
2006;47:1310-8. 
18. Flynn OJ, Cukras CA, Jeffrey BG. Characterization of Rod Function Phenotypes Across a 
Range of Age-Related Macular Degeneration Severities and Subretinal Drusenoid Deposits. 
Invest Ophthalmol Vis Sci. 2018;59:2411-2421. 
19. Thompson AC, Luhmann UF, Stinnett SS et al. Association of Low Luminance 
Questionnaire with objective functional measures in early and intermdediate age-related 
maculardegeneration. Invest Opthalmol Vis Sci 2018;59:289-297. 


























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Table 13. AEs by System Organ Class (SOC) and Preferred Term (PT) 
MedDRA System 
Organ Class/ 
Preferred Terma,b 
Participants with Events 
N (%)c 
Number of Events 
N 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Overall 
(N=X) 
Cohort 1  
Cohort 2 
Overall 
SOC1 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT1 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT2 
x (x) 
x (x) 
x (x) 
x 
x 
x 
     … 
x (x) 
x (x) 
x (x) 
x 
x 
x 
SOC2 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT1 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT2 
x (x) 
x (x) 
x (x) 
x 
x 
x 
… 
x (x) 
x (x) 
x (x) 
x 
x 
x 
… 
x (x) 
x (x) 
x (x) 
x 
x 
x 
a MedDRA version XX.X. 
b System organ classes (SOCs) are presented in descending order of number of events reported; preferred terms 
(PTs) within each SOC are also presented in descending order of number of events reported. 
c Column header counts and denominators are the number of participants in the safety population in the respective 
cohort or overall. Percentages are rounded to the nearest whole number. Participants are counted at most once in 
each row. Therefore, a participant may experience events corresponding to multiple PTs within an SOC, but the 
sum of participants in the PT rows may not add up to the corresponding SOC row. 
 
 


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Table 14. Summary of Laboratory Assessments Over Time 
 
Abnormal Findingsa 
n/N (%) 
Any Change from Baseline 
n/N (%) 
Clinically Significant  
Change from Baseline 
n/N (%) 
Visit 
Cohort 1 
Cohort 2 
 Overall 
Cohort 1 
Cohort 2 
Overall 
Cohort 1 
Cohort 2 
Overall 
Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
 
 
 
 
 
 
Month 1 
 
 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Month 2 
 
 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Month 3b 
 
 
 
x/x (x) 
 
 
x/x (x) 
 
 
Denominators are the number of participants in the safety population who completed the specified visit, in the respective cohort or overall. Percentages are 
rounded to the nearest whole number.  
a Abnormal results from screening are reported at baseline. 
b Only participants in Cohort 1 complete Month 3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 














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Table 21. Summary of Additional Ophthalmic Assessments 
 
 
Participants with Events 
N (%)a  
 
Cohort 1 
Cohort 2 
Overall 
Visit / Assessment    
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Baseline 
 
 
 
 
 
 
     Drusen  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - small 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - intermediate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes – large  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Hypo/hyper pigmentation 
 
 
 
 
 
 
         No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     RPE detachment 
 
 
 
 
 
 
          No  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - drusenoid 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes – non-drusenoid 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     CNV 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Subretinal/Intraretinal fluid 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Geographic Atrophy 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - foveal 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - extra-foveal 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Aphakia  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Pseudophakic lens 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Nuclear Cataract Score  
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Clear 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          < STD2 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD2 but < STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Cannot Evaluate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Not Done 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     PSC Cataract Score 
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Clear 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          < STD2 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD2 but < STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Cannot Evaluate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Not Done 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
a Denominators are the number or participants in the safety population with a non-missing value for the parameter 
at the specified visit, in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
b Cataract scores are only assessed in participants without aphakia or pseudophakic lens. 
c Only participants in Cohort 1 complete Month 3.  
 


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Participants with Events 
N (%)a  
 
Cohort 1 
Cohort 2 
Overall 
Visit / Assessment   
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
     Reticular Pseudodrusen 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
Month 1 
 
 
 
 
 
 
     Drusen  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - small 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - intermediate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes – large  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Hypo/hyper pigmentation 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     RPE detachment 
 
 
 
 
 
 
          No  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - drusenoid 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes – non-drusenoid 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     CNV 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Subretinal/Intraretinal fluid 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Geographic Atrophy 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - foveal 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - extra-foveal 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Aphakia  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Pseudophakic lens 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Nuclear Cataract Score  
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Clear 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          < STD2 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD2 but < STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Cannot Evaluate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Not Done 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     PSC Cataract Score 
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Clear 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          < STD2 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD2 but < STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
a Denominators are the number or participants in the safety population with a non-missing value for the parameter 
at the specified visit, in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
b Cataract scores are only assessed in participants without aphakia or pseudophakic lens. 
c Only participants in Cohort 1 complete Month 3.  
           
 
 
 
 
 
 


DA VitA AMD SAP 
December 18, 2023 
 
Table 21. Summary of Additional Ophthalmic Assessments (continued) 
 
Version 2.0 
CONFIDENTIAL 
Page 44 
 
Participants with Events 
N (%)a  
 
Cohort 1 
Cohort 2 
Overall 
Visit / Assessment   
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
          Cannot Evaluate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Not Done 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
Month 2 
 
 
 
 
 
 
     Drusen  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - small 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - intermediate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes – large  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Hypo/hyper pigmentation 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     RPE detachment 
 
 
 
 
 
 
          No  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - drusenoid 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes – non-drusenoid 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     CNV 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Subretinal/Intraretinal fluid 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Geographic Atrophy 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - foveal 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes - extra-foveal 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Aphakia  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Pseudophakic lens 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Yes  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     Nuclear Cataract Score  
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Clear 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          < STD2 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD2 but < STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Cannot Evaluate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Not Done 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
     PSC Cataract Score 
 
 
 
 
 
 
           Not assessedb 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Clear 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          < STD2 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
a Denominators are the number or participants in the safety population with a non-missing value for the parameter 
at the specified visit, in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
b Cataract scores are only assessed in participants without aphakia or pseudophakic lens. 
c Only participants in Cohort 1 complete Month 3.  


DA VitA AMD SAP 
December 18, 2023 
 
Table 21. Summary of Additional Ophthalmic Assessments (continued) 
 
Version 2.0 
CONFIDENTIAL 
Page 45 
 
Participants with Events 
N (%)a  
 
Cohort 1 
Cohort 2 
Overall 
Visit / Assessment   
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
          ≥ STD2 but < STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          ≥ STD3 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Cannot Evaluate 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
          Not Done 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
Month 3c 
 
 
 
 
 
 
     Drusen  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes - small 
x (x)  
x (x)  
 
 
 
 
          Yes - intermediate 
x (x)  
x (x)  
 
 
 
 
          Yes – large  
x (x)  
x (x)  
 
 
 
 
     Hypo/hyper pigmentation 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes  
x (x)  
x (x)  
 
 
 
 
     RPE detachment 
 
 
 
 
 
 
          No  
x (x)  
x (x)  
 
 
 
 
          Yes - drusenoid 
x (x)  
x (x)  
 
 
 
 
          Yes – non-drusenoid 
x (x)  
x (x)  
 
 
 
 
     CNV 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes 
x (x)  
x (x)  
 
 
 
 
     Subretinal/Intraretinal fluid 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes 
x (x)  
x (x)  
 
 
 
 
     Geographic Atrophy 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes - foveal 
x (x)  
x (x)  
 
 
 
 
          Yes - extra-foveal 
x (x)  
x (x)  
 
 
 
 
     Aphakia  
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes 
x (x)  
x (x)  
 
 
 
 
     Pseudophakic lens 
 
 
 
 
 
 
          No 
x (x)  
x (x)  
 
 
 
 
          Yes  
x (x)  
x (x)  
 
 
 
 
     Nuclear Cataract Score  
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
 
 
 
 
          Clear 
x (x)  
x (x)  
 
 
 
 
          < STD2 
x (x)  
x (x)  
 
 
 
 
          ≥ STD2 but < STD3 
x (x)  
x (x)  
 
 
 
 
          ≥ STD3 
x (x)  
x (x)  
 
 
 
 
          Cannot Evaluate 
x (x)  
x (x)  
 
 
 
 
          Not Done 
x (x)  
x (x)  
 
 
 
 
a Denominators are the number or participants in the safety population with a non-missing value for the parameter 
at the specified visit, in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
b Cataract scores are only assessed in participants without aphakia or pseudophakic lens. 
c Only participants in Cohort 1 complete Month 3.  


DA VitA AMD SAP 
December 18, 2023 
 
Table 21. Summary of Additional Ophthalmic Assessments (continued) 
 
Version 2.0 
CONFIDENTIAL 
Page 46 
 
Participants with Events 
N (%)a  
 
Cohort 1 
Cohort 2 
Overall 
Visit / Assessment  
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
     PSC Cataract Score 
 
 
 
 
 
 
          Not assessedb 
x (x)  
x (x)  
 
 
 
 
          Clear 
x (x)  
x (x)  
 
 
 
 
          < STD2 
x (x)  
x (x)  
 
 
 
 
          ≥ STD2 but < STD3 
x (x)  
x (x)  
 
 
 
 
          ≥ STD3 
x (x)  
x (x)  
 
 
 
 
          Cannot Evaluate 
x (x)  
x (x)  
 
 
 
 
          Not Done 
x (x)  
x (x)  
 
 
 
 
a Denominators are the number or participants in the safety population with a non-missing value for the parameter 
at the specified visit, in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
b Cataract scores are only assessed in participants without aphakia or pseudophakic lens. 
c Only participants in Cohort 1 complete Month 3.